NZ613870B2 - Pharmaceutical compositions comprising human antibodies to pcsk9 - Google Patents

Abstract

Disclosed is pharmaceutical composition comprising 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350mg, 400 mg, 450 mg or 500mg of an antibody or an antigen-binding fragment thereof which specifically binds human proprotein convertase subtilisin/kexin type 9 (hPCSK9) together with a pharmaceutically acceptable excipient or carrier, wherein the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs set forth in SEQ ID NOs: 76, 78, and 80 and the three light chain CDRs set forth in SEQ ID NOs: 84, 86, and 88; wherein the sequences are as defined in the specification. pharmaceutically acceptable excipient or carrier, wherein the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs set forth in SEQ ID NOs: 76, 78, and 80 and the three light chain CDRs set forth in SEQ ID NOs: 84, 86, and 88; wherein the sequences are as defined in the specification.

Description

Description PHARMACEUTICAL COMPOSITIONS SING HUMAN ANTIBODIES TO PCSK9 The present invention relates to pharmaceutical compositions comprising proprotein convertase subtilisin/keXin type 9 (PCSK9)-specif1c antibodies or antigen-binding nts thereof an inhibitor of 3-hydroxymethyl-glutaryl-CoA reductase , preferably comprising (HlVlG-COA reductase). The t invention further relates to injection solutions, dry formulations and unit dosage forms comprising PCSK9-specific antibodies or antigen-binding fragments thereof as well as their use (preferably in combination with HlVlG-COA reductase inhibitors) for use in the treatment of diseases or conditions in which PCSK9 expression or activity causes an impact.

The present invention also relates to articles of manufacture sing packaging material, PCSK9-specific antibodies or antigen-binding fragments thereof, and a label or packaging insert indicating e. g. which groups of ts can be treated with said antibodies or fragments, which groups of patients must not be d with said antibodies or nts, and which dosage regimen should be used.

BACKGROUND OF THE INVENTION Proprotein convertase subtilisin/keXin type 9 (PCSK9) is a tein convertase belonging to the proteinase K subfamily of the secretory subtilase family. The encoded protein is synthesized as a e zymogen that oes autocatalytic intramolecular processing in the endoplasmic reticulum. Evidence suggest that PCSK9 increases plasma LDL cholesterol by promoting ation of the LDL receptor, which mediates LDL endocytosis in the liver, the major route of LDL clearance from circulation. The structure of PCSK9 protein shows that it has a signal sequence, followed by a prodomain, a catalytic domain that ns a conserved triad of residues (D186, H226 and S386), and a C-terminal domain. It is synthesized as a soluble 74-kDa precursor that undergoes autocatalytic cleavage in the ER, generating a 14-kDa prodomain and 60-kDa catalytic fragment. The autocatalytic activity has been shown to be required for secretion.

After cleavage the prodomain remains tightly associated with the tic domain.

WO 01253 dies to PCSK9 are described in, for example, , , , , , and US 2008/0008697. CSK9 antibodies that are particularly well-suited for practicing the present invention are disclosed in US 2010/0166768 Al, the t of which is hereby incorporated by reference in its entirety.

TECHNICAL PROBLEMS UNDERLYING THE PRESENT INVENTION Statins are among the most widely used drugs in the world. Although statins generally exhibit an excellent safety profile, it is ble to further optimize the safety profile by reducing the already low rate of unwanted side-effects (such as myopathies).

Despite the widespread availability of lipid-lowering agents such as statins, approximately 30% of all adult patients treated for hypercholesterolemia in the United States between 1999 and 2006 failed to achieve their recommended LDL-C targets. Reasons for this include poor adherence to y, drug-resistance/intolerance and the positive onship between adverse event rates and sing dosage. Moreover, since the most ive lipid- lowering agents can only reduce LDL-C levels by up to 55%,target attainment rates in patients that require substantial reductions in LDL-C, such as those with familial hypercholesterolemia, are often significantly lower than might be expected. More effective lipid-lowering agents and treatment regimes are therefore required to improve target ment rates in these patients.

Quite surprisingly, the inventors of the present invention found that the administration of anti-PCSK9 antibodies or fragments thereof increases the LDL-cholesterol lowering activity of statins, when stered in particular dosage regimens and/or to particular groups of patient.

Thus, the co-administration of anti-PCSK9 antibodies or fragments thereof enhances the efficacy of a statin therapy and allows a ion in the dosage of statins, thereby reducing unwanted side-effects.

Furthermore, the inventors of the present invention found out that particular dosage regimens of anti-PCSK9 antibodies and/or s are better suited for reducing LDL-cholesterol levels than others. The inventors also found out that some sub-groups of patients benefit more than others from a treatment with anti-PCSK9 dies or fragments thereof and/or statins. The Funhennore, the inventors of the t invention found out that particular dosage ns of anti-PCSK9 antibodies and/or statins are better suited for reducing LDL- cholesterol levels than others, The inventors also found out that some sub-groups of ts t more than others from a treatment with anti-PCSK9 antibodies or fragments thereof and/or statins. The ors further found out that treatment with anti PCSK9 antibodies or fragments thereof and/or statins is contraindicated for some sub- groups of patients.

The above overview does not arily describe all problems solved by the present Invention.

SUMMARY OF THE INVENTION In one embodiment of the invention, there is provided a phannaceutical composition comprising 40 ing, 50 ing, 75 ing, 100 ing, 150 ing, 200 ing, 250 ing, 300 ing, 350mg, 400 ing, 450 ing or 500mg of an antibody or an antigen-binding fragment thereof which specifically binds human proprotein convertase subtilisin/kexin type 9 (hPCSK9) together with a phannaceutically acceptable excipient or r, wherein the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs set forth in SEQ ID Nos: 76,78, and 80 and the three Iig}It chain CDRs set forth in SEQ ID Nos: 84,86, and 88, The present invention also provides an injectable solution as herein bed comprising the antibody or antigen-binding nt thereof of present invention, and preferably comprising about 40 ing to about 200 ing or about 50 to about 200 ing, e. g. about 40 ing, about 50 ing, about 75 ing, at about 100 ing, about 150 ing or about 200 ing of the antibody or antigen-binding fragment thereof per I inI volume.

In another embodiment, the present invention es an article of manufacture comprising, the pharmaceutical composition of present invention In yet another embodiment, the present invention provides a phannaceutical composition comprising 75 ing of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9, n the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID NOs: 90 and 92, respectively, and n the antibody or antigen-binding fragment thereof is in a 1 ml injectable solution.

In yet another embodiment, there is ed a pharmaceutical composition comprising 150 mg of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9, wherein the antibody or n-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID NOs: 90 and 92, respectively, and wherein the antibody or n-binding fragment thereof is in a 1 ml injectable solution.

In yet another ment, there is provided a ceutical composition comprising 300 mg of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID NOs: 90 and 92, respectively, and wherein the dy or antigen-binding fragment thereof is in a 1 ml injectable solution. (this page has been ionally left blank) (this page has been ionally left blank) (this page has been ionally left blank) (this page has been ionally left blank) (this page has been ionally left blank) (this page has been ionally left blank) This summary of the invention does not necessarily be all features of the present invention. Other embodiments will become apparent from a review of the ensuing ed description.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows the percentage reduction in LDL-cholesterol ) levels relative to the baseline for three groups of patients upon treatment with anti-PCSK9 antibody 316P. These patient groups are: (1) patients with familial hypercholesterolemia (HeFH); (2) patients with other forms of primary hypercholesterolemia (non-FH) on diet and on stable atorvastatin therapy; and (3) patients with other forms of primary hypercholesterolemia (non-FH) on diet alone. A dose of 50 mg of the anti-PCSK9 antibody was administered subcutaneously on days 1, 29 and 43. Results from patient groups receiving the antibody (50-mg-FH-no; 50-mg-FH-Yes; 50-mg-combined) are shown in solid lines, while results from patients receiving a placebo H-no; PBOFH-Yes ; PBO-combined) are shown in dashed lines.

Fig. 2 shows the percentage reduction in LDL-cholesterol (LDL-C) levels relative to the baseline for three groups of patients upon ent with anti-PCSK9 antibody 316P. These patient Fig. 5 shows the study design of study 2 for the group of patients receiving atorvastatin mg at stable dose for at least 6 weeks prior to screening.

Fig. 6 shows the distribution of the LDL-C mean values of ts of study 1 receiving antibody 3 16 P at stable atorvastatin ent over 12 weeks and LOCF (last observation carried forward). The study was ed to assess the efficacy and safety of antibody 3 l6P in hypercholesteremia patients with an elevated LDL-C (3 100 mg/dL or 2.59 mmol/L) treated with stable dose of atorvastatin (10 mg, 20 mg, or 40 mg). During the run-in period, patients were stabilized to atorvastatin treatment (10 mg, 20 mg, or 40 mg) if the were not already. After one onal week, patients were centrally randomized via IVRS/IWRS in a l:l:l:l:l:l ratio to one 1O of the 6 treatment groups bo, 3 l6P 50mg E2W, 3 l6P 100 mg E2W, 3 l6P 150 mg E2W, 3 l6P 200 mg E4W, 3 l6P 300 mg E4W) and treated in a double-bind manner for approximately 12 weeks. Thr randomization is stratified by the dose of atorvastatin received prior to ization. During the double-bind treatment period patients returned to the site every 2 weeks to receive the study treatment (3 16 P or placebo). The double-bind treatment period was then followed ba an 8-week follow up period. As can be gained from figure 6, all treatment groups except for the group of patients receiving placebo had a significant and persistent reduction of LDL-C levels over the whole study period.

DETAILED DESCRIPTION OF THE INVENTION Definitions Before the t invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be tood that the terminology used herein is for the purpose of describing ular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. ably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word ise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. l documents (for example: s, patent applications, scientific publications, manufacturer's specifications, instructions, GenBank Accession Number sequence submissions 1O etc.) are cited throughout the text of this specification. g herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Some of the nts cited herein are characterized as being “incorporated by nce In the event of a t between the definitions or teachings of such incorporated nces and definitions or teachings recited in the present specification, the text of the present specification takes precedence.

Sequences: All sequences referred to herein are disclosed in the attached sequence listing that, with its whole content and disclosure, is a part of this specification.

The term “about” when used in connection with a numerical value is meant to encompass numerical values within a range having a lower limit that is 5% smaller than the indicated numerical value and having an upper limit that is 5% larger than the indicated numerical value.

The term “human proprotein convertase subtilisin/kexin type 9” or "hPCSK9", as used herein, refers to hPCSK9 having the nucleic acid sequence shown in SEQ ID NO: 754 and the amino acid sequence of SEQ ID NO: 755, or a biologically active fragment thereof.

The terms "specifically binds", "specific binding" or the like, mean that an antibody or antigen-binding fragment thereof forms a complex with an n that is relatively stable under physiologic ions. Specific binding can be characterized by an equilibrium dissociation constant of at least about lxlO'6 M or less (e.g., a smaller KD s a tighter binding).

Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon nce, and the like. An isolated dy that specifically binds hPCSK9 may, however, exhibit cross-reactivity to other antigens such as PCSK9 molecules from other species. Moreover, multi-specific antibodies (e.g., bispecifics) that bind to hPCSK9 and one or more additional antigens are nonetheless considered antibodies that “specifically bind” hPCSK9, as used herein.

The term "KD ", as used herein, is intended to refer to the brium dissociation constant of a particular antibody-antigen interaction. The equilibrium dissociation constant is typically measured in “mol/L” (abbreviated as “M”).

By the term “slow off rate”, “Koff’ or “kd” is meant an antibody that dissociates from hPCSK9 with a rate nt of l X 10'3 s'1 or less, preferably 1 X 10'4 s'1 or less, as ined by surface plasmon resonance, e.g., ETM.

The term “high affinity” dy refers to those mAbs having a binding affinity to hPCSK9 of at least 10'10 M, preferably 10'11 M, even more preferably 10'12 M, as measured by surface n resonance, e.g., BIACORETM or solution-affinity ELISA.

The term "surface plasmon resonance", as used herein, refers to an l phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORETM system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).

An “epitope”, also known as antigenic determinant, is the region of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. As used herein, an “epitope” is the part of an n capable of binding to an antibody or antigen-binding fragment f as described herein. In this context, the term “binding” preferably relates to a fic binding”, as defined herein. Epitopes usually consist of chemically active surface groupings of les such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups and may have specific three-dimensional structural characteristics and/or specific charge teristics. Conformational and non-conformational epitopes can be distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.

A “paratope” is the part of an antibody that specifically binds to the epitope.

The term "antibody", as used herein, is intended to refer to immunoglobulin molecules sed of four ptide chains, two heavy (H) chains and two light (L) chains inter- connected by disulfide bonds. The term “antibody” also includes all inant forms of antibodies, in particular of the antibodies described , e.g. antibodies expressed in prokaryotes, unglycosylated antibodies, and any antigen-binding antibody nts and tives as described below. Each heavy chain is comprised of a heavy chain variable region (“HCVR” or “VH”) and a heavy chain constant region (comprised of domains CH1, CH2 and CH3). Each light chain is sed of a light chain variable region (“LCVR or “VL”) and a light chain constant region (CL). The VH and VL regions can be further subdivided into regions 1O of hypervariability, termed complementarity determining regions (CDR), persed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to y-terminus in the following order: FRl, CDRl, FR2, CDR2, FR3, CDR3, FR4. The variable s of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the globulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

Substitution of one or more CDR residues or omission of one or more CDRs is also possible. Antibodies have been described in the scientific literature in which one or two CDRs can be dispensed with for binding. Padlan et al. (1995 FASEB J. 9: 133-139) analyzed the contact regions between antibodies and their antigens, based on published crystal structures, and concluded that only about one fifth to one third of CDR residues actually contact the antigen.

Padlan also found many antibodies in which one or two CDRs had no amino acids in contact with an antigen (see also, Vaj dos et al. 2002 J Mol Biol 320:415-428).

CDR residues not contacting antigen can be identified based on us studies (for example residues H60-H65 in CDRH2 are often not required), from regions of Kabat CDRs lying outside Chothia CDRs, by molecular modeling and/or empirically. If a CDR or residue(s) f is omitted, it is usually substituted with an amino acid occupying the corresponding position in another human antibody sequence or a consensus of such sequences. Positions for substitution within CDRs and amino acids to substitute can also be selected cally.

Empirical substitutions can be conservative or non-conservative substitutions.

The term “antigen-binding fragment” of an antibody (or simply “binding portion”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to hPCSK9. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding nts encompassed within the term “antigen-binding fragment” of an antibody include (i) Fab fragments, monovalent fragments consisting of the VL, VH, CL and CH domains, (ii) F(ab')2 fragments, bivalent fragments comprising two Fab nts linked by a ide bridge at the hinge region, (iii) Fd fragments consisting of the VH and CH domains, (iv) Fv fragments consisting of the VL and VH domains of a single arm of an antibody, (V) dAb fragments (Ward et al., (1989) Nature 341: 6), which consist of a VH domain, (vi) isolated complementarity determining regions (CDR), and (vii) combinations of two or more ed CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv nt, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv , see e.g., Bird et al. (1988) Science 242: 423-426, and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879- 5883). Such single chain antibodies are also intended to be assed within the term en-binding fragment” of an antibody. A further example is a binding-domain immunoglobulin fusion protein comprising (i) a binding domain polypeptide that is fused to an immunoglobulin hinge region polypeptide, (ii) an immunoglobulin heavy chain CH2 constant region fused to the hinge region, and (iii) an immunoglobulin heavy chain CH3 constant region fused to the CH2 constant region. The binding domain polypeptide can be a heavy chain variable region or a light chain variable region. The binding-domain immunoglobulin fusion proteins are further disclosed in US 118592 and US 2003/0133939. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. Further examples of “antigen-binding fragments” are so-called microantibodies, which are derived from single CDRs.

For example, Heap et al. be a 17 amino acid residue microantibody derived from the heavy chain CDR3 of an antibody directed t the gp120 pe glycoprotein of HIV-1 (Heap CJ et al. (2005) J. Gen. Virol. 86:1791-1800). Other examples include small antibody mimetics comprising two or more CDR regions that are fused to each other, preferably by cognate framework regions. Such a small dy mimetic comprising VH CDRl and VL CDR3 linked by the cognate VH FR2 has been described by Qiu et al. (Qiu X-Q, et al. (2007) Nature biotechnology 25(8):921-929).

Thus, the term “antibody or antigen-binding fragment thereof’, as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e. molecules that contain an antigen-binding site that immunospecif1cally binds an antigen.

Antibodies and antigen-binding nts thereof usable in the invention may be from any animal origin including birds and mammals. Preferably, the antibodies or fragments are from human, chimpanzee, rodent (e.g. mouse, rat, guinea pig, or rabbit), chicken, turkey, pig, sheep, goat, camel, cow, horse, donkey, cat, or dog origin. It is particularly preferred that the antibodies are of human or murine origin. Antibodies of the invention also include chimeric les in which an antibody constant region derived from one species, preferably human, is combined with the antigen binding site d from another species, e. g. mouse. Moreover antibodies of the ion include humanized molecules in which the antigen binding sites of an antibody derived from a non-human species (e. g. from mouse) are combined with constant and framework regions of human origin.

As exemplified herein, antibodies of the invention can be ed directly from hybridomas which express the antibody, or can be cloned and recombinantly expressed in a host cell (e.g., a CHO cell, or a lymphocytic cell). Further examples of host cells are microorganisms, such as E. coli, and fungi, such as yeast. atively, they can be produced recombinantly in a transgenic non-human animal or plant.

The term “chimeric antibody” refers to those antibodies wherein one portion of each of the amino acid sequences of heavy and light chains is homologous to ponding sequences in dies derived from a particular species or belonging to a particular class, while the remaining segment of the chain is homologous to corresponding ces in another species or class. Typically the le region of both light and heavy chains mimics the variable regions of dies derived from one species of mammals, while the constant portions are homologous to sequences of antibodies derived from another. One clear age to such chimeric forms is that the variable region can conveniently be derived from presently known sources using readily available B-cells or hybridomas from non-human host sms in combination with constant regions derived from, for example, human cell preparations. While the variable region has the advantage of ease of preparation and the specificity is not ed by the source, the constant region being human is less likely to elicit an immune response from a human subject when the antibodies are injected than would the constant region from a non-human source. However, the definition is not limited to this particular example.

The term “humanized antibody” refers to a le having an antigen binding site that is substantially derived from an immunoglobulin from a non-human species, wherein the remaining immunoglobulin structure of the molecule is based upon the structure and/or sequence of a human immunoglobulin. The antigen binding site may either comprise complete variable domains fused onto constant domains or only the complementarity determining regions (CDR) grafted onto riate framework regions in the variable domains. Antigen-binding sites may be wild-type or ed by one or more amino acid substitutions, e. g. modified to resemble human globulins more closely. Some forms of humanized antibodies preserve all CDR sequences (for example a humanized mouse antibody which contains all six CDRs from the mouse antibody). Other forms have one or more CDRs which are altered with respect to the original dy.

Different methods for humanizing dies are known to the skilled person, as ed by Almagro & on, the content of which is herein incorporated by reference in its entirety (Almagro JC and Fransson J (2008) ers in Bioscience 13:1619-1633). o & Fransson distinguish between rational approaches and empirical approaches. Rational approaches are characterized by generating few variants of the engineered antibody and assessing their binding or any other property of interest. If the designed ts do not produce the expected results, a new cycle of design and binding assessment is initiated. Rational approaches include CDR grafting, Resurfacing, Superhumanization, and Human String t Optimization. In st, empirical approaches are based on the generation of large libraries of humanized variants and selection of the best clones using enrichment technologies or high- throughput screening. Accordingly, empirical approaches are dependent on a le selection and/or screening system that is able to search through a vast space of antibody variants. In vitro display technologies, such as phage display and ribosome display fulfill these ements and are well-known to the skilled person. Empirical approaches include FR libraries, Guided selection, Framework-shuffling, and Humaneering.

The term "human dy", as used , is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human mAbs of the invention may include amino acid residues not encoded by human germline globulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in viva), for example in the CDRs and in particular CDR3.

However, the term "human antibody", as used herein, is not intended to include mAbs in which CDR sequences derived from the gerrnline of another mammalian species (e.g., mouse), have been grafted onto human FR sequences. Human antibodies of the invention include dies isolated from human globulin libraries or from animals transgenic for one or more 1O human immunoglobulin and that do not s endogenous immunoglobulins, as described for example in US. Patent No. 5,939,598 by Kucherlapati & Jakobovits.

The term “monoclonal antibody” as used herein refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody displays a single binding city and affinity for a particular epitope. In one embodiment, the monoclonal dies are produced by a hybridoma which includes a B cell obtained from a non-human animal, e. g. mouse, fused to an immortalized cell.

The term “recombinant antibody”, as used herein, includes all antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal with respect to the immunoglobulin genes or a hybridoma prepared rom, (b) antibodies isolated from a host cell transformed to express the antibody, e. g. from a transfectoma, (c) antibodies ed from a recombinant, combinatorial antibody library, and (d) antibodies prepared, expressed, created or ed by any other means that involve splicing of immunoglobulin gene sequences to other DNA sequences.

The term “transfectoma”, as used herein, includes recombinant eukaryotic host cells sing an antibody, such as CHO cells, NS/O cells, HEK293 cells, T cells, plant cells, or fungi, ing yeast cells.

As used herein, a “heterologous antibody” is defined in relation to a transgenic organism producing such an antibody. This term refers to an dy having an amino acid sequence or an encoding nucleic acid sequence corresponding to that found in an organism not consisting of the transgenic organism, and being generally derived from a species other than the transgenic organism.

As used , a “heterohybrid antibody” refers to an antibody having light and heavy chains of different organismal origins. For example, an antibody having a human heavy chain associated with a murine light chain is a heterohybrid antibody.

Thus, “antibodies and antigen-binding fragments thereof’ suitable for use in the t invention include, but are not limited to, polyclonal, monoclonal, monovalent, bispecific, heteroconjugate, multispecif1c, recombinant, heterologous, heterohybrid, chimeric, humanized (in particular CDR-grafted), deimmunized, or human antibodies, Fab nts, Fab' fragments, F(ab')2 fragments, fragments produced by a Fab expression library, Fd, Fv, disulf1de-linked Fvs (dst), single chain dies (e.g. scFv), diabodies or tetrabodies (Holliger P. et al. (1993) Proc. Natl. Acad. Sci. USA. 90(14), 6444-6448), nanobodies (also known as single domain antibodies), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the ion), and epitope-binding fragments of any of the above.

The antibodies described herein are preferably ed. An "isolated antibody", as used herein, is intended to refer to an antibody that is substantially free of other mAbs having different antigenic specif1cities (e.g., an isolated antibody that specifically binds hPCSK9 is substantially free of mAbs that specifically bind antigens other than hPCSK9). An isolated antibody that specifically binds hPCSK9 may, r, have cross-reactivity to other antigens, such as PCSK9 les from other s.

As used herein, a “PCSK9 nist” denotes a compound that inhibits at least one biological activity of PCSK9, ably the proteinase activity of PCSK9. Preferred PCSK9 antagonists are characterized in that they bind from 10% to 100% rably from 50% to 100%) of the PCSK9 present in the blood when used in stoichiometric amounts. Preferred PCSK9 antagonists of the present invention are neutralizing antibodies.

A "neutralizing dy", as used herein (or an "antibody that lizes PCSK9 activity"), is intended to refer to an antibody whose binding to hPCSK9 results in inhibition of at least one biological activity of PCSK9, preferably inhibition of the proteinase activity of PCSK9.

This inhibition of the biological activity of PCSK9 can be assessed by measuring one or more tors of PCSK9 biological activity by one or more of several standard in vitro or in vivo assays known in the art. Such assays are described for e in US 2010/0166768 Al, the content of which is hereby incorporated by reference in its entirety.

Since PCSK9 increases plasma LDL cholesterol by promoting degradation of the LDL receptor, the activity of PCSK9 has an effect on several diseases associated with increased plasma LDL terol levels. Accordingly, PCSK9 antagonists, such as neutralizing anti- hPCSK9 dies or antigen-binding fragments thereof, are useful to reduce elevated total cholesterol, non-HDL cholesterol, LDL cholesterol, and/or apolipoprotein B100 (ApoB 100).

Consequently, PCSK9 antagonists are useful for ameliorating, improving, inhibiting or 1O preventing several such diseases, including without limitation hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases.

In specific embodiments, the anti-PCSK9 antibodies or antigen-binding fragments thereof described herein may be conjugated to a therapeutic moiety noconjugate”), such as a cytotoxin, a chemotherapeutic drug, an immunosuppressant or a sotope.

A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with r chemical properties (e.g., charge or hydrophobicity). In l, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution.

Means for making this adjustment are well known to those of skill in the art. See, e.g., Pearson (1994) Methods MoI. Biol. 24: 307- 331. Examples of groups of amino acids that have side chains with r chemical properties include 1) aliphatic side : glycine, alanine, valine, leucine and isoleucine, 2) aliphatic- hydroxyl side chains: serine and threonine, 3) amide-containing side chains: gine and glutamine, 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan, ) basic side chains: lysine, arginine, and histidine, 6) acidic side chains: aspartate and ate, and 7) sulfur-containing side chains: cysteine and nine.

Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine- glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443-45. A "moderately conservative" replacement is any change having a ative value in the PAM250 log-likelihood matrix. Given the known c code, and recombinant and synthetic DNA techniques, the skilled scientist can readily construct DNAs encoding conservative amino 1O acid variants.

As used herein, “non-conservative substitutions” or “non-conservative amino acid exchanges” are defined as exchanges of an amino acid by r amino acid listed in a different group of the seven rd amino acid groups 1) to 7) shown above.

The term "substantial ty" or "substantially identical," when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another c acid (or its mentary strand), there is nucleotide sequence identity in at least about 90%, and more preferably at least about 95%, 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or GAP, as sed below.

As applied to polypeptides, the term "substantial similarity" or “substantially similar” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using t gap weights, share at least 90% sequence identity, even more preferably at least 95%, 98% or 99% sequence identity. Preferably, residue positions which are not identical differ by conservative amino acid substitutions.

Sequence similarity for polypeptides is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, ons and other modifications, including vative amino acid substitutions. For instance, GCG software contains programs such as GAP and BESTFIT which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of sms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA with default or recommended parameters; a program in GCG n 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best p between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and (1997) Nucleic Acids Res. 9 402, each of which is herein incorporated by reference.

When percentages of sequence identity are referred to in the present application, these tages are calculated in relation to the full length of the longer sequence, if not specifically indicated otherwise. This calculation in relation to the full length of the longer sequence applies both to c acid sequences and to polypeptide sequences.

As used herein, "treatH H 7 treating" or “treatment” of a disease or disorder means accomplishing one or more of the ing: (a) reducing the severity and/or on of the disorder, (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated, (c) inhibiting worsening of symptoms teristic of the disorder(s) being treated, (d) limiting or preventing recurrence of the disorder(s) in ts that have previously had the disorder(s), and (e) ng or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s).

As used herein, “prevent77 (L 77 (L 7 preventing 7 tion”, or “prophylaxis” of a disease or disorder means preventing that a disorder occurs in subject.

As used herein, the expressions “is for administration” and “is to be administered” have the same meaning as “is prepared to be administered”. In other words, the statement that an active compound “is for administration” has to be understood in that said active compound has been formulated and made up into doses so that said active compound is in a state e of exerting its therapeutic activity.

The terms “therapeutically effective amount” or “therapeutic amount” are intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, l doctor or other clinician. The term “prophylactically effective amount” is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, l doctor or other clinician. Particularly, the dosage a patient receives can be selected so as to achieve the amount of LDL (low density lipoprotein) cholesterol lowering desired, the dosage a patient receives may also be titrated over time in order to reach a target LDL level. The dosage regimen utilizing an antibody or an n-binding fragment thereof as described herein is selected in accordance with a variety of factors including type, s, age, weight, body mass indeX, seX and medical condition of the t, the severity of the condition to be treated, the potency of the compound chosen to be stered, the route of administration, the purpose of the administration, and the renal and hepatic function of the patient.

As used herein, a “patient” means any human or non-human animal, such as mammal, reptile or bird who may benefit from a ent with the antibodies and antigen-biding fragments thereof described herein. Preferably, a “patient” is selected from the group consisting of laboratory animals (e. g. mouse or rat), domestic animals (including e.g. guinea pig, rabbit, chicken, turkey, pig, sheep, goat, camel, cow, horse, , cat, or dog), rodent or primates including chimpanzee, gorilla, bonobo and human beings. It is particularly preferred that the “patient” is a human being.

The terms “me—ct” or “individual” are used hangeably herein. As used herein, a "subject" refers to a human or a non-human animal (e.g. a mammal, avian, reptile, fish, amphibian or invertebrate, preferably an dual that can either benefit from one of the different aspects of present ion (e. g. a method of treatment or a drug identified by present methods) or that can be used as laboratory animal for the identification or characterisation of a drug or a method of treatment. The individual can e.g. be a human, a wild-animal, domestic animal or laboratory animal, es comprise: mammal, e.g. human, man primate (chimpanzee, bonobo, gorilla), dog, cat, rodent (e.g. mouse, guinea pig, rat, hamster or rabbit, horse, donkey, cow, sheep, goat, pig, camel, avian, such as duck, dove, turkey, goose or chick, reptile such as: turtle, tortoise, snake, lizard, amphibian such as frog (e.g. Xenopus laevis), fish such as koy or zebrafish, invertebrate such as a worm (e.g. c.elegans) or an insect (such as a fly, e.g. drosophila melanogaster). The term individual also comprises the different morphological developmental stages of avian, fish, reptile or insects, such as egg, pupa, larva or imago. It is further preferred if the subject is a “patient”.

As used herein, "unit dosage form" refers to physically discrete units suitable as unitary dosages for human and/or animal subjects, each unit containing a predetermined ty of active material (e.g., about 50 to about 500mg of PCSK5 antibody and/or of e.g. 0.05mg to 100 mg HlVlG—CoA reductase inhibitor) calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active material for therapeutic use in animals or humans, as disclosed in this cation, these being features of the present invention. es of suitable unit dosage forms in accord with this invention are vials, tablets, capsules, troches, suppositories, powder packets, wafers, cachets, ampules, segregated multiples of any of the foregoing, and other forms as herein described or generally known in the art. One or more such unit dosage forms of the dy can be comprised in an article of manufacture of present invention, optionally further comprising one or more unit dosage forms of an ENIG- CoA reductase inhibitor (e.g. a blister of tablets comprising as active ient the HMG-CoA reductase inhibitor).

The term “active material” refers to any material with therapeutic activity, such as one or more active ingredients. The active ingredients to be employed as therapeutic agents can be easily prepared in such unit dosage form with the employment of ceutical materials which themselves are available in the art and can be prepared by established procedures.

The ing preparations are illustrative of the ation of the unit dosage forms of the present ion, and not as a limitation thereof. Several dosage forms may be prepared embodying the present invention. For example, a unit dosage per vial may contain 0,5 ml, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, or 20 ml 5 antibody or a fragment thereof g from about 40 to about 500 mg of PCSK5 antibody. If necessary, these preparations can be adjusted to a desired concentration by adding a e diluent to each vial. In one embodiment, the ingredients of formulation of the invention are supplied either separately or mixed together in unit dosage form, for e, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as a vial, an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile ceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

The formulations of the invention e bulk drug itions useful in the manufacture of pharmaceutical compositions (e.g., compositions that are le for administration to a subject 1O or patient) which can be used in the preparation of unit dosage forms. In a preferred embodiment, a composition of the invention is a pharmaceutical composition. Such compositions comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., an antibody of the invention or other lactic or eutic agent), and a pharmaceutically acceptable carrier. Preferably, the ceutical compositions are formulated to be suitable for the route of administration to a subject.

The active materials or ingredients (e.g. antibodies or fragments f and HlVlG-CoA reductase inhibitors) can be formulated as various dosage forms including solid dosage forms for oral administration such as capsules, tablets, pills, powders and granules, liquid dosage forms for oral administration such as pharmaceutically acceptable ons, microemulsions, solutions, suspensions, syrups and elixirs, injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, compositions for rectal or vaginal administration, preferably itories, and dosage forms for topical or transdermal administration such as ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.

In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the US. Federal or a state government or the EMA (European Medicines Agency) or listed in the US. Pharmacopeia Pharmacopeia (United States Pharmacopeia- 33/National Formulary-28 Reissue, published by the United States Pharmacopeial Convention, Inc., Rockville Md, publication date: April 2010) or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant {e.g., Freund's adjuvant (complete and lete)), ent, or vehicle with which the therapeutic is administered. Such ceutical carriers can be e liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and s dextrose and glycerol solutions can also be employed as liquid rs, particularly for injectable solutions. Suitable ceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, ene, glycol, water, ethanol and the like. For the use of er) excipients and their use see also “Handbook of _ Pharmaceutical ents”, fifth edition, R.C.Rowe, P.J. Seskey and SC. Owen, Pharmaceutical Press, London, Chicago. The 1O composition, if d, can also contain minor amounts of wetting or emulsifying agents, or pH buffering . These compositions can take the form of solutions, suspensions, on, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral ation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of le pharmaceutical carriers are described in "Remington's ceutical Sciences" by E.

W. . Such compositions will contain a prophylactically or therapeutically effective amount of the antibody, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

Generally, the ingredients of compositions of the invention are supplied either separately or mixed together in unit dosage form, for example, as a dry formulation for dissolution such as a lyophilized powder, freeze-dried powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. The ingredients of compositions of the invention can also be supplied as d liquid formulation (i.e. injection or infusion solution) in a hermetically sealed container such as an ampoule, sachette, a lled syringe or autoinjector, or a cartridge for a reusable syringe or applicator (e.g. pen or autoinjector). Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

The invention also provides that the formulation is packaged in a hermetically sealed container such as an ampoule or sachette indicating the ty of antibody. In one embodiment, the formulation of the invention sing an antibody is supplied as a dry formulation, such as a sterilized lized powder, freeze-dried powder, spray —dried powder or water free concentrate in a hermetically sealed container and can be reconstituted, e.g., with water or saline to the appropriate tration for administration to a subject. In another embodiment the antibody or antigen binding fragment thereof is supplied as a liquid formulation such as an injection or infusion solution. In one embodiment, the formulation of the invention comprising an antibody is supplied as a dry formulation or as a liquid formulation in a hermetically sealed container at a unit dosage of at least 40 mg, at least 50 mg, more preferably at least 75 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, or at least 500 mg, of dy or antigen-binding fragment thereof The lyophilized formulation of the invention comprising an antibody should be stored at between 2 and 8° C in its al container and the antibody should be administered within 12 hours, preferably within 6 hours, within 5 hours, within 3 hours, or within 1 hour after being tituted. The formulation of the invention comprising antibodies can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric ides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

Adult subjects are characterized as having “hypertension” or a high blood pressure when they have a systolic blood pressure of more than 140 mmHg and/or a diastolic blood re of more than 90 mmHg.

Specific populations treatable by the therapeutic s of the invention include subjects with one or more of the following conditions: subjects indicated for LDL apheresis, subjects with PCSK9-activating ons (gain of function mutations, “GOF”), subjects with elevated total cholesterol levels, subjects with ed low-density lipoprotein cholesterol (LDL-C) levels, ts with primary hypercholesterolemia, such as subjects y with Familial or Non-Familial Hypercholesterolemia, subjects with heterozygous Familial Hypercholesterolemia (heFH), subjects with hypercholesterolemia, especially primary hypercholesterolemia, who are statin intolerant or statin uncontrolled, and subjects at risk for developing hypercholesterolemia who may be preventably treated. Other indications include hyperlipidemia and dyslipidemia, especially if associated with secondary causes such as Type 2 diabetes mellitus, cholestatic liver diseases ry biliary cirrhosis), nephrotic syndrome, hypothyroidism, obesity, and the tion and treatment of sclerosis and cardiovascular es, such as coronary heart disease (CHD). The ions or ers as listed for the above populations or subjects are conditions or disorders, for which treatment with the antibody of the invention is especially suitable.

However, ing on the severity of the afore-mentioned diseases and conditions, the treatment of subjects with the antibodies and antigen-binding fragments of the invention may be contraindicated for certain diseases and conditions.

The term “adverse effect” (or side-effect) refers to a harmful and undesired effect resulting from a tion. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. Some adverse s occur only when starting, increasing or discontinuing a treatment. Adverse effects may cause medical cations of a disease and negatively affect its prognosis. Examples of side effects are allergic reactions, vomiting, headache, or dizziness or any other effect herein described.

As used herein, "treat", "treating" or “treatment” of a disease or disorder means accomplishing one or more of the following: (a) ng the severity and/or duration of the disorder, (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated, (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated, (d) limiting or preventing recurrence of the disorder(s) in patients that have previously had the disorder(s), and (e) limiting or preventing recurrence of symptoms in ts that were previously symptomatic for the disorder(s).

As used herein, “prevent”, “preventing”, “prevention”, or “prophylaxis” of a disease, condition or disorder means preventing that a er, disease or condition occurs in subject.

Elevated total cholesterol levels are understood in the context of present invention to be total terol levels of 200 mg/dL or more, especially 240mg/dL or more. International treatment guidelines recommend lowering LDL-C to <2.0-2.6 mmol/L (<77-lOO mg/dL) in patients with established cardiovascular diseases (CVDs) and to <1 .8-2.0 mmol/L (<70-77 mg/dL) in high-risk groups such as those with CVDs plus diabetes, smoking, poorly controlled hypertension, metabolic syndrome, or previous myocardial infarction. Elevated LDL-C levels are thus understood in the context of present invention to be LDL-C levels of 77 mg/dL or more (especially for ts with one or more of the following characteristics: established CVDs and diabetes, with g, poorly controlled hypertension, metabolic syndrome or previous myocardial infarction) and 100 mg/dL or more (especially for patients with established CVDs) ,l30mg/dL or more or 160 mg/dL or l90mg/dL or more. Low High-density lipoprotein levels (HDL-levels) in the context of present invention are understood to be preferably less than 1O about L.

Elevated total cholesterol levels are understood in the t of present invention to ably be total cholesterol levels of 200 mg/dL or more, especially 240mg/dL or more.

International treatment guidelines recommend lowering LDL-C to <2.0-2.6 mmol/L (<77-lOO mg/dL) in patients with established cardiovascular diseases (CVDs) and to <1 .8-2.0 mmol/L 7 mg/dL) in high-risk groups such as those with CVDs plus diabetes, smoking, poorly controlled hypertension, metabolic syndrome, or previous myocardial infarction. Elevated LDL- C levels are thus tood in the context of present invention to be LDL-C levels of 77 mg/dL or more (especially for patients with one or more of the following characteristics: established CVDs and one or more of [diabetes, with smoking, poorly lled hypertension, metabolic syndrome or previous myocardial infarction]) and 100 mg/dL or more (especially for patients with established CVDs) /dL or more or 160 mg/dL or l90mg/dL or more. Low High- density lipoprotein levels (HDL-levels) in the context of present invention are understood to be preferably less than about 40mg/dL.

The terms “uncontrolled by s” or “statin-resistant”, especially in the context of ipidemia, hypercholesterolemia etc., are used synonymously herein and refer to conditions such as hyperlipidemia, wherein treatment with a statin (i.e. regular administration of a statin such as atorvastatin to a t) does not significantly lower total cholesterol or LDL-C or does not suffice to establish normolipidemic levels for the t or to establish a lipidemic (e. g. total cholesterol or LDL-C) level that is not a significant risk factor for developing cardiovascular diseases. This means for example that statin-treatment does not suffice to establish levels of less than 130 mg/dL in general, or of less than 100 mg/dL (e. g. about 377mg/dL to about 100 mg/dL), especially in ts with established cardiovascular diseases, or to establish levels of about less than 77 mg/dL (e.g. about 370-77 mg/dL), especially in high-risk groups such as those with CVDs plus diabetes, smoking, poorly controlled hypertension, metabolic syndrome, or previous myocardial infarction. In the context of present ion, statin resistance preferably relates to atorvastatin resistance.

Embodiments of the Invention The present invention will now be further described. In the ing passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the ry. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous, unless clearly indicated to the ry.

In a first aspect the present invention is directed to a pharmaceutical composition comprising about 40 to about 500 mg of an antibody binding specifically to tein convertase subtilisin/keXin type 9 ) together with a pharmaceutically acceptable excipient or carrier.

Suitable antibodies or fragments thereof for practicing the first aspect are bed in the n, rredAntibodiesfor Practicing the Present Invention Preferred embodiments of the antibodies or fragments thereof are e. g. described in the fourth, seventh and eleventh aspect of present invention.

According to a preferred embodiment, the pharmaceutical composition comprises about 40 to about 500 mg or about 50 to about 500 mg of the antibody or antigen-binding fragment per dose.

According to another preferred embodiment, the pharmaceutical composition comprises about 50 mg to about 500mg, about 50 mg to about 300mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350mg, of about 400 mg, about 450 mg or about 500 mg of the antibody or n-binding fragment thereof.

According to another preferred embodiment, the pharmaceutical composition comprises about 150, 200 or 300 mg of the antibody or antigen-binding fragment thereof.

According to another preferred embodiment, the pharmaceutical composition comprises an effective dose of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/keXin type 9), wherein the dose is sufficient for sustained reduction of low-density lipoprotein (LDL-C) levels over a period of at least 14, at least 15, at least 16, at least 17, at least18, at least 19, at least 20, at least 21, at least 22, at least 23 or at least 28 days after administration, together with a pharmaceutically able excipient or carrier. According to another preferred embodiment, the dose is sufficient for sustained reduction of LDL-C levels over a period of at least 14 days, 28 days or 1 month.

According to r preferred embodiment, the pharmaceutical composition comprises an effective amount of an CoA reductase inhibitor.

According to another red embodiment the pharmaceutical composition is arranged together with an effective amount of an HlVlG—CoA ase inhibitor.

According to another preferred embodiment, the HlVlG—CoA reductase inhibitor is a statin, preferably ed from the list consisting or: cerivastatin, statin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin or pravastatin and is preferably atorvastatin. ing to another preferred embodiment, the pharmaceutical composition comprises about 0.05 mg to about 100 mg, about 0,5 mg to about 100 mg, about 5 mg to about 90 mg, about 10 mg, about 20 mg, about 40 mg or about 80 mg of HlVlG—CoA ase inhibitor and preferably about 10, about 20, about 40 or about 80 mg.

In more preferred embodiments of the first and the other s of present invention, the statin is — cerivastatin in an amount of between 0.05 mg and 2 mg, preferably of 0.2 mg, 0.4 mg, or 0.8 — atorvastatin in an amount of between 2 mg and 100 mg, preferably of 10 mg, 20 mg, 40 mg, or 80 mg, — simvastatin in an amount of between 2 mg and 100 mg; of 5 mg; 10 mg; 20 mg; 40 mg; or 80 mg; — pitavastatin in an amount of n 0.2 mg and 100 mg; preferably in a daily dosage of 1 mg; 2 mg; 5 mg; 10 mg; or 20 mg; — rosuvastatin in an amount of between 2 mg and 100 mg; preferably in a daily dosage of 5 mg; mg; 20 mg; or 40 mg; — atin in an amount of between 2 mg and 100 mg; preferably in a daily dosage of 20 mg; 40 mg; or 80 mg; — lovastatin in an amount of between 2 mg and 100 mg; preferably in a daily dosage of 10 mg; 20 mg; 40 mg; or 80 mg; or — pravastatin in an amount of between 2 mg and 100 mg; preferably in a daily dosage of 10 mg; 20 mg; 40 mg; or 80 mg.

According to another preferred embodiment; the pharmaceutical composition comprises an effective dose of CoA reductase inhibitor for lowering LDL-D levels by administration once per day.

In more preferred embodiments of the first aspect of present invention; the statin is — cerivastatin in a daily dosage of between 0.05 mg and 2 mg; ably in a daily dosage of 0.2 mg; 0.4 mg; or 0.8 mg; — atorvastatin in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of 10 mg; 20 mg; 40 mg; or 80 mg; — simvastatin in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of 5 mg; 10 mg; 20 mg; 40 mg; or 80 mg; — pitavastatin in a daily dosage of between 0.2 mg and 100 mg; preferably in a daily dosage of 1 mg; 2 mg; 5 mg; 10 mg; or 20 mg; — rosuvastatin ain a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of mg; 10 mg; 20 mg; or 40 mg; — fluvastatin in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of 20 mg; 40 mg; or 80 mg; — lovastatin in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of 10 mg; 20 mg; 40 mg; or 80 mg; or — pravastatin in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of mg; 20 mg; 40 mg; or 80 mg.

According to a preferred embodiment; the antibody or antigen-binding fragment thereof has one or more of the following features when stered to a t; such as a human or non-human mammal: a. reduction of low-density lipoprotein (LDL-C) levels of at least about -25% to about -40% relative to a predose level with a sustained reduction over at least a 14 day-period upon administration to a t; wherein the sustained ion is preferably at least -25% and more preferably at least -30% relative to a predose level; particularly if administered in a dose of about 40 to about 60 mg; preferably about 45 to about 55 mg and more ably about 50 mg in a biweekly administration regime (every other week; E2W); reduction of low-density lipoprotein (LDL-C) of at least about -50% to about - 65% relative to a predose level with a sustained reduction over at least a 14 day- period upon administration to a t; wherein the sustained reduction is preferably at least -40% and more preferably at least -45% relative to a predose level; particularly if administered in a dose of about 100 mg E2W. reduction of low-density lipoprotein (LDL-C) of at least about -60 % to at least about -75% [e.g. at least about -60 %; at least about -65%; at least about -70 or at least about -75%] ve to a predose level with a sustained reduction over at least a 14 day-period upon stration to a subject; wherein the sustained reduction is preferably at least -55% and more preferably at least -60% relative to a predose level, particularly when administered in a dose of about 150 mg E2W, d. reduction of low-density otein (LDL-C) of at least about 40% to about 75% relative to a predose level with a sustained reduction over at least a 28 day period wherein the sustained reduction is preferably at least -3 5% and more preferably at least -40% relative to a predose level, particularly when administered in a dose of about 200 mg E4W e. reduction of low-density lipoprotein (LDL-C) of at least about -50 % to about - 75% relative to a predose level with a sustained reduction over at least a 28 day- period upon administration to a subject, wherein the sustained reduction is preferably at least -40% and more preferably at least -45% relative to a predose level, particularly when administered in a dose of about 300 mg E4W, f se of serum HDL cholesterol levels of at least 2%, at least 2.5%, at least, 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5% or at least 5.5% ve to a predose level upon administration to a subject, particularly when admimistered in a dose of about 150 mg E2W, g. little or no measurable effect on troponin levels upon administration to a subject, h. se of one or more of: Total-Cholesterol levels, ApoB , non HDL-C levels, Apo-B/ApoA-l ratio, upon administration to a subject.

According to another preferred ment, the antibody or antigen-binding fragment thereof is capable of overcoming statin resistance when administered to a t with statin- resistant hypercholesterolemia.

According to another preferred embodiment, the antibody or antigen-binding fragment thereof comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92 substantially identical sequences having at least 98% or 99% identity therewith.

According to another preferred embodiment, the antibody or antigen-binding fragment f ses a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92 or a pair of substantially identical sequences having at least 98% or 99% identity therewith.

According to another preferred embodiment, the antibody or antigen-binding fragment thereof competes for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

According to another preferred ment, the antibody or antigen-binding nt thereof binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:755).

According to r red embodiment, the antibody or antigen-binding fragment thereof binds an epitope comprising one or more of amino acid residues at positions 23 8, 153, 1O 159 and 343 of hPCSK9 (SEQ ID NO:755).

According to another preferred embodiment, the antibody or antigen-binding fragment thereof binds an e which does not comprise an amino acid residue at positions 192, 194, 197 and/or 237 of hPCSK9 (SEQ ID NO:755).

The pharmaceutical composition can be formulated according to any pharmaceutically applicable formulation as known in the art, and specifically as herein described, such as dry formulation for dissolution or liquid formulation. Suitable ations of antibodies are known in the art and se dry formulations (e.g. freeze-dried, spray-dried or lyophilized, water-free concentrate) as well as liquid formulations (e.g. solutions). Suitable formulations of statins are as well known in the art and comprise dry formulations as well as liquid formulations, e.g suspensions, dispersions and solutions (for a reference, see e.g. “Statins therapy: a reView on conventional and novel formulation approaches” R. Tiwari and K. Pathak, Journal of Pharmacy and Pharmacology, 2011, that is hereby incorporated in entirety). ing to a preferred ment, the pharmaceutical composition comprises the antibody or antigen-binding fragment thereof as dry formulation for dissolution such as a lyophilized powder, freeze-dried or spray-dried powder or water free concentrate. ing to another preferred embodiment, the pharmaceutical composition comprises the antibody or antigen-binding fragment f as liquid formulation, e. g. ion or infusion solution.

According to another preferred embodiment, the pharmaceutical composition comprises the CoA reductase inhibitor as oral or peroral formulation, e. g. capsule or tabled, or as liquid formulation, e.g. suspension, dispersion or solution, e. g. for peroral administration, injection or infusion.

According to another preferred embodiment the pharmaceutical composition is for use in the treatment of a disease or condition in which PC SK9 expression or activity causes an impact or for ng elevated total cholesterol or elevated LDL-C levels. Further preferred uses, dosage regimens, administration regimens of the dy or fragment f or of the WG- CoA reductase inhibitor, or populations to be treated with the pharmaceutical composition described in present application, for example in the h, eleventh to thirteenth or eighteenth to nineteenth .

In a second aspect, the present invention concerns an injection solution as herein described comprising the antibody or antigen-binding fragment thereof of present invention, and preferably comprising about 40 mg to about 200 mg or about 50 to about 200 mg, e.g. about 40 mg, about 50 mg, about 75 mg, at about 100 mg, about 150 mg or about 200 mg ofthe antibody or antigen-binding nt thereof per 1 ml .

The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an ic solution containing glucose and other auxiliary agents, etc., which may be used in ation with an appropriate lizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-SO (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl te, benzyl alcohol, etc. The injection thus ed is preferably filled in an appropriate ampoule. A pharmaceutical composition of the present invention can be delivered subcutaneously or enously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen ry device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be le or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that ns the pharmaceutical composition. The pen ry device can then be . In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefllled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

In a third aspect the present invention concerns a dry formulation as herein described sing the antibody or antigen-binding fragment f of present invention, and ably comprising about 40 mg to about 500 mg, 50 to about 500 mg, about 50 to about 400, about 50 to about 300 e.g. about 40 mg, about 50 mg, about 75 mg, at about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500mg and more preferably about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg and even more preferably about 150 mg, about 200 mg or about 300 mg of the antibody or antigen-binding nt thereof per dose.

Suitable formulations of antibodies in general are known in the art and comprise dry formulations (e.g. freeze-dried, spray-dried or lized, water-free concentrate) as well as liquid formulations (e.g. solutions). Suitable formulations of statins are as well known in the art and comprise dry formulations as well as liquid formulations, e. g suspensions, dispersions and solutions (for a reference, see e.g. “Statins therapy: a review on conventional and novel formulation ches” R. Tiwari and K. Pathak, Journal of Pharmacy and Pharmacology, 2011, that is hereby incorporated in ty).

The formulations of present invention can comprise further active ingredients such as an HJVIG- CoA reductase inhibitor as herein described. Preferred embodiments of the formulations according to present invention are described in other sections of present application, e. g. in the other aspects of present invention such as the first or fourth aspect.

According to a fourth aspect, present invention concerns an antibody or antigen binding fragment thereof specifically binding hPCSK9 (human proprotein convertase subtilisin/keXin type 9), as comprised in one of the pharmaceutical compositions of the invention.

According to a preferred embodiment, the antibody is characterized by one or more of the following features upon administration to a subject, preferably a human or non-human mammal: 1. reduction of nsity lipoprotein (LDL-C) levels of at least about -25% to about -40% relative to a e level with a sustained reduction over at least a 14 day-period, n the ned reduction is preferably at least -25% and more preferably at least - % relative to a predose level, particularly if administered in a dose of about 40 to about 60 mg, preferably about 45 to about 55 mg and more preferably about 50 mg in a biweekly administration regime (every other week, E2W) , 2. reduction of nsity otein (LDL-C) of at least about -50% to about -65% relative to a predose level with a sustained reduction over at least a 14 day-period, wherein the sustained reduction is preferably at least -40% and more preferably at least - 45% relative to a predose level, ularly if stered in a dose of about 100 mg 2. reduction of low-density lipoprotein (LDL-C) of at least about -60 % to at least about - 75% [e.g. at least about -60 %, at least about -65%, at least about -70 or at least about - 75%] relative to a predose level with a ned reduction over at least a 14 day-period, wherein the sustained reduction is preferably at least -55% and more preferably at least - 60% ve to a predose level, particularly when administered in a dose of about 150 mg 3. reduction of low-density lipoprotein (LDL-C) of at least about 40% to about 75% relative to a predose level with a sustained reduction over at least a 28 day period, wherein the sustained reduction is preferably at least -3 5% and more preferably at least - 40% relative to a predose level, particularly when administered in a dose of about 200 mg 4. reduction of low-density lipoprotein (LDL-C) of at least about -50 % to about -75% relative to a predose level with a sustained reduction over at least a 28 day-period, wherein the sustained reduction is preferably at least -40% and more preferably at least - 45% relative to a predose level, particularly when administered in a dose of about 300 mg increase of serum HDL cholesterol levels of at least 2%, at least 2.5%, at least, 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5% or at least 5.5% relative to a predose level, particularly when admimistered in a dose of about 150 mg E2W, reduction of serum total cholesterol at least about 25% to about 35% relative to a predose level with a sustained ion over at least a 24 day period,. ion of serum total cholesterol at least about 65% to about 80% relative to a predose level with a sustained reduction over at least a 24 day period, ion of serum triglyeride levels at least about 25% to about 40% relative to a predose level, little or no measurable effect on liver function, as determined by ALT and AST measurements, 10. little or no able effect on troponin levels, ll. Increase of one or more of: Cholesterol levels, ApoB levels, non HDL-C levels, Apo-B/ApoA-l ratio, The antibody ing to present invention exhibits the above properties ably if administered in combination with an HlVlG—CoA reductase inhibitor treatment. Preferred embodiments of HlVlG—CoA reductase inhibitors to be used in conjunction with the antibody of the invention and dosage and administration regimes thereof can be found throughout the specification, particularly as described in the aspects related to medical uses and methods of treatment.

According to a preferred embodiment of the antibodies and antigen-binding fragments thereof of present invention, particularly of the antibody or antigen-binding fragment according to the fourth aspect, the dy or antigen binding fragment thereof has one or more of the following characteristics: (i) The antibody or the antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. (ii) The antibody or antigen-binding nt thereof ses a CVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. (iii) The antibody or antigen-binding fragment thereof competes for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

According to r preferred ment of the antibodies and antigen-binding fragments thereof of present invention, particularly of the antibody or antigen-binding fragment according to the fourth aspect, the antibody or antigen binding fragment thereof has one or more of the following characteristics: (0 overcomes statin resistance in mammals, especially in rodents such as hamster (ii) increase in LDLR expression in mammals, particularly in rodents such as hamster (iii) se of serum LDL-C in rodents such as hamster (iV) istic decrease of LDL-C in conjunction with HlVlG—CoA reductase inhibitor administration, particularly in rodents such as r, wherein the HlVlG—CoA reductase tor is preferably Atorvastatin.

Further suitable characteristics and structural features of the antibody of present invention and particularly of the antibody of the fourth aspect, as well as antibodies and n-binding fragments thereof that can be used for practicing the fifteenth aspect and the other aspects of the present invention are described in the section “PreferredAntibodiesfor Practicing the Present Invention The antibody of present invention, such as the dy according to the fourth aspect, is preferably formulated as a pharmaceutically able formulation as known in the art, and specifically as herein described, such as dry formulation for dissolution or liquid formulation, e. g. as described at the second or third aspect.

In a fifth aspect the present invention is directed to a unit dosage form comprising the antibody, antigen-binding fragment thereof or pharmaceutical composition of present invention.

Suitable embodiments of the antibody, pharmaceutical composition or formulation to be used for practicing the fifth aspect of present invention can be gained from the respective sections of present application, such as the first to fourth aspects or from the section “PreferredAntibodies for Practicing the Present Invention According to a preferred embodiment, the unit dosage form comprises about 40 mg, about 50 mg, about 75 mg, at about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg of the antibody or n-binding fragment thereof. ing to another preferred embodiment, the unit dosage form comprises the antibody or fragment thereof as dry formulation for dissolution in a hermetically sealed ner such as a vial, an ampoule or sachette.

According to r preferred embodiment, the unit dosage form comprises the antibody or fragment thereof as liquid formulation in a hermetically sealed container such as a vial, a sachette, a pre-filled syringe, a pre-filled autoinjector or a cartridge for a le e or applicator.

According to another preferred embodiment, the quantity of active ingredient is indicated on the ically-sealed container.

As used in the different aspects and embodiments of present invention and in particularly of the fifth aspect, the term "unit dosage form" refers to ally discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of active material (e.g., about 40mg or about 50mg to about 500mg of PCSK5 antibody and/or of e. g. 0.05mg to 100 mg HlVlG-CoA reductase inhibitor) calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The cations for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the ular therapeutic effect to be achieved, and (b) the limitation nt in the art of compounding such an active material for eutic use in animals or humans, as disclosed in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are vials, s, capsules, troches, suppositories, powder packets, wafers, cachets, ampules, segregated multiples of any of the foregoing, and other forms as herein described or generally known in the art.

One or more such unit dosage forms of the antibody can be comprised in an article of manufacture of present ion, optionally further comprising one or more unit dosage forms of an HMG-CoA reductase inhibitor (e.g. a blister of tablets comprising as active ingredient the I-flVlG—CoA reductase inhibitor).

The term “active material” refers to any material with therapeutic activity, such as one or more active ients. The active ients to be employed as therapeutic agents can be easily prepared in such unit dosage form with the employment of pharmaceutical materials which themselves are available in the art and can be prepared by ished ures. Preferred active ingredients of present invention are the antibody or fragment thereof or an HlVlG—CoA reductase inhibitor such as a statin.

In a preferred embodiment, the unit dosage form comprises 40 — about 500 mg of the antibody or an antigen-binding fragment of present invention. According to another preferred embodiment, the unit dosage form comprises about 40 mg, about 50 mg, about 75 mg, at about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg and more ably about 150 mg, about 200 mg or about 300 mg of the antibody or n-binding fragment thereof. Further preferred dosages, and dosage regimens are as described elsewhere in the application, such as at the first, second or f1fteenth to nineteenth aspect.

According to r red aspect, the unit dosage form comprises the dy, antigen-binding fragment thereof or pharmaceutical composition as dry formulation for dissolution such as a lyophilized powder, freeze-dried powder or water free concentrate.

According to another preferred embodiment the dry formulation is comprised in a hermetically sealed container such as a vial, an ampoule or sachette.

According to another red embodiment, the unit dosage form comprises the antibody, n-binding fragment thereof or pharmaceutical composition as liquid formulation, e. g. ion or infusion solution. According to another preferred embodiment the liquid formulation is comprised in a hermetically sealed container such as a vial, a te, a pre-fllled syringe, a pre-fllled autoinjector or a cartridge for a reusable syringe or applicator.

It is further preferred, if the quantity of active ingredient (e. g. antibody) is ted on the hermetically-sealed container of the unit dosage form.

The following preparations are illustrative of the preparation of the unit dosage forms of the present invention, and not as a limitation thereof. Several dosage forms may be ed ing the present invention. For example, a unit dosage per vial may contain 0,5 ml, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, or 20 ml ofPCSK5 antibody or a fragment thereof ranging from about 40 to about 500 mg or from about 50mg to about 500 mg of 1O PCSK5 antibody. If necessary, these preparations can be adjusted to a desired concentration by adding a sterile diluent to each vial.

In one embodiment, the ingredients of the compositions of the invention are supplied either separately or mixed together in a unit dosage form, for example, as a dry ation for dissolution or a liquid formulation. The preparation of ceutically acceptable ations of proteinaceous biomolecules such as antibodies or antigen-binding fragments thereof or of small molecule compounds such as statins is generally known in the art. In addition, see section “Preferred antibodies for practicing the invention” or the second or third aspect of present invention for some suitable formulations of antibodies and for small molecule HlVlG—CoA reductase inhibitors such as s, see e. g. “Statins therapy: a review on conventional and novel formulation approaches”, r.Tiwari and K. Pathak, l of Pharmacy and Pharmacology 2011, p. 983-998. According to a preferred embodiment, the active ingredients, active material or pharmaceutical composition according to present invention is a dry formulation for liquid dissolution, such as a lyophilized powder, -dried powder or water free concentrate, preferably comprised in a hermetically sealed container such as a vial, an ampoule or sachette, and preferably ting the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an on bottle containing e pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for ion or saline can be provided so that the ingredients may be mixed prior to administration.

The formulations of the invention e bulk drug compositions useful in the manufacture of pharmaceutical compositions (e.g., compositions that are suitable for administration to a subject or patient) which can be used in the preparation of unit dosage forms.

In a preferred embodiment, a composition of the ion is a pharmaceutical composition.

Such compositions comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., an antibody of the invention or other prophylactic or therapeutic agent), and a pharmaceutically able carrier. Preferably, the pharmaceutical compositions are formulated to be suitable for the route of stration to a subject.

In a specific embodiment, the term "pharmaceutically acceptable" means ed by a 1O regulatory agency of the US. Federal or a state government or the EMA (European Medicines Agency) or listed in the US. Pharmacopeia Pharmacopeia (United States Pharmacopeia- ional Formulary-28 Reissue, published by the United States Pharmacopeial Convention, Inc., Rockville Md, publication date: April 2010) or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term "carrier" refers to a diluent, adjuvant {e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile s, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered enously. Saline solutions and aqueous dextrose and glycerol solutions can also be ed as liquid carriers, ularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, e, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium de, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained- release formulations and the like. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, e, starch, magnesium te, sodium saccharine, ose, magnesium carbonate, etc. es of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will contain a prophylactically or therapeutically effective amount of the antibody, preferably in purified form, together with a suitable amount of carrier so as to e the form for proper administration to the t. The ition may further contain one or more other active ingredients such as an CoA reductase inhibitor. The formulation should suit the mode of administration.

Generally, the ingredients of compositions of the invention are supplied either separately or mixed together in unit dosage form, for example, as a dry formulation for dissolution such as a lyophilized powder, freeze-dried powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. The ingredients of compositions of the invention can also be supplied as admixed liquid ation (i.e. injection or infusion solution) in a hermetically sealed ner such as an ampoule, sachette, a pre-fllled syringe or jector, or a cartridge for a reusable syringe or applicator (e. g. pen or autoinjector). Where the composition is to be administered by on, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. The composition can also comprise two or more active ingredients that are each ated in a different or the same manner, e.g. a combination of an antibody of present invention together with an HlVlG—CoA reductase inhibitor or present ion.

The invention also provides that the formulation is packaged in a hermetically sealed container such as an ampoule or sachette indicating the quantity of dy. In one embodiment, the formulation of the invention comprising an dy is supplied as a dry sterilized lyophilized powder, freeze-dried powder or water free concentrate in a hermetically sealed container and can be reconstituted, e.g., with water or saline to the appropriate concentration for administration to a subject. In one embodiment, the ation of the invention comprising an antibody is supplied as a dry sterile lyophilized powder in a hermetically sealed container at a unit dosage of at least 40 mg, at least 50 mg, more preferably at least 75 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, or at least 500 mg, of dy or antigen-binding fragment thereof The lyophilized formulation of the invention comprising an antibody should be stored at between 2 and 8° C in its original container and the antibody should be administered within 12 hours, preferably within 6 hours, within 5 hours, within 3 hours, or within 1 hour after being reconstituted. The formulation of the invention comprising dies can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, ium, ammonium, calcium, ferric hydroxides, pylamine, triethylamine, lamino ethanol, histidine, procaine, etc.

In a sixth aspect, present invention ns an article of manufacture comprising the pharmaceutical composition of present invention, the liquid formulation of present invention or the dry formulation of present ion, the antibody or antigen-binding fragment f of present invention or one or more unit dosage forms of present invention and a container or 1O package.

According to a red embodiment, the article of manufacture ses suff1cient unit dosage forms of antibody for a two-week (14 day), four-week (28 day) or one month period, with either E2W, E4W or once-a-month administration regime.

The article of cture can comprise one or more unit dosage form that contain(s) both, the antibody and the HlVlG CoA-inhibitor, e. g. a unit dosage form comprising a liquid formulation for injection or infusion comprising both active ingredients. The article of manufacture can also comprise the antibody (or n-binding fragment thereof) and the HlVlG—CoA reductase inhibitor in two or more separate unit dosage forms.

According one embodiment, the article of manufacture comprises one or more separate unit dosage forms of the and the CoA ase tor according to present invention.

According to a preferred embodiment, each unit dosage form of HlVlG—CoA reductase inhibitor comprises about 0.05 mg to about 100 mg HlVlG—CoA reductase inhibitor.

According to another preferred embodiment the HlVlG—CoA reductase inhibitor is a statin, preferably selected from the list containing: cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin or pravastatin and ably atorvastatin.

According to another preferred embodiment the HlVlG—CoA reductase inhibitor, e. g. the statin, is in an effective dose for administration once per day.

According to another preferred embodiment, the unit dosage form of HlVlG—CoA reductase inhibitor comprises about 0,5 to about 100 mg, about 5 to about 90 mg, of about 10, 20, 40 or 80 mg HlVlG—CoA reductase inhibitor.

According to r preferred embodiment, the e of manufacture comprises suff1cient unit dosage forms of HlVlG—CoA ase inhibitor for a daily administration regime.

According to another red embodiment, the unit dosage form comprising the antibody is a sachette, a pre-fllled syringe, a pre-fllled autoinjector or a cartridge for a reusable syringe or applicator, ally comprising 1 ml or 2 ml of injection solution.

According to another embodiment, the article of manufacture comprises one or more of the following components: a. One or more unit dosage forms comprising the antibody of present invention b. One or more unit dosage forms comprising the HlVlG—CoA reductase inhibitor of present invention, c. Instructions for use, d. A deVice for application of the antibody such as a syringe.

According to another preferred embodiment, the article of cture comprises suff1cient unit dosage forms of the antibody and preferably also of the CoA reductase inhibitor... (a) for one single administration of antibody and HlVlG—CoA reductase inhibitor, e. g. comprising an ampoule, sachette, Vial, cartridge or pre- fllled syringe sing about 50mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg dy and preferably about 150 mg antibody, about 200 mg antibody or about 300 mg antibody, together with tablet or capsule, e. g. for oral or peroral administration comprising the HlVlG, CoA-inhibitor, e.g. comprising about 10mg, about mg, about 40 mg or about 80 mg of the HlVlG CoA-inhibitor such as atorvastatin. (b) for a two-week (i.e. 14-day) treatment with antibody and HlVlG—CoA reductase inhibitor, e. g. comprising an ampoule, sachette, Vial, cartridge or pre-fllled syringe comprising about 50mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg antibody and preferably about 150 mg antibody, about 200 mg antibody or about 300 mg dy; together with sufficient units comprising of CoA reductase inhibitor (e. g. tablets or capsules, e. g. for oral or peroral administration) for a 14-day treatment, e. g. 14 units for a once-a day administration regime of HlVlG—CoA reductase inhibitor or 28 units for a twice-a day administration regime etc, wherein the units per day of HlVlG CoA- inhibitor preferably comprise about lOmg, about 20 mg, about 40 mg or about 80 mg of the HlVlG CoA-inhibitor such as atorvastatin. In the case the antibody is to be administered in a dosage of more than 200 mg, two unit dosage forms of antibody together comprising the total dose may be able (e. g. two pre-fllled syringes comprising about 150 mg of antibody in 1 ml of liquid ation each for a total administration (e. g. subcutaneous injection) of about 300 mg dy in two shots) may be preferable (or two units with about 100 mg each for a total administration of about 200 mg antibody, two units with about 175 mg for a total administration of about 350 antibody, etc. . .). (c) for a four week (i.e, 28-day) treatment with antibody and HlVlG—CoA reductase tor, e.g. l. for a E2W administration regimen of the antibody with about 50 to about 200 mg antibody per two weeks: sing two unit dosage forms (e.g. as exempliefled above) with each about 50 mg, about 100 mg, about 150 mg or about 200 mg antibody or antigen- binding fragment thereof together with 28 unit dosage forms of CoA reductase inhibitor (as exemplified above) for a daily once a day administration regime or together with 56 unit dosage forms of HlVlG—CoA reductase inhibitor for a daily twice-a day administration regime, preferably 28 unit dosage forms (e. g. capsules or tablets) of about 10 mg, about 20 mg, about 40 mg or about 80 mg atorvastatin 2. for an E4W stration regime of the antibody or fragment thereof with an administration of about 200 mg per four weeks (28 days): e. g. comprising one unit dosage form of the antibody with about 200 mg antibody (e.g. as exemplified above) together with 28 or 56, and preferably 28 unit dosage forms of HlVlG—CoA reductase inhibitor (e.g. as exemplified above) 3. for an E4W administration regime of the dy with more than 200 mg per four weeks (28 days): comprising two unit dosage forms that together se the total dose of antibody (e. g. two pre-filled syringes each comprising 1 ml of liquid antibody formulation with 150 mg antibody each) or comprising one unit dosage form that comprises the total amount of antibody to be administered (e.g. a vial sing about 300 mg antibody for dissolution or a vial, cartridge or pre-filled syringe comprising about 300 mg of the antibody in liquid formulation (i.e. about 2 ml of liquid formulation, wherein 1 ml of liquid formulation comprises about 150 mg of the antibody), together with 28 or 56, and preferably 28 unit dosage forms of HlVlG—CoA reductase inhibitor (e.g. as exemplified above) (d) for a one-month ent with antibody and HlVlG—CoA reductase inhibitor: sing the same numbers of unit dosage forms of antibody as ified under (c) for an administration once or twice per month, e. g. every first day of the month or every first Monday etc. of the month for a once a month administration, or e. g. every first and 14th or 15th day of the month for a twice-a-month administration regime, in addition the article of manufacture comprises 31 unit dosage forms of HlVlG—CoA reductase inhibitor, preferably tablets or capsules arranged in a r containing a consecutive numbering from 1-31 for the days of the month (wherein the uous tablets or capsules for excess days are to be discarded).

According to another preferred embodiment the article of manufacture ses: (a) a packaging material; (b) an antibody or an antigen-binding fragment f which specifically binds hPCSK9; and (c) a label or packaging insert contained within the packaging material indicating that patients receiving treatment with said antibody or antigen-binding fragment can be treated for a disease or condition selected from the group consisting of hypercholesterolemia; hyperlipidemia; dyslipidemia; atherosclerosis and cardiovascular diseases.

According to another preferred ment the e of manufacture comprises: (a) a packaging al; (b) an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9; and (c) a label or packaging insert contained within the packaging material indicating the treatment of patients with said antibody or antigen-binding fragment thereof together with the application of an HlVlG Co A inhibitor such as a statin.

According to another preferred embodiment the article of manufacture comprises: (a) a packaging material; (b) an antibody or an n-binding fragment thereof which specifically binds hPCSK9; and (c) a label or packaging insert indicating that the treatment of patients with said antibody or antigen-binding fragment thereof together with an Co A inhibitor such as a statin is contraindicated for ts ing to one or more of the following groups: (i) smokers; (ii) persons being 70 years old or older; (iii) persons suffering from hypertension; (iv) women who are pregnant; (V) women who are trying to become pregnant; (vi) women who are breast-feeding; (vii) persons who have or ever had a disease affecting the liver; (viii) persons who had any ained abnormal blood tests for liver function; (ix) persons who drink excessive amounts of alcohol; (x) persons having kidney problems; (xi) persons suffering from hypothyroidism; (xii) persons suffering from muscle disorders; (xiii) persons having tered previous ar problems during treatment with lipid-lowering medicine; (xiv) persons having serious problems with their breathing; (xv) persons taking one or more of the following medicines: medicines altering the way the immune systems works (e.g. porin or antihistamines); antibiotics or antifungal medicines (e. g. erythromycin; clarithromycin; ketoconazole; itraconazole; rifampicin; fusidic acid); medicines regulating lipid levels (e.g. gemf1brozil; colestipol); calcium channel blockers (e.g. verapamil; diltiazem); nes regulating the heart rhythm (digoxin; amiodarone); protease inhibitors used in the treatment ofHIV (e. g. nelf1navir); warfarin; oral contraceptives, ds or St. John’s Wort; or (xvi) persons drinking more than 0.1 L of grapefruit juice per day or eating more than half a grapefruit per day; (xvii) persons having a body mass index (BMI) of more than 40; (xviii) s having a body mass index (BMI) of less than 18; (xix) persons ing from type 1 diabetes or type 2 diabetes; (xx) persons positive for hepatitis B or hepatitis C; (xxi) persons having a known sensitivity to monoclonal antibody therapeutics; (xxii) persons having a phil concentration of less than 15OO/mm3; (xxiii) persons having a platelet concentration of less than /mm3; (xxiv) men having a serum creatinine level larger than 1.5 x ULN (upper limit of normal); (xxv) women having a serum creatinine level larger than 1.4 x ULN (upper limit of normal); (xxvi) persons having an alanine transaminase (ALT) level or aspartate transaminase (AST) level larger than 2 x ULN; or (xxvii) persons having a CPK level larger than 3 x ULN.

In red ments of the sixth aspect; the antibody or antigen-binding fragment is an antibody or antigen-binding fragment as specified below in the section “PreferredAntibodies for Practicing the Present ion The label or packaging insert according to the different aspects and embodiments of the invention; particularly in respect to the different articles of manufacture of the invention; can be any kind of data carrier suitable to be arranged within (either loose or attached to another component of the article of manufacture; e. g. to a blister or a vial containing unit dosage forms of the dy and/or the HlVlG—CoA reductase inhibitor) the package or container or on the outside of the package or container. Preferably; the data carrier (i.e. label or; chip; bar code or leaflet or label comprising a bar code etc.) comprises information such as (i) composition; formulation; concentration and total amount; identity of active ingredient (s) ned in the article of manufacture; i.e. of the antibody or antigen-fragments; HlVlG—CoA reductase tor; pharmaceutical compositon; unit dosage form or formulation of present invention (ii) number and composition of unit dosage form contained in the e of manufacture (iii) indications, contra-indications of the antibody or antigen-fragments, pharmaceutical compositon, unit dosage form or ation of present invention (iv) (ii) subjects/patients or subject/patient populations indicated or contra- ted for treatment with the antibody or antigen-fragments, ceutical compositon, unit dosage form or formulation of present invention (V) instructions for use, dosage regimens and/or administration regimes (vi) quality information such as information about the lot/batch number of the of the antibody or antigen-fragments, ceutical compositon, unit dosage form or formulation of present ion, the manufacturing or assembly site or the expiry or sell-by date, (vii) information concerning the correct storage or handling of the article of manufacture, of the device for application, or of the antibody or antigen- fragments, pharmaceutical compositon, unit dosage form or formulation of present invention, (iv) information concerning the composition of the buffer(s), diluent(s), reagent(s), excipients, carriers, formulations of of the antibody or antigen-fragments, pharmaceutical compositon, unit dosage form or formulation of present invention,, (vi) a warning concerning le consequences when applying unsuitable dosage or administration regimens and/or use in contraindicated indications of patient populations.

In red embodiments of the sixth aspect, the label or packaging insert contains reference to a method of treatment or medical use according to the seventh, eleventh to thirteenth, eighteenth or nineteenth aspect and the ments of the first or second aspect as described herein.

According to another preferred embodiment, the article of manufacture comprises (a) a packaging al, (b) an antibody or an antigen-binding fragment thereof which ically binds hPCSK9, and (c) a label or packaging insert contained within the ing material indicating that ts receiving treatment with said antibody or antigen-binding fragment can be treated for a e or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases and further indicating that ts falling into one or more groups of subjects as recited in the eighteenth aspect can be treated.

According to another preferred embodiment the article of manufacture comprises: (a) a packaging material; (b) an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9, and (c) a label or packaging insert contained within the packaging material ting that patients receiving treatment with said antibody or antigen-binding fragment can be treated for a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and vascular diseases and further indicating that the treatment of patients with said antibody or antigen-binding fragment thereof is contraindicated for patients belonging to one or more groups of ts as recited in the enth aspect.

In preferred embodiments of sixth aspect, the label or packaging insert ns a reference to a method of treatment according to the medical uses and methods of treatment as herein bed, e. g. according to the seventh, th to thirteenth, eighteenth or nineteenth aspect and the embodiments thereof as described herein.

According to a seventh aspect, present invention concerns the pharmaceutical composition, antibody or antigen-binding fragment thereof of t invention, for use in the treatment of a disease or condition in which PCSK9 expression or activity causes an impact.

According to a preferred embodiment of the h aspect, the disease or condition is selected from the group consisting of: elevated total cholesterol levels, ed low-density otein (LDL-C) levels, holesterolemia, hyperlipidemia, dyslipidemia, and atherosclerosis, particularly primary hypercholesterolemia, familial hypercholesterolemia, or hypercholesteremia which is uncontrolled by statins.

According to another preferred embodiment, the composition, the antibody or antigen- binding fragment thereof is administered to the t every other week (EZW), every fourth week (E4W) or once a month.

According to another preferred embodiment an HlVlG—CoA reductase inhibitor is co- administered with the pharmaceutical composition, the antibody or antigen-binding fragment thereof, preferably an HIVIG—CoA reductase inhibitor according to one of the different aspects of present invention, such as according to the first or second aspect.

According to another preferred ment the HIVIG—CoA ase inhibitor is administered once a day and preferably every day.

In a second aspect the t invention is directed to an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/keXin type 9) for use in the treatment of a disease or condition in which PCSK9 expression or activity causes an impact, wherein the antibody or antigen-binding fragment thereof is for stration in a dosage 1O amount g from 5 mg to 500 mg, wherein the antibody or antigen-binding fragment thereof is further for administration in combination with an HIVIG—CoA ase inhibitor at a dosage amount ranging from 0.05 mg to 100 mg.

In preferred embodiments of seventh the other aspects of present invention, the disease or condition in which PCSK9 expression or activity causes an impact is rated, improved, inhibited or prevented with a PCSK9 antagonist.

In r preferred embodiments of the seventh and the other aspects of present invention, the disease or condition is selected from the group consisting of: elevated low-density lipoprotein cholesterol (LDL-C) levels, hypercholesterolemia, particularly holesterolemia uncontrolled by statins, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases, particularly primary hypercholesterolemia such as primary familial holesterolemia or primary non-familial hypercholesterolemia.

In preferred embodiments of the seventh and the other aspects of present invention, the antibody or n-binding fragment thereof is for administration to a subject indicated for LDL apheresis, a subject with PC SK9-activating mutations, a subject with heterozygous Familial Hypercholesterolemia, a t with primary hypercholesterolemia, a subject with primary holesterolemia who is statin uncontrolled, a subject at risk for developing hypercholesterolemia, a subject with hypercholesterolemia, a subject with hyperlipidemia, a subject with dyslipidemia, a subject with atherosclerosis or a subject with cardiovascular diseases. Most preferably, the subject is a human subject.

In some embodiments of the seventh and the other aspects of present ion, the antibody or antigen-binding nt thereof is for administration in combination with an HIVIG— CoA reductase tor, which is to be stered three times per day, twice per day, or once per day. In some embodiments of the second and the other aspects of present ion, the HIVIG—CoA reductase inhibitor is to be administered every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. In some embodiments of the second and the other aspects of present invention, the HIVIG—CoA reductase inhibitor is to be administered every 1O week, every other week, every third week, or every fourth week. In some embodiments of the second and the other aspects of present invention, the HIVIG—CoA reductase inhibitor is to be administered in the morning, at noon or in the evening. In preferred embodiments, the HIVIG— CoA reductase inhibitor is to be administered once per day, preferably orally, ably in the evening.

In preferred embodiments of the seventh and the other aspects of present invention, the HIVIG—CoA reductase inhibitor is a statin. More ably, the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin.

In more red embodiments of the seventh and the other s of present invention, the statin is — cerivastatin which is to be administered in a daily dosage of between 0.05 mg and 2 mg, preferably in a daily dosage of 0.2 mg, 0.4 mg, or 0.8 mg, — atorvastatin which is to be administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg, — simvastatin which is to be administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg, — pitavastatin which is to be administered in a daily dosage of n 0.2 mg and 100 mg, preferably in a daily dosage of 1 mg, 2 mg, 5 mg, 10 mg, or 20 mg, — rosuvastatin which is to be administered in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of 5 mg; 10 mg; 20 mg; or 40 mg; — fluvastatin which is to be administered in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of 20 mg; 40 mg; or 80 mg; — lovastatin which is to be administered in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of 10 mg; 20 mg; 40 mg; or 80 mg; or — pravastatin which is to be stered in a daily dosage of n 2 mg and 100 mg; preferably in a daily dosage of 10 mg; 20 mg; 40 mg; or 80 mg.

In further preferred embodiments of the seventh and the other aspects of t invention; the antibody or antigen-binding fragment thereof is for administration to the subject every other week ,every fourth week or once a month. stration every fourth week or stration once a month is preferred in view of patient compliance. Administration every other week is preferred in viw of a very low variation of blood cholesterol levels. Other suitable time schedules for administration of the antibody or n-binding fragment thereof include without limitation an administration once per day; every other day; every third day; every fourth day; every fifth day; every sixth day; every week; every third week; every fifth week; every sixth week; every eighth week; every tenth week; and every twelfth week.

In a further preferred embodiment of the seventh and the other aspects of present invention; the antibody or antigen-binding fragment thereof is for administration in a dosage amount g from about 40 mg to about 500 mg or from about 50mg to about 500 mg or from about 50mg to about 400mg or from about 50 mg to about 300 mg; or from about 100mg to about 300 mg or from about 100 mg to about 200 mg. In more preferred embodiments; the antibody or antigen-binding fragment thereof is for administration in a dosage amount of about 50mg; of about 100mg; of about 150mg; of about 200mg; of about 250 mg; of about 300mg; of about 350 or of about 400 mg.

According to another preferred embodiment of the seventh aspect, the dy or antigen- binding fragment thereof is administered to the subject every other week (E2W), every fourth week (E4W) or once a month.

In preferred embodiments of the seventh and the other aspects of t invention the dy or antigen-binding fragment thereof is for administration in a dosage amount (i.e. a dosage regimen) ranging from about 50 mg to about 200 mg every other week (E2W), ably about 50 mg E2W, about 100 mg E2W, about 150 mg E2W, about 200 mg E2W, about 250 mg E2W or about 300 mg E2W, with about 50 mg E2W, about 100 mg E2W, about 150 mg E2W, about 200 mg E2W, being even more preferred. According to an especially advantageous embodiment of the second and the other aspects of present invention of present ion the antibody or antigen-binding fragment thereof is for administration in a dosage amount (i.e. a dosage n) E2W from about 50 mg to about 200mg from about 100 mg to about 180 mg, from about 130 mg to about 170 mg, from about 140 to about 160 mg or about 90, about 100, about 110, about 120, about 130, about 140, about 145, about 150, about 155, about 160, about 170, about 180, about 190 or about 200 mg E2W, with dosage regimens of about 145 mg to about 155 mg E2W and particularly about 150 mg E2W belonging to the particularly preferred embodiments.

In other preferred ments of the seventh and the other aspects of present invention, the antibody or antigen-binding fragment thereof is for administration in a dosage amount ranging from about 100 mg to about 400 mg every fourth week (E4W), preferably about 100 mg E4W, about 150 mg E4W, about 200 mg E4W, about 250 mg E4W, about 300 mg E4W, about 350 mg E4W or about 400 mg E4W, with dosage amounts of about 190 to about 310 E4W of about 200 to about 300 mg E4W, about 190 to about 210 E4W, about 195 to about 205 E4W, about 290 to about 310 E4W, about 295 to about 305 E4W about 200 mg E4W or about 300 mg E4W belonging to the particularly preferred embodiments. These dosage amounts indicated for administration E4W are also suitable for administration once a month.

The seventh aspect is further directed to an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/keXin type 9) for use in the treatment of a disease or ion in which PCSK9 expression or activity causes an impact, wherein the antibody or antigen-binding fragment thereof is for administration in a dose of about 50 to 500 mg.

Antibodies and n-binding fragments thereof that can be used for practicing the sixteenth aspect of the present invention are described in the section “PreferredAntibodiesfor Practicing the t Invention Preferred embodiments of the seventh aspect of present invention are described in the fourth aspect.

According to r preferred embodiment of the h , the antibody or antigen- binding fragment thereof is for administration in a dose of about 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg and preferably of about 150, 200 or 300 mg.

According to another preferred embodiment of the seventh aspect, the disease or condition is selected from the group consisting of: elevated total cholesterol levels, elevated low-density 1O lipoprotein (LDL-C) levels, hypercholesterolemia, hyperlipidemia, dyslipidemia, and atherosclerosis, particularly primary hypercholesterolemia, familial hypercholesterolemia. or hypercholesteremia which is uncontrolled by statins.

According to another preferred embodiment of the seventh , the antibody or antigenbinding fragment thereof has one or more of the following characteristics: (i) is for use in the reduction of low-density lipoprotein (LDL-C) levels of at least about -25% to about -40% relative to a predose level with a sustained reduction over at least a 14 day-period, wherein the sustained reduction is preferably at least -25% and more preferably at least -30% relative to a predose level, n the dy or antigenbinding fragment thereof is preferably administered in a dose of about 40 to about 60 mg, about 45 to about 55 mg or about 50 mg E2W. (ii) is for use in the reduction of low-density lipoprotein ) of at least about -50% to about -65% relative to a predose level with a sustained reduction over at least a 14 day-period, wherein the sustained reduction is preferably at least -40% and more preferably at least -45% ve to a predose level, wherein the antibody or fragment thererof is preferably administered in a dose of about 100 mg E2W. (iii) is for use in the reduction of low-density lipoprotein ) of at least about -60 % to at least about -75% [e.g. at least about -60 %, at least about -65%, at least about - 70 or at least about -75%] relative to a predose level with a sustained reduction over at least a 14 day-period, n the ned reduction is preferably at least -55% and more preferably at least -60% relative to a predose level. n the antibody or fragment thereof is preferably stered in a dose of about 150 mg E2W.

(M is for use in the reduction of low-density lipoprotein (LDL-C) of at least about 40% to about 75% ve to a predose level with a sustained reduction over at least a 28 day period, wherein the sustained reduction is preferably at least -3 5% and more preferably at least -40% relative to a predose level, n the antibody or fragment thereof is preferably administered in a dose of about 200 mg E4W.

(V) is for use in the reduction of low-density lipoprotein (LDL-C) of at least about -50 % to about -75% relative to a predose level with a sustained reduction over at least a 28 1O day-period, wherein the sustained reduction is ably at least -40% and more preferably at least -45% relative to a predose level, wherein the antibody or fragment thereof is preferably administered in a dose of about 300 mg E4W. (vi) is for use in the increase of serum HDL cholesterol levels of at least 2%, at least 2.5%, at least, 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5% or at least 5.5% relative to a predose level. (vii) Is for use in the reduction of serum total cholesterol at least about 25% to about 35% ve to a predose level with sustained reduction over at least a 24 day period. (viii) Is for use in the reduction of serum total cholesterol at least about 65% to about 80% relative to a predose level with ned reduction over at least a 24 day period. 12. Is for use in the reduction of serum triglyeride levels at least about 25% to about 40% ve to a predose level. 13. has little or no measurable effect on liver function, as determined by ALT and AST measurements, or on troponin levels. 14. Is for use in the increase of one or more of: Total-Cholesterol levels, ApoB , non HDL-C levels, Apo-B/ApoA-l ratio.

According to another preferred embodiment of the seventh aspect, the antibody or antigen- binding fragment thereof is for use together with an CoA reductase inhibitor, wherein the HlVlG—CoA reductase inhibitor is preferably administered in a dosage amount in the range of about 0.05 mg to about 100 mg and is preferably a statin, wherein the statin is preferably selected from the group ting of: cerivastatin, atorvastatin, simvastatin, pitavastatin, statin, fluvastatin, lovastatin or pravastatin.

According to another preferred embodiment of the seventh aspect the statin is administered according to one or more of the following dosage or admimistration regimes: (i) the statin is administered once per day, (ii) the statin administered at a dosage of about 0,5 to about 100 mg, about 5 to about 90 mg, of about 10, 20, 40 or 80 mg and is preferably atorvastatin. 1O Further dosage and admimistration regimes of the antibody, antigen fragment therof or the HlVlG—CoA reductase inhibitor are bed at the other aspects of present invention and preferably at the eleventh aspect.

In a further preferred embodiment of the seventh aspect the present ion is directed to an antibody or an antigen-binding nt thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/keXin type 9) for use in the treatment of a disease or condition in which PCSK9 expression or activity causes an , wherein the antibody or antigen-binding fragment thereof is for stration to a subject g at least into one of the following groups of subjects: (i) subjects having a serum LDL cholesterol (LDL-C) level of at least 100 mg/dL, preferably at least 130 mg/dL, more preferably at least 160 mg/dL, even more preferably at least 200 mg/dL, (ii) subjects having a serum HDL-C level of less than 40 mg/dL, (iii) subjects having a serum cholesterol level of at least 200 mg/dL, preferably at least 240 mg/dL, (iv) subjects having a serum triacylglycerol level of at least 150 mg/dL, e.g. at least 200 mg/dL or at least 500 mg/dL, wherein said triacylglycerol level is determined after fasting for at least 8 hours, (v) subjects being at least 35 years old, e.g. at least 40 years old, at least 45 years old, at least 50 years old, at least 55 years old, at least 60 years old, at least 65 years old, or at least 75 years old, (vi) subjects younger than 75 years, e. g. younger than 70 years, younger than 65 years, younger than 60 years, younger than 55 years, younger than 50 years, younger than 45 years, or younger than 40 years, (vii) subjects having a BMI of 25 or more (e. g. 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more; 32 or more; 33 or more; 34 or more; 35 or more; 36 or more; 37 or more; 38 or more; or 39 or more); (viii) male subjects; (ix) female ts; (X) subjects in which the administration of said antibody or antigen-binding fragment thereof leads to a reduction in the serum LDL-C level by at least 30 mg/dL; preferably by at least 40 mg/dL; more preferably by at least 50 mg/dL; more preferably by at least 60 mg/dL; more preferably by at least 70 mg/dL; relative to predose level; or (xi) subjects in which the administration of said antibody or antigen- binding fragment thereof leads to a reduction in the serum LDL-C level by at least 20%; ably by at least 30%; more preferably by at least 40%; more preferably by at least 50%; more preferably by at least 60%; relative to predose level.

In a further preferred embodiment of the seventh aspect the t invention is directed to an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/kexin type 9) for use in the treatment of a disease or condition in which PCSK9 expression or activity causes an impact; wherein the antibody or antigen-binding fragment thereof is for administration to a subject who does not fall into one or more of the ing groups of subjects: (i) smokers; (ii) persons being 70 years old or older; (iii) s suffering from hypertension; (iv) women who are pregnant; (v) women who are trying to become pregnant; (vi) women who are breast- feeding; (vii) persons who have or ever had a disease affecting the liver; (viii) persons who had any unexplained abnormal blood tests for liver function; (ix) persons who drink excessive s of alcohol; (x) persons having kidney problems; (xi) persons suffering from yroidism; (xii) persons suffering from muscle ers; (xiii) s having encountered previous ar problems during treatment with lipid-lowering medicine; (xiv) persons having serious problems with their breathing; (xv) persons taking one or more of the ing medicines: medicines altering the way the immune s works (e.g. ciclosporin or antihistamines); antibiotics or antifungal medicines (e.g. erythromycin; clarithromycin; ketoconazole; itraconazole; rifampicin; fusidic acid); nes regulating lipid levels (e. g. gemf1brozil; colestipol); calcium channel blockers (e.g. verapamil; diltiazem); medicines regulating the heart rhythm (digoxin; amiodarone); protease inhibitors used in the treatment of HIV (e. g. nelf1navir); warfarin; oral contraceptives; antacids or St. John’s Wort; or (xvi) persons drinking more than 0.1 L of grapefruit juice per day or eating more than half a grapefruit per day; (xvii) s having a body mass index (BMI) of more than 40; (xviii) persons having a body mass index (BMI) of less than 18; (xix) persons suffering from type 1 diabetes or type 2 diabetes; (xx) persons positive for hepatitis B or hepatitis C; (xxi) persons having a known sensitivity to onal antibody therapeutics; (xxii) persons having a neutrophil concentration of less than 15OO/mm3; (xxiii) persons having a platelet concentration of less than lOOOOO/mm3; (xxiv) men having a serum creatinine level larger than 1.5 x ULN (upper limit of normal); (xxv) women having a serum creatinine level larger than 1.4 x ULN (upper limit of normal); (xxvi) persons having an alanine minase (ALT) level or aspartate transaminase (AST) level larger than 2 x ULN; or (xxvii) persons having a CPK level larger than 3 x ULN.

In preferred embodiments of the seventh aspect; the disease or condition in which PCSK9 expression or activity causes an impact is ameliorated; improved; inhibited or prevented with a PCSK9 antagonist.

In preferred embodiments of the seventh aspect; the disease or condition in which PCSK9 expression or activity causes an impact is ed from the group consisting of: elevated LDL-C levels; hypercholesterolemia; hyperlipidemia; dyslipidemia; sclerosis and cardiovascular diseases; or any other of the diseases and conditions described in the first or second aspect.

In preferred seventh aspect; the antibody or antigen-binding fragment thereof is for stration to a subject ted for LDL apheresis; a subject with PC SK9-activating mutations; a subject with heterozygous Familial Hypercholesterolemia; a subject with primary hypercholesterolemia a subject with primary Familial or primary non-Familial ; e.g. holesterolemia; a t with hypercholesterolemia such as primary hypercholesterolemia who is statin uncontrolled; a subject at risk for developing hypercholesterolemia; a subject with hypercholesterolemia; a subject with hyperlipidemia; a subject with dyslipidemia; a subject with atherosclerosis or a t with cardiovascular es or any other of the subjects as described in the first or second aspect. Most ably; the subject is a human subject.

In preferred embodiments of the seventh aspect; the antibody or antigen-binding fragment thereof is for administration in combination with a dosage of between 0.05 mg to 100 mg of an CoA reductase inhibitor. In some ments; the HIVIG—CoA reductase inhibitor is to be administered three times per day, twice per day, or once per day. In some embodiments, the HIVIG—CoA reductase inhibitor is to be administered every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. In some ments, the HIVIG—CoA reductase inhibitor is to be administered every week, every other week, every third week, or every fourth week. In some embodiments, the CoA ase inhibitor is to be administered in the morning, at noon or in the evening. In preferred embodiments, the HIVIG— CoA reductase inhibitor is to be administered once per day, preferably orally, ably in the evening. Preferably, the HIVIG—CoA reductase inhibitor is a statin. More preferably, the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, atin, and pravastatin. In further preferred embodiment of the sixteenth to eighteenth aspect, the dy or antigen-binding fragment thereof is for administration in combination with a statin, n the statin is — cerivastatin which is to be administered in a daily dosage of between 0.05 mg and 2 mg, preferably in a daily dosage of 0.2 mg, 0.4 mg, or 0.8 mg, — atorvastatin which is to be administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg, — simvastatin which is to be administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg, — pitavastatin which is to be administered in a daily dosage of between 0.2 mg and 100 mg, preferably in a daily dosage of 1 mg, 2 mg, 5 mg, 10 mg, or 20 mg, — rosuvastatin which is to be administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 5 mg, 10 mg, 20 mg, or 40 mg, — fluvastatin which is to be administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 20 mg, 40 mg, or 80 mg, — lovastatin which is to be administered in a daily dosage of n 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg, or — pravastatin which is to be administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg.

In an eight aspect, t invention concerns a method for preparing a ceutical composition of present invention, e. g. a pharmaceutical composition according to the first aspect, comprising miXing the antibody or antigen-binding fragment thereof and optionally the HIVIG— CoA reductase inhibitor with one or more pharmaceutical excipients or carriers.

The skilled person knows how to prepare the compositions of the invention. Moreover, reference is given elsewhere in this specification.

In a ninth aspect, present invention concerns a method for preparing a unit dosage form of present ion (e.g. the fifth aspect) comprising admeasuring an amount of the pharmaceutical composition, of the antibody or antigen-binding nt thereof, of the liquid formulation or of the dry formulation according to present invention comprising one or more doses of the antibody or antigen fragment thereof and optionally of the HIVIG—CoA reductase tor and tailoring them as physically discrete units suitable as unitary s for human and/or animal administration.

In a tenth aspect, present invention ns a method for preparing or ling an article of manufacture of present invention comprising packaging the pharmaceutical composition, of the antibody according, of the liquid formulation, of the dry formulation according or of or more of the unit dosage forms of present ion in a container, optionally together with one or more of the following: a label, instructions for use, an application device (e.g. a syringe).

In an eleventh aspect the present invention is ed to a method for ng a disease or condition in which PCSK9 expression or activity causes an, comprising: stering a therapeutic amount of an antibody or an antigen-binding nt f which specifically binds hPCSK9 (human tein tase subtilisin/kexin type 9) to a subject in need thereof, wherein the antibody or n-binding fragment f is administered in a dosage amount ranging from 5 mg to 500 mg, and administering a therapeutic amount of an HIVIG—CoA reductase tor to said subject, wherein the HIVIG—CoA reductase inhibitor is preferably stered in a dosage amount ranging from 0.05 mg to 100 mg.

In the context of present application, the term “a disease or condition in which PCSK9 expression or activity causes an impact” is understood to comprise any disease or condition in which the application of a PCSK-9 antibody causes an impact.

In preferred embodiments of the eleventh and the other aspects of present invention, the disease or condition in which PCSK9 expression or activity causes an impact is ameliorated, improved, inhibited or prevented with a PCSK9 antagonist.

In further preferred ments of the eleventh and the other aspects of present ion, the disease or condition is selected from the group consisting of: elevated total cholesterol levels, elevated low-density lipoprotein cholesterol (LDL-C) levels, hypercholesterolemia, particularly hypercholesteremia uncontrolled by statins, hyperlipidemia, dyslipidemia, atherosclerosis, cardiovascular diseases, primary hypercholesterolemia, such as primary familial holesterolemia or primary non-familial hypercholesterolemia, hypercholesterolemia (especially primary hypercholesterolemia) uncontrolled by statins (particularly uncontrolled by atorvastatin).

In preferred embodiments of the eleventh and the other aspects of present ion, the subject in need thereof is a subject indicated for LDL apheresis, a subject with PC SK9-activating mutations, a subject with heterozygous Familial Hypercholesterolemia, a subject with primary hypercholesterolemia, a subject with primary holesterolemia who is statin uncontrolled, a subject at risk for developing hypercholesterolemia, a subject with hypercholesterolemia, a t with hyperlipidemia, a subject with dyslipidemia, a subject with atherosclerosis or a subject with cardiovascular diseases. Most preferably, the subject in need thereof is a human subject.

In some embodiments of the eleventh and other aspects of the invention, the HIVIG—CoA reductase tor is administered three times per day, twice per day, or once per day. In some embodiments of the first and the other aspects of present ion, the HIVIG—CoA reductase inhibitor is administered every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. In some embodiments of the first and the other aspects of present invention, the HIVIG—CoA reductase inhibitor is administered every week, every other week, every third week, or every fourth week. In some embodiments of the first and the other aspects of present invention, the HIVIG—CoA reductase inhibitor is administered in the morning, at noon or in the evening. In preferred embodiments, the HIVIG—CoA reductase inhibitor is administered once per day, preferably orally, preferably in the evening.

Preferably, the CoA ase inhibitor is a statin. More preferably, the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin.

In more preferred embodiments of the first and the other aspects of present invention, the statin is — cerivastatin administered in a daily dosage of between 0.05 mg and 2 mg, preferably in a daily dosage of 0.2 mg, 0.4 mg, or 0.8 mg, — atorvastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg, — tatin stered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg, — pitavastatin administered in a daily dosage of between 0.2 mg and 100 mg, preferably in a daily dosage of 1 mg, 2 mg, 5 mg, 10 mg, or 20 mg, — rosuvastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 5 mg, 10 mg, 20 mg, or 40 mg, — atin administered in a daily dosage of n 2 mg and 100 mg, preferably in a daily dosage of 20 mg, 40 mg, or 80 mg, — lovastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg, or — pravastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg.

In preferred embodiments of the eleventh and the other aspects of t invention, the antibody or antigen-binding fragment thereof is administered to the subject every other week, every fourth week or once a month. Administration every fourth week or administration once a month (i.e. once per calendar month, e. g. every first, second etc. day of the month or every first, second third Monday, y etc. each month, in contrast to administration every fourth week) is preferred in view of patient compliance. Administration every other week is preferred in view of a very low variation of blood cholesterol . Other le time schedules for administration of the antibody or antigen-binding fragment thereof e without limitation an administration once per day, every other day, every third day, every fourth day, every fifth day, every sixth day, every week, every third week, every fifth week, every sixth week, every eighth week, every tenth week, and every twelfth week.

In preferred embodiments of the th and the other aspects of present invention, the antibody or antigen-binding fragment thereof is administered in a dosage amount ranging e. g. from about 40 mg to about 500 mg, from about 50 mg to about 500mg, from about 50mg to 300mg or from about 100mg to 200mg. In more preferred embodiments, the antibody or antigen- binding fragment thereof is administered in a dosage amount of about 50 mg, of about 100 mg, of about 150 mg, of about 200 mg, of about 250 mg, of about 300 mg, of about 350mg, of about 400 mg, of about 450 mg or of about 500 mg. Doses of about 50 to about 200 mg, e.g. of about 50 mg, about 100 mg, about 150 mg or about 200 mg are especially suitable for a biweekly dosage regimen (i.e. the application every other week), doses of about 150 mg to about 400 mg, e.g. about 150 mg, about 200 mg, about 250 mg, about 300 mg about 350 mg or about 400 mg are especially suitable for an administration regime with longer intervals, e. g. an administration every third or every fourth week or once a month.

Antibodies and n-binding fragments f that can be used for practicing the first and the other aspects of the present invention are described in the section rredAntibodiesfor Practicing the Present Invention ” or in the fourth aspect and its embodiments.

In a twelfth aspect the present invention is directed to a method of testing the efficacy of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 for the treatment of a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases or any of the other conditions or diseases according to the first or second aspect of present invention, said method comprising: treating a selected patient population with said antibody or antigen-binding fragment thereof, wherein each patient in said population has an LDL cholesterol (LDL-C) level of more than lOOmg/dL, and determining the efficacy of said antibody or antigen-binding fragment thereof by determining the LDL-C level in the t population before and after administration of said dy or antigen-binding fragment thereof, wherein a reduction of the LDL-C level by at least % relative to a predose level in at least 75% of the t population indicates that said antibody or antigen-binding nt thereof is ious for the treatment of said disease or condition in said patient population.

In a thirteenth aspect the present ion is directed to a method of g the efficacy of an antibody or an antigen-binding fragment f which cally binds hPCSK9 for the treatment of a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases or any of the other conditions or diseases according to the first or second aspect of t invention, said method comprising: determining the efficacy of an antibody or antigen-binding fragment thereof that has been used for the treatment of a selected patient population with said antibody or antigen-binding fragment thereof, wherein each patient in said population has an LDL cholesterol (LDL-C) level of more than dL by ining the LDL-C level in the patient population before and after administration of said antibody or antigen-binding fragment thereof, wherein a reduction of the LDL-C level by at least 25% relative to a predose level in at least 75% of the patient population indicates that said antibody or antigen-binding fragment thereof is efficacious for the treatment of said disease or condition in said patient population.

In preferred embodiments of the twelfth and thirteenth aspect, each patient in said population has received a lipid lowering treatment by administration of an HIVIG CoA-Inhibitor, such as a statin for at least 6 weeks prior to treatment with said antibody or antigen-binding fragment f.

In preferred embodiments of the twelfth and thirteenth aspect, the antibody or antigen- binding fragment is an dy or antigen-binding fragment as specified below in the section rredAntibodiesfor Practicing the t Invention 1O In preferred embodiments of the h and thirteenth aspect, the selected patient population is treated with a method of treatment according to the first aspect and the embodiments of the first or second aspect as described herein.

In a enth aspect the present invention is directed to a package comprising an antibody or antigen-binding fragment thereof which specifically binds hPCSK9 of the invention and a label.

According to one embodiment the label is a data r containing one or more of the following: a printed statement, a chip or a bar code.

According to a preferred embodiment of the fourteenth aspect, the label comprises or is a data carrier (e. g. a d statement, chip or bar code) which informs the t that the treatment of the antibody together with an HIVIG—CoA reductase inhibitor such as a statin is indicated in one or more of the indications selected from the group consisting of hypercholesterolemia, hyperlipidemia, idemia, atherosclerosis and cardiovascular diseases or any of the other conditions or diseases according to the first or second aspect of present invention. Antibodies and antigen-binding nts f that can be used for practicing the eighth aspect of the present invention are described in the section “PreferredAntibodiesfor Practicing the Present Invention According to another preferred embodiment, said the label comprises or is a data carrier (e. g. a printed statement, chip or bar code) which informs the patient that the treatment of the antibody together with a statin is contraindicated for patients belonging to one or more of the following groups: (i) smokers; (ii) persons being 70 years old or older; (iii) s suffering from hypertension; (iv) women who are pregnant; (V) women who are trying to become pregnant; (vi) women who are breast-feeding; (vii) persons who have or ever had a disease affecting the liver; (viii) persons who had any unexplained al blood tests for liver function; (ix) persons who drink excessive amounts of alcohol; (X) persons having kidney problems; (xi) persons ing from hypothyroidism; (xii) persons suffering from muscle 1O disorders; (xiii) s having encountered previous muscular problems during treatment with lipid-lowering ne; (xiv) persons having serious problems with their breathing; (xv) persons taking one or more of the following medicines: medicines altering the way the immune systems works (e.g. ciclosporin or antihistamines); antibiotics or antifungal medicines (e.g. erythromycin; clarithromycin; ketoconazole; itraconazole; rifampicin; fusidic acid); nes regulating lipid levels (e. g. gemf1brozil; colestipol); m channel blockers (e. g. verapamil; diltiazem); medicines regulating the heart rhythm (digoxin; amiodarone); protease inhibitors used in the treatment of HIV (e.g. nelf1navir); warfarin; oral ceptives; antacids or St. John’s Wort; or (xvi) persons drinking more than 0.1 L of grapefruit juice per day or eating more than half a grapefruit per day; (xvii) s having a body mass index (BMI) of more than 40; (xviii) s having a body mass index (BMI) of less than 18; (xix) persons suffering from type 1 diabetes or type 2 diabetes; (xx) s positive for hepatitis B or hepatitis C; (xxi) persons having a known sensitivity to monoclonal antibody therapeutics; (xxii) persons having a neutrophil concentration of less than 15OO/mm3; (xxiii) persons having a platelet concentration of less than lOOOOO/mm3; (xxiv) men having a serum creatinine level larger than 1.5 x ULN (upper limit of normal); (xxv) women having a serum creatinine level larger than 1.4 x ULN (upper limit of normal); (xxvi) persons having an alanine transaminase (ALT) level or ate transaminase (AST) level larger than 2 x ULN; or (xxvii) persons having a CPK level larger than 3 x ULN. Antibodies and n-binding fragments thereof that can be used for practicing the fourteenth aspect of the present invention are described in the section “Preferred Antibodiesfor Practicing the Present Invention In a f1fteenth aspect the present ion is directed to a method of regulating the LDL level in the blood comprising: administering a therapeutic amount of an antibody or an n-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/kexin type 9) to a subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered in a dosage amount ranging from 5 mg to 500 mg, and administering a therapeutic amount of an HIVIG—CoA ase inhibitor to said subject, n the HIVIG—CoA reductase inhibitor is administered in a dosage amount ranging from 0.05 mg to 100 mg.

In a sixteenth aspect the present invention is directed to a method of preventing effects of a (persistently) increased LDL level in the blood comprising: administering a therapeutic amount of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human tein convertase subtilisin/kexin type 9) to a subject in need thereof, wherein the dy or antigen-binding fragment thereof is administered in a dosage amount ranging from 5 mg to 500 mg, and administering a therapeutic amount of an HIVIG—CoA reductase inhibitor to said subject, wherein the HIVIG—CoA reductase inhibitor is stered in a dosage amount ranging from 0.05 mg to 100 mg.

In preferred embodiments of the fifteenth and sixteenth aspect, the disease or ion in which PCSK9 expression or activity causes an impact is ameliorated, improved, inhibited or prevented with a PCSK9 antagonist. In further preferred ments of the tenth and eleventh aspect, the disease or condition in which PCSK9 expression or activity causes an impact is selected from the group ting of: elevated LDL-C levels, hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases or any of the other ions or diseases ing to the eleventh, eighteenth or nineteenth aspect of present invention.

In preferred embodiments of the fifteenth and sixteenth aspect, the subject in need thereof is a subject ted for LDL apheresis, a subject with PCSK9-activating mutations, a subject with heterozygous Familial Hypercholesterolemia, a subject with primary hypercholesterolemia who is statin uncontrolled, a t at risk for developing hypercholesterolemia, a subject with hypercholesterolemia, a subject with hyperlipidemia, a subject with dyslipidemia, a subject with atherosclerosis or a subject with cardiovascular diseases or any of the subjects as described in the th, enth or nineteenth aspect of present invention. Most preferably, the t in need thereof is a human subject.

In some embodiments of the fifteenth and sixteenth aspect, the HIVIG—CoA reductase tor is administered three times per day, twice per day, or once per day. In some ments, the HIVIG—CoA reductase inhibitor is administered every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. In some embodiments, the HIVIG—CoA reductase inhibitor is administered every week, every other week, every third week,every fourth week, or every month. In some embodiments, the HIVIG—CoA ase 1O inhibitor is administered in the morning, at noon or in the evening. In red embodiments, the HIVIG—CoA reductase inhibitor is administered once per day, preferably orally, preferably in the evening. Further suitable stration regimes are described in the first or second aspect.

In further preferred embodiments of the fifteenth and sixteenth aspect, the HIVIG—CoA reductase inhibitor is a statin. More preferably, the statin is selected from the group consisting of cerivastatin, atorvastatin, tatin, pitavastatin, rosuvastatin, fiuvastatin, lovastatin, and pravastatin.

In more preferred embodiments of the tenth and eleventh aspect, the statin is — cerivastatin administered in a daily dosage of between 0.05 mg and 2 mg, preferably in a daily dosage of 0.2 mg, 0.4 mg, or 0.8 mg, — atorvastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg, — simvastatin administered in a daily dosage of between 2 mg and 100 mg, ably in a daily dosage of 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg, — pitavastatin administered in a daily dosage of between 0.2 mg and 100 mg, preferably in a daily dosage of 1 mg, 2 mg, 5 mg, 10 mg, or 20 mg, — rosuvastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 5 mg, 10 mg, 20 mg, or 40 mg, — fluvastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 20 mg, 40 mg, or 80 mg, — lovastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg, or — pravastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg.

In further red embodiments of the fifteenth and sixteenth aspect, the antibody or antigen-binding fragment thereof is administered to the subject every other week, every fourth week or once a month. Administration every fourth week or every month is preferred in view of t compliance. Administration every other week is preferred in view of a very low variation of blood cholesterol levels. Other suitable time schedules for administration of the antibody or antigen-binding fragment thereof include without limitation an administration once per day, every other day, every third day, every fourth day, every fifth day, every sixth day, every week, every third week, every fifth week, every sixth week, every eighth week, every tenth week, and every twelfth week.

In preferred embodiments of the th and sixteenth aspect, the dy or antigen- binding fragment thereof is administered in a dosage amount ranging from 50mg to 300mg, e. g. from 100mg to 200mg. In more preferred embodiments, the dy or antigen-binding fragment thereof is stered in a dosage amount of about 50 mg, of about 100 mg, of about 150 mg, of about 200 mg, or of about 300 mg. Further le and preferred dosage regimens are described elsewhere in this specification, e. g. in the eleventh aspect.

Antibodies and antigen-binding nts thereof that can be used for practicing the tenth and eleventh aspect of the present invention are bed in the section “Preferred Antibodiesfor Practicing the Present Invention In a seventeenth aspect the present invention is directed to a method of determining whether a pharmaceutical compound is utilizable for ameliorating, improving, ting or preventing a disease or condition in which PCSK9 activity or expression has an impact comprising: (a) administering to a subject a compound that cally binds to PCSK9, preferably an antibody or antigen-binding fragment thereof cally binding to PCSK9, and (b) determining what fraction of PCSK9 in the blood is attached to the compound from (a). lly, compounds that specifically bind from 10% to 100% (preferably from 20% to 100%, more preferably from 30% to 100%, more preferably from 40% to 100%, more preferably from 50% to 100%) of the PCSK9 present in the blood when used in stoichiometric amounts, will be utilizable for ameliorating, improving, inhibiting or preventing a disease or condition in which PCSK9 activity or expression has an impact.

Preferably, the e or condition in which PCSK9 expression or activity has an impact is selected from the group consisting of: elevated LDL-C levels, hypercholesterolemia, hyperlipidemia, dyslipidemia, sclerosis and cardiovascular diseases or any of the other diseases described herein, such as in the eleventh aspect.

Antibodies and antigen-binding nts thereof that can be used for practicing the twelfth aspect of the present invention are described in the section “PreferredAntibodiesfor Practicing the Present Invention In an eighteenth aspect the t invention is directed to a method for treating a disease or ion in which PCSK9 expression or ty causes an impact comprising administering a therapeutic amount of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/kexin type 9) to a subject in need thereof, wherein the subject in need thereof falls into one or more of the following groups of subjects: (i) subjects having a serum LDL cholesterol (LDL-C) level of at least 100 mg/dL, preferably at least 130 mg/dL, more ably at least 160 mg/dL, even more preferably at least 200 mg/dL, (ii) subjects having a serum HDL-C level of less than 40 mg/dL, (iii) subjects having a serum cholesterol level of at least 200 mg/dL, preferably at least 240 mg/dL, (iv) subjects having a serum triacylglycerol level of at least 150 mg/dL, e.g. at least 200 mg/dL or at least 500 mg/dL, wherein said triacylglycerol level is determined after fasting for at least 8 hours; (V) ts being at least 35 years old, e.g. at least 40 years old, at least 45 years old, at least 50 years old, at least 55 years old, at least 60 years old, at least 65 years old, or at least 75 years old, (vi) subjects younger than 75 years, e.g. younger than 70 years, younger than 65 years, r than 60 years, younger than 55 years, younger than 50 years, younger than 45 years, or younger than 40 years, (vii) subjects having a BMI of 25 or more (e.g. 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more, 32 or more, 33 or more, 34 or more, 35 or more, 36 or more, 37 or more, 38 or more, or 39 or more), (viii) male subjects, (ix) female subjects, (X) subjects in which the administration of said antibody or antigen-binding fragment thereof leads to a reduction in the serum LDL-C level by at least 30 mg/dL, preferably by at least 40 mg/dL, more preferably by at least 50 mg/dL, more preferably by at least 60 mg/dL, more preferably by at least 70 mg/dL, relative to predose level, or (xi) subjects in which the administration of said antibody or antigen-binding fragment thereof leads to a reduction in the serum LDL-C level by at least 20%, preferably by at least 30%, more preferably by at least 40%, more preferably by at least 50%, more preferably by at least 60%, relative to predose level.

In a nineteenth aspect the present invention is directed to a method for treating a disease or ion in which PCSK9 sion or activity causes an impact comprising administering a therapeutic amount of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/kexin type 9) to a subject in need thereof, wherein the subject in need thereof does not fall into one or more of the following groups of subjects: (i) smokers, (ii) persons being 70 years old or older, (iii) persons suffering from hypertension, (iv) women who are pregnant, (v) women who are trying to become pregnant, (vi) women who are -feeding, (vii) persons who have or ever had a disease affecting the liver, (viii) persons who had any unexplained al blood tests for liver function, (ix) persons who drink excessive amounts of alcohol, (x) s having kidney problems, (xi) persons suffering from hypothyroidism, (xii) persons ing from muscle disorders, (xiii) persons having encountered previous ar problems during treatment with lipid- lowering medicine, (xiv) persons having serious problems with their breathing, (xv) persons taking one or more of the following medicines: medicines altering the way the immune systems works (e. g. ciclosporin or stamines), antibiotics or antifungal medicines (e. g. erythromycin, clarithromycin, nazole, itraconazole, rifampicin, c acid), medicines regulating lipid levels (e.g. gemf1brozil; ipol); m channel rs (e.g. verapamil; diltiazem); medicines regulating the heart rhythm (digoxin; amiodarone); protease inhibitors used in the treatment ofHIV (e.g. nelf1navir); warfarin; oral contraceptives, antacids or St. John’s Wort; or (xvi) persons ng more than 0.1 L of grapefruit juice per day or eating more than half a grapefruit per day; (xvii) persons having a body mass index (BMI) of more than 40; (xviii) persons having a body mass index (BMI) of less than 18; (xix) persons suffering from type 1 diabetes or type 2 diabetes; (xx) persons positive for hepatitis B or hepatitis C; (xxi) persons having a known sensitivity to monoclonal antibody therapeutics; (xxii) persons having a neutrophil concentration of less than 1500/mm3; (xxiii) persons having a platelet concentration of less than lOOOOO/mm3; (xxiv) men having a serum creatinine level larger than 1.5 x ULN (upper limit of normal); (xxv) women having a serum creatinine level larger than 1.4 x ULN (upper limit of normal); (xxvi) persons having an alanine transaminase (ALT) level or aspartate transaminase (AST) level larger than 2 x ULN; or (xxvii) s having a CPK level larger than 3 x ULN.

In preferred embodiments of the eighteenth and nineteenth aspect; the disease or condition in which PCSK9 expression or activity causes an impact is ameliorated; improved; inhibited or ted with a PCSK9 antagonist.

In preferred embodiments of the thirteenth and the fourteenth aspect; the disease or condition in which PCSK9 expression or activity causes an impact is selected from the group consisting of: ed LDL-C levels; hypercholesterolemia; hyperlipidemia; dyslipidemia; sclerosis and cardiovascular diseases or any of the other diseases or conditions described in the other aspects of present invention; such as the eleventh aspect.

In preferred embodiments of the thirteenth and the fourteenth aspect; the subject in need thereof is a subject indicated for LDL apheresis; a subject with PCSK9-activating mutations; a subject with heterozygous al Hypercholesterolemia; a subject with y hypercholesterolemia; e.g. a subject with primary Familial or primary non-Familial Hypercholesterolemia; a subject with hypercholesterolemia such as primary hypercholesterolemia who is statin uncontrolled; a subject at risk for ping hypercholesterolemia; a t with hypercholesterolemia; a t with hyperlipidemia; a subject with dyslipidemia; a subject with atherosclerosis or a subject with cardiovascular diseases; or any of the other subjects described in the first or second aspects. Most preferably; the t in need f is a human subject. Further preferred or suitable subjects are described at the other aspects of present invention such as the eighteenth or nineteenth aspect.

Antibodies and antigen-binding fragments thereof that can be used for practicing the enth and fourteenth aspect and the other s of the present ion are described in the section “PreferredAntibodiesfor Practicing the Present Invention In preferred embodiments of the enth and nineteenth aspect, the method further comprises: administering a therapeutic amount of an HIVIG—CoA reductase inhibitor to the subject in a dosage of between 0.05 mg to 100 mg. In some embodiments, the HIVIG—CoA reductase inhibitor is administered three times per day, twice per day, or once per day. In some embodiments, the HIVIG—CoA reductase inhibitor is administered every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. In some embodiments, the HIVIG—CoA reductase tor is administered every week, every other week, every third week, or every fourth week. In some embodiments, the HIVIG—CoA reductase inhibitor is administered in the morning, at noon or in the evening. In preferred embodiments, the HIVIG—CoA reductase inhibitor is administered once per day, preferably orally, ably in the evening. Preferably, the HIVIG—CoA reductase tor is a statin. More preferably, the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, statin, rosuvastatin, fluvastatin, lovastatin, and pravastatin. In further preferred embodiment of the thirteenth and the fourteenth aspect, the method comprises administering a therapeutic amount of a statin to the subject, wherein the statin is: — cerivastatin administered in a daily dosage of between 0.05 mg and 2 mg, ably in a daily dosage of 0.2 mg, 0.4 mg, or 0.8 mg, — atorvastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 10 mg, 20 mg, 40 mg, or 80 mg, — simvastatin administered in a daily dosage of between 2 mg and 100 mg, preferably in a daily dosage of 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg, — pitavastatin administered in a daily dosage of between 0.2 mg and 100 mg, preferably in a daily dosage of 1 mg, 2 mg, 5 mg, 10 mg, or 20 mg, — rosuvastatin administered in a daily dosage of between 2 mg and 100 mg; ably in a daily dosage of 5 mg; 10 mg; 20 mg; or 40 mg; — fluvastatin administered in a daily dosage of n 2 mg and 100 mg; preferably in a daily dosage of 20 mg; 40 mg; or 80 mg; — lovastatin administered in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of 10 mg; 20 mg; 40 mg; or 80 mg; or — pravastatin administered in a daily dosage of between 2 mg and 100 mg; preferably in a daily dosage of 10 mg; 20 mg; 40 mg; or 80 mg.

A further preferred embodiment of the t invention combines the features of the eighteenth and nineteenth aspect as described herein.

In a twentieth aspect the present invention is ed to a method of testing the efficacy of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 for the treatment of a disease or condition ed from the group consisting of elevated LDL-C levels; hypercholesterolemia; hyperlipidemia; dyslipidemia; atherosclerosis and cardiovascular diseases; or any other disease or condition described in the first or second aspect; said method comprising: treating a selected patient population with said antibody or antigen-binding fragment f; wherein each patient in said population has an LDL cholesterol (LDL-C) level of more than lOOmg/dL; and determining the efficacy of said antibody or n-binding fragment thereof by determining the LDL-C level in the t population before and after administration of said antibody or antigen-binding fragment thereof; wherein a reduction of the LDL-C level by at least % relative to a predose level in at least 75% of the patient population indicates that said antibody or antigen-binding fragment thereof is efficacious for the treatment of said e or condition in said patient population; wherein each patient falls into one or more groups of subjects as recited in the thirteenth aspect.

In a twentyfirst aspect the present invention is directed to a method of testing the efficacy of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 for the treatment of a e or ion selected from the group consisting of elevated LDL-C levels, hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases (or any other method as described in the first or second aspect), said method comprising: ining the efficacy of an antibody or antigen-binding fragment thereof that has been used for the treatment of a selected patient tion with said antibody or antigen-binding fragment thereof, wherein each patient in said population has an LDL cholesterol ) level of more than lOOmg/dL by determining the LDL-C level in the patient population before and after administration of said dy or antigen-binding fragment thereof, wherein a reduction of the LDL-C level by at least 25% relative to a predose level in at least 75% of the patient population indicates that said antibody or antigen-binding fragment thereof is efficacious for the treatment of said disease or condition in said patient population, wherein each patient falls into one or more groups of subjects as d in the thirteenth aspect.

In preferred ments of the 20th and 21St aspect, each patient in said population has received a lipid lowering treatment by administration of an HIVIG—CoA reductase inhibitor such as a statin for at least 6 weeks prior to treatment with said antibody or antigen-binding nt thereof.

Antibodies and antigen-binding fragments thereof that can be used for practicing the nineteenth and twentieth aspect of the present invention are described in the section “Preferred Antibodiesfor Practicing the Present Invention ” or the other section of present application describing dies of present invention, such as e.g. the fourth aspect.

In preferred ments of the 20th and 21St aspect, the selected patient tion is or has been treated with a method of treatment according to the eleventh, eighteenth or nineteenth aspect and the ments thereof as described herein.

In further preferred embodiments of the 20th and 21St aspect, the efficacy of said antibody or said n-binding fragment thereof is determined for sub-groups of said selected patient population, n said sub-groups have been stratified by at least one stratification factor selected from the group consisting of: tion with heterozygous familial hypercholesterolemia (heFH), prior history of myocardial infarction (MI), prior history of stroke; receiving high-intensity statin therapy; and geographical region of the patient (e.g. North America, Western Europe, Eastern Europe, and rest of the world).

In hamsters and other rodents statins are not effective on LDL clearance from blood.

More specifically, the administration of statins alone (e.g. atorvastatin) has no effect on the sion of the LDL receptor (LDLR) in hamsters or other rodents, presumably due to the activity of the endogenous PCSK9. The experiments contained in the present ation (see study 4) show that tion of PCSK9 by administration of an anti-PCSK9 dy renders rodents (e.g. hamsters) ive to statin treatment. Accordingly, the present application provides a new animal model for testing the efficacy of statins or other drugs that lower cholesterol levels.

Thus, in a twentysecond aspect the present invention is directed to a method for testing the efficacy of a compound in lowering cholesterol levels in a t, sing the steps: (a) ing a rodent, (b) administering an antibody or an antigen-binding fragment thereof which specifically binds PCSK9 to the rodent, (c) administering a test compound to said rodent, (d) determining the effect of the test compound in the rodent, wherein a lowering of the cholesterol level in the rodent as ed to the cholesterol level of a control animal indicates that the test compound is efficacious in lowering cholesterol levels in a subject, wherein the control animal is from the same species as said rodent, and wherein the control animal has not been challenged with the test compound.

In preferred embodiments of the 22nd aspect, the rodent is selected from the group consisting of hamster, mouse, rat, guinea pig, and .

Antibodies and antigen-binding nts thereof that can be used for practicing the 22nd aspect of the present invention are described the other sections of present application such as the fourth aspect of in the section “PreferredAntibodiesfor cing the Present Invention Preferably, the antibody or antigen-binding fragment thereof is administered to the rodent in a concentration of 1 mg/kg body weight, 3 mg/kg body weight, or 10 mg/kg body weight.

In preferred embodiments of the 22nd , the ng of the cholesterol level is determined by measuring the level of total cholesterol in the serum. In more preferred embodiments, the lowering of the cholesterol level is determined by measuring the level of LDL cholesterol (LDL-C) in the serum.

In preferred embodiments of the 22nd aspect, the control animal is from the same strain as the rodent. Preferably, the same antibody or antigen-binding fragment thereof is administered to the rodent and to the control animal. Preferably, the same concentration (measured in mg/kg body weight) of the antibody or antigen-binding fragment thereof is administered to the rodent and to the control animal.

In one embodiment of the 22nd , the control animal is a different animal, i.e. a different individual, than the rodent. It is also possible to determine the cholesterol level in two or more control animals and to calculate the mean value of the cholesterol level in these two or more control animals. Likewise, it is possible to challenge two or more s with the dy or antigen-binding nt thereof, to determine the cholesterol level in these two or more rodents and to ate the mean value of the cholesterol level in these two or more rodents.

In an alternative embodiment of the 22nd aspect, the control animal is the very same animal as the rodent but it is ed at a different time-point. More specifically, the cholesterol level in the rodent after administration of the test compound can be compared to a pre-dose cholesterol level in the same animal. Preferably, said pre-dose cholesterol level is determined between steps (b) and (c) recited above. ing to a twentythird aspect, present invention concerns a method of enhancing the LDL-C lowering activity in a subject undergoing statin therapy, the method comprising administering to the subject an antibody, or antigen-binding fragment thereof, which cally binds to human tein convertase subtilisin/keXin type 9 (hPC 8K9), wherein the antibody or antigen-binding fragment thereof is administered at a dosage amount within the range of about 5 mg to about 500 mg, y enhancing LCL-C lowering activity of the statin therapy in the subject. ing to a preferred embodiment of the 23rd aspect, the subject is ant to the statin therapy prior to administration of the antibody. ing to another red embodiment, the subject suffers from a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, and atherosclerosis.

According to another preferred embodiment, the disease condition is primary hypercholesterolemia or al hypercholesterolemia.

According to another preferred embodiment, the antibody or antigen-binding fragment is administered in a dosage amount within the range of about 50 mg to about 300 mg. ing to another preferred embodiment, the antibody or antigen-binding fragment is administered in a dosage amount of about 150 mg.

According to another preferred embodiment, the antibody or antigen-binding fragment thereof is administered to the subject every other week (EZW).

According to another preferred ment, the antibody or antigen-binding nt thereof is administered to the subject every fourth week (E4W).

According to another preferred embodiment, the treatment reduces serum total cholesterol at least about 25% to about 35% relative to a predose level and sustains the reduction over at least a 24 day period.

According to another preferred embodiment, the ent reduces serum total cholesterol at least about 65% to about 80% relative to a predose level and sustains the ion over at least a 24 day period.

According to another preferred embodiment, the treatment reduces serum triglyeride levels at least about 25% to about 40% relative to a predose level.

According to another preferred embodiment, the treatment reduced serum HDL cholesterol no more than 5% relative to a predose level.

According to another preferred embodiment, the treatment has little or no measurable effect on liver function, as determined by ALT and AST measurements.

According to another preferred embodiment, the antibody or the antigen-binding fragment comprises lthe heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

According to another preferred embodiment, the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. ing to another preferred embodiment, the antibody or antigen-binding fragment thereof es for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid ce pair as shown in SEQ ID NOs: 90/92.

According to another preferred embodiment, the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin. ing to another red embodiment, the statin is atorvastatin administered at a dosage of 10 mg, 20mg, 40 mg or 80 mg.

In a twentyfourth aspect, present invention concerns a kit for treating elevated low- y lipoprotein cholesterol (LDL-C) levels in a subject, the kit comprising (a) pharmaceutical unit dosage form comprising an antibody, or antigen-binding fragment thereof, which specifically binds to hPCSK9, and pharmaceutically acceptable carrier, n the antibody or antigen-binding fragment is present in a dosage amount within the range of about 5 mg to about 500 mg, and (b) a label or packaging insert with ctions for use.

According to a preferred embodiment of the 24th aspect, the label tes that patients receiving treatment with said antibody or n-binding fragment can be treated for a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, idemia, and atherosclerosis and cardiovascular diseases.

According to another preferred embodiment, the disease or condition is primary holesterolemia or familial hypercholesterolemia. According to another preferred embodiment, the e or condition is hypercholesterolemia which is uncontrolled by statins.

According to another preferred embodiment, the dy or antigen-binding fragment is present in dosage amount within the range of about 50 mg to about 300 mg. According to another preferred embodiment, the antibody or antigen-binding fragment is present in a dosage amount of about 150 mg.

According to another preferred embodiment, the label or packaging insert indicates that the antibody or n-binding fragment thereof is administered to the subject every other week (E2W).

According to another preferred ment, the label or packaging insert indicates that the antibody or antigen-binding fragment thereof is administered to the subject every fourth 1O week (E4W).

According to another preferred embodiment, the dy or the n-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92 According to another preferred embodiment, the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

According to another preferred embodiment, the antibody or n-binding fragment thereof competes for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid ce pair as shown in SEQ ID NOs: 90/92.

According to r preferred embodiment, the kit further comprises an HIVIG—CoA reductase inhibitor. According to r preferred embodiment, the inhibitor is in a dosage amount in the range of about 0.05 mg to 100 mg. According to another red embodiment, the HIVIG—CoA reductase inhibitor is a statin. According to r preferred embodiment, the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, statin, fluvastatin, lovastatin, and pravastatin.

According to another preferred embodiment, the instructions indicate that the statin is atorvastatin administered at a dosage of 10 mg, 20 mg, 40 mg or 80 mg.

According to another preferred embodiment, the instructions indicate that treatment with the antibody or an is contraindicated for patients belonging to one or more of the following groups: (0 smokers; (ii) persons being 70 years old or older; (iii) persons suffering from hypertension; (iV) women who are pregnant; women who are trying to become pregnant; (vi) women who are breast-feeding; (vii) persons who have or ever had a disease affecting the liver; (viii) persons who had any unexplained abnormal blood tests for liver function; (iX) persons who drink excessive amounts of alcohol; (X) persons having kidney problems; (xi) persons suffering from yroidism; (xii) persons suffering from muscle disorders; (xiii) persons having encountered previous muscular ms during treatment with lowering medicine; (xiv) s having serious problems with their breathing; (XV) s taking one or more of the following medicines: medicines ng the way the immune systems works (e.g. ciclosporin or antihistamines); antibiotics or antifungal medicines (e.g. erythromycin; clarithromycin; ketoconazole; itraconazole; rifampicin; fusidic acid); nes regulating lipid levels (e.g. gemf1brozil; colestipol); calcium channel blockers (e.g. verapamil; diltiazem); medicines regulating the heart rhythm (digoxin; amiodarone); se inhibitors used in the treatment of HIV (e.g. nelf1navir); warfarin; oral contraceptives, antacids or St. John’s Wort; or (xvi) persons drinking more than 0.1 L of grapefruit juice per day; (xvii) persons having a body mass index (BMI) of more than 40; (xviii) s having a body mass index (BMI) of less than 18; (xix) persons ing from type 1 es or type 2 diabetes; (xx) persons positive for hepatitis B or hepatitis C; or (xxi) persons having a known ivity to monoclonal antibody therapeutics.

In a twentyf1fth aspect; present invention concerns a method of treating a subject suffering from a disease or disorder characterized by elevated low-density lipoprotein terol (LDL-C) levels; the method comprising: (a) selecting a subject with a blood LDL-C level greater than 100 mg/dL; and (b) administering to said subject a composition comprising an antibody or antigen binding fragment thereof that specifically binds to human proprotein convertase subtilisin/kexin type 9 (hPC SK9); y lowering cholesterol levels in the subject in need thereof.

According to a preferred ment; the disease or condition is ed from the group consisting of: hypercholesterolemia; ipidemia; dyslipidemia; and atherosclerosis.

According to another preferred embodiment; the disease condition is primary hypercholesterolemia or familial hypercholesterolemia.

According to another preferred embodiment; the disease or condition is hypercholesterolemia which is uncontrolled by statins.

According to another preferred embodiment; the t has a body mass index (BMI) of less than 18 kg/m2 or greater than 40 kg/mz.

According to another preferred ment; subject was not previously instructed to partake in a cholesterol-lowering diet.

According to another preferred embodiment; the subject has not previously taken a cholesterol-lowering drug except for atorvastatin.

According to another red embodiment, the atorvastatin was administered at about mg per day.

According to another preferred embodiment, cholesterol-lowering drug is selected from the group consisting of f1brates, bile acid resins, niacin, intestinal cholesterol absorption (ICA) rs, and omega-3 fatty acids. According to another preferred embodiment, the niacin is administered at greater than 500 mg per day. According to r preferred embodiment, the omega-3 fatty acids are administered at r than 1000 mg per day.

According to another preferred embodiment, the subject does not suffer from diabetes.

According to r preferred embodiment, the diabetes is type 1 diabetes. According to another red embodiment, the diabetes is type 2 diabetes. According to another preferred embodiment, the type 2 diabetes is treated with insulin.

According to another preferred embodiment, the subject has a blood ed hemoglobin concentration greater than or equal to 8.5%.

According to r preferred embodiment, the subject is negative for hepatitis B and C surface antigen.

According to another preferred ment, the subject has a blood triglycerides tration of greater than 350 mg/dL.

According to r preferred ment, the subject has fewer than 1500 neutrophils per cubic mm of blood.

According to another preferred embodiment, the subject has fewer than 100,000 platelets per cubic mm of blood.

According to another preferred embodiment, the subject is female.

According to another red embodiment, the subject is not pregnant.

According to another preferred embodiment, the subject has a blood thyroid stimulating hormone concentration that is above the lower limit of normal and below the upper limit of normal.

According to another preferred embodiment, the subject has serum creatine of less than 1.4 of the upper limit of normal.

According to another preferred embodiment, the subject is a male.

According to another preferred embodiment, the subject has serum creatine of less than 1.5 of the upper limit of normal.

According to another preferred embodiment, the subject has an amount of aspartate transaminase that is less than two times the upper limit of normal. ing to another preferred embodiment, the subject has an amount of alanine transaminase that is less than two times the upper limit of normal.

According to another preferred embodiment, the antibody or antigen-binding fragment is administered in a dosage amount within the range of about 5 mg to about 500 mg.

According to another preferred embodiment, the antibody or antigen-binding fragment is administered in a dosage amount within the range of about 50 mg to about 300 mg.

According to another preferred embodiment, the antibody is administered at between 200 and 300 mg every four weeks.

According to another preferred embodiment, the antibody or antigen-binding fragment is administered in a dosage amount of about 150 mg.

According to another preferred embodiment, the antibody or n-binding fragment thereof is administered to the subject every other week (E2W).

According to r preferred embodiment, the antibody or antigen-binding fragment thereof is administered to the subject every fourth week (E4W). ing to another preferred embodiment, the antibody or the antigen-binding fragment comprises the heavy and light chain CDRs of a CVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

According to another preferred embodiment, the antibody or antigen-binding fragment ses a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. ing to another preferred embodiment, the antibody or antigen-binding fragment thereof competes for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

According to another preferred embodiment, the antibody is stered subcutaneously.

According to another preferred embodiment, the antibody is administered in the abdomen.

According to another preferred embodiment, an CoA ase tor is administered to the t.

According to another preferred embodiment, the HIVIG—CoA reductase tor is administered in a dosage amount in the range of about 0.05 mg to 100 mg.

According to another preferred embodiment, the HIVIG—CoA ase inhibitor is a statin.

According to another preferred embodiment, the statin is ed from the group ting of cerivastatin, atorvastatin, simvastatin, statin, rosuvastatin, fluvastatin, lovastatin, and pravastatin.

According to another preferred embodiment, the statin is atorvastatin administered at a dosage of 10 mg or 80 mg.

According to another preferred embodiment, the atorvastatin is stered at about 10 mg per day and at 80 mg one day in an 8 week period.

In a sixth aspect, present invention concerns a method of lowering cholesterol levels in a t in need thereof, comprising: (a) selecting a t with a blood low density lipoprotein cholesterol (LDL-C) level greater than 100 mg/dL, and (b) administering to said subject a ition comprising an antibody or antigen binding fragment thereof that specifically binds to human proprotein convertase subtilisin/keXin type 9 (hPC 8K9), thereby lowering cholesterol levels in the subject in need thereof.

According to a preferred embodiment of the 26th aspect, the the disease or condition is selected from the group consisting of: hypercholesterolemia, hyperlipidemia, dyslipidemia, and atherosclerosis.

According to another preferred embodiment, the disease condition is primary hypercholesterolemia or familial holesterolemia.

According to another preferred embodiment, the disease or condition is hypercholesterolemia which is uncontrolled by s.

According to another preferred embodiment, the t has a body mass indeX (BMI) of less than 18 kg/m2 or greater than 40 kg/mz.

According to another preferred embodiment, the subject was not previously instructed to partake in a cholesterol-lowering diet.

According to another red embodiment, the subject has not previously taken a cholesterol-lowering drug except for atorvastatin.

According to another preferred embodiment, the atorvastatin was administered at about 10 mg per day.

According to another preferred embodiment, the cholesterol-lowering drug is selected from the group consisting of f1brates, bile acid resins, niacin, intestinal terol absorption (ICA) blockers, and omega-3 fatty acids. ing to another preferred embodiment, the niacin is administered at greater than 500 mg per day.

According to another preferred embodiment, the omega-3 fatty acids are administered at r than 1000 mg per day.

According to r preferred embodiment, the subject does not suffer from diabetes.

According to another preferred embodiment, the diabetes is type 1 diabetes.

According to another preferred embodiment, the diabetes is type 2 diabetes.

According to another red embodiment, the type 2 diabetes is treated with insulin.

According to another preferred embodiment, the subject has a blood glycated hemoglobin concentration greater than or equal to 8.5%.

According to another preferred embodiment, the subject is negative for tis B and C surface antigen.

According to r preferred ment, the subject has a blood triglycerides concentration of greater than 350 mg/dL.

According to another preferred embodiment, the subject has fewer than 1500 phils per cubic mm of blood.

According to r preferred embodiment, the subject has fewer than 100,000 platelets per cubic mm of blood.

According to another preferred embodiment, the t is female.

According to another preferred embodiment, the subject is not pregnant.

According to another preferred ment, the subject has a blood thyroid stimulating hormone concentration that is above the lower limit of normal and below the upper limit of normal.

According to another preferred embodiment, the subject has serum creatine of less than 1.4 of the upper limit of normal.

According to another preferred embodiment, the subject is a male.

According to another preferred embodiment, the subject has serum creatine of less than 1.5 of the upper limit of normal.

According to r preferred embodiment, the t has an amount of aspartate transaminase that is less than two times the upper limit of normal.

According to another preferred embodiment, the subject has an amount of alanine transaminase that is less than two times the upper limit of normal.

According to another preferred embodiment, the antibody or antigen-binding fragment is administered in a dosage amount within the range of about 5 mg to about 500 mg.

According to another preferred embodiment, the antibody or antigen-binding fragment is administered in a dosage amount within the range of about 50 mg to about 300 mg.

According to another red embodiment, the antibody is administered at between 200 and 300 mg every four weeks.

According to another red embodiment, the antibody or antigen-binding fragment is stered in a dosage amount of about 150 mg.

According to another preferred embodiment, the antibody or antigen-binding fragment thereof is administered to the subject every other week (E2W).

According to another preferred embodiment, the antibody or antigen-binding fragment thereof is administered to the subject every fourth week (E4W).

According to another preferred embodiment, the antibody or the antigen-binding nt comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. According to another preferred embodiment, the antibody or antigen-binding nt comprises a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. According to another preferred embodiment, the antibody or antigen- g fragment thereof es for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

According to another preferred embodiment, the antibody is administered subcutaneously.

According to another preferred embodiment, the antibody is administered in the abdomen.

According to another preferred embodiment, the methog further comprises stering a HlVlG—CoA reductase inhibitor to the subject. According to another preferred embodiment, the HlVlG—CoA reductase tor is administered in a dosage amount in the range of about 0.05 mg to 100 mg. According to another preferred embodiment, the HlVlG—CoA reductase tor is a statin. According to another preferred embodiment, the statin is ed from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin. ing to another preferred embodiment, the statin is atorvastatin administered at a dosage of 10 mg, 20mg, 40mg or 80 mg. According to another preferred embodiment, the atorvastatin is administered at about 10 mg per day and at 80 mg one day in an 8 week period.

Several aspects of the invention can be combined with each other. For example, the method for treating a disease or condition according to the eleventh aspect and the method for treating a disease or condition according to the eighteenth aspect can be combined. As a result of this combination the present invention relates to a method for ng a disease or condition which es the treatment of certain groups of subjects by certain dosage regimens. In an analogous manner, different embodiments of the aspects bed herein can be combined with 1O eachother, e. g. the antibody or antigen-binding nt for use in the ent of a disease or condition related to n dosage regimens according to the seventh aspect can be combined with the antibody or antigen-binding fragment for use in the treatment of a disease or condition related to certain patient populations according to the seventh aspect. As a result of this combination the present invention relates to an antibody or antigen-binding fragment thereof for use in the treatment of certain groups of subjects by certain dosage regimens.

According to another example, the method for ng a disease or ion according to the eleventh aspect and the method for treating a disease or ion according to the nineteenth aspect can be combined. As a result of this combination the t ion relates to a method for treating a disease or condition which es n groups of subjects from a treatment by a certain dosage regimen. In an analogous manner, different embodiments of the aspects described herein can be combined with eachother, e. g. the antibody or antigen-binding fragment for use in the treatment of a disease or condition according to an embodiment of the seventh aspect related to certain dosage regimens can be combined with the antibody or antigen-binding fragment for use in the treatment of a disease or condition according to an embodiment of the seventh aspect related to the exclusion of certain groups of subjects from the ent.. As a result of this combination the present invention s to an antibody or antigen-binding fragment thereof for use in the treatment by a certain dosage regimen, n certain groups of subjects are excluded from the treatment.

The skilled artisan will recognize other red embodiments resulting of suitable combinations of different aspects and embodiments of present invention.

The pharmaceutical uses of present invention as herein described also relate to uses of the given antibody or antigen-binding fragment thereof, of the given pharmaceutical composition, etc for the manufacture of a medicament for the treatment of one or more of the diseases or conditions as herein described.

PREFERRED ANTIBODIES FOR PRACTICING THE PRESENT INVENTION The following n describes onal and structural features of antibodies and antigen-binding fragments thereof that can be used for practicing all -one aspects of the present invention. Thus, expressions such as “in preferred embodiments77 (4' 1n some embodiments”, “in another preferred embodiment” and similar expressions should be understood as referring to embodiments of the first aspect of the present invention, the second aspect of the present invention, the third aspect of the present invention, the fourth aspect of the present invention, the fifth aspect of the present invention, the sixth aspect of the present invention, the seventh aspect of the present invention, the eighth aspect of the present invention, the ninth aspect of the present invention, the tenth aspect of the t invention, the eleventh aspect of the present invention, the twelfth aspect of the present invention, the thirteenth aspect of the present invention, the fourteenth aspect of the present invention, the fifteenth aspect of the t invention, the sixteenth aspect of the present invention, the seventeenth aspect of the present invention, the eighteenth aspect of the present ion, the nineteenth aspect of the present invention, the twentieth aspect, and the twenty-first aspect of the present invention, the twentysecond aspect of present invention, the twentythird aspect of present invention, the twentyfourth aspect of present invention, the twentyfifth the twentysixth aspect of t ion.

All antibodies or antigen-binding fragments thereof le for cing the present invention specifically bind hPCSK9. In preferred embodiments of any aspect of the present invention, the antibody or antigen-binding nt thereof is a recombinant human antibody or fragment thereof. In more specific ments, the antibody or antigen-binding fragment thereof is a fully human monoclonal antibody or antigen-binding fragment thereof that specifically binds hPCSK9 and neutralizes PCSK9 activity.

The mAbs usable in the present invention can be full-length (e.g., an IgGl or IgG4 antibody) or may comprise only an antigen-binding portion (e.g., a Fab, 2 or scFv nt), and may be modified to affect functionality, e.g., to eliminate residual effector functions (Reddy et al. (2000) J. Immunol. 164:1925-1933).

In preferred embodiments, the antibodies of t invention are characterized by one or more of the following features upon stration to a subject, preferably a human or non- human mammal and more preferably a human: - reduction of low density lipoprotein-C (LDL-C) levels of at least about -25% to about - 40% relative to a e level with a sustained reduction over at least a 14 day-period, wherein the sustained reduction is ably at least -25% and more preferably at least - % relative to a predose level, particularly if administered in a dose of about 40 to about 60 mg, preferably about 45 to about 55 mg and more preferably about 50 mg in a ly administration regime (every other week, E2W) - ion of low density lipoprotein-C (LDL-C) of at least about -50% to about -65% relative to a predose level with a sustained reduction over at least a 14 day-period, wherein the sustained reduction is preferably at least -40% and more preferably at least -45% relative to a predose level, particularly if administered in a dose of about 100 mg E2W, - reduction of low-density lipoprotein-C (LDL-C) of at least about -60 % to at least about - 75% [e.g. at least about -60 %, at least about -65%, at least about -70 or at least about -75%] relative to a predose level with a sustained reduction over at least a 14 day-period, n the ned reduction is preferably at least -55% and more preferably at least -60% relative to a predose level, particularly when administered in a dose of about 150 mg E2W, - reduction of low density lipoprotein-C (LDL-C) of at least about 40% to about 75% relative to a predose level with a sustained reduction over at least a 28 day period, n the sustained reduction is preferably at least -3 5% and more preferably at least -40% relative to a predose level, particularly when administered in a dose of about 200 mg E4W, - reduction of low density lipoprotein-C (LDL-C) of at least about -50 % to about -75% relative to a predose level with a sustained reduction over at least a 28 day-period, wherein the sustained reduction is preferably at least -40% and more ably at least -45% ve to a predose level, particularly when administered in a dose of about 300 mg E4W, - increase of serum HDL cholesterol levels of at least 2%, at least 2.5%, at least, 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5% or at least 5.5% ve to a predose level, particularly when admimistered in a dose of about 150 mg E2W, - little or no detectable effect on troponin , - Increase of one or more of: Total-Cholesterol levels, ApoB levels, non HDL-C levels, Apo-B/ApoA-l ratio, The antibodies according to t invention exhibit the above properties preferably if 1O administered in combination with an HIVIG—CoA reductase inhibitor treatment. Preferred embodiments of HIVIG—CoA reductase inhibitors to be used in conjunction with the antibody of the invention and dosage and administration regimes thereof can be found throughout the specification, particularly as described in the aspects related to medical uses and methods of treatment. ing to another preferred embodiment of the antibodies and antigen-binding fragments thereof of present invention, the antibody or antigen binding fragment thereof has one or more of the following characteristics: - The dy or the antigen-binding nt comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

- The antibody or antigen-binding fragment thereof comprises a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

- The antibody or antigen-binding fragment f competes for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

According to another preferred embodiment of the antibodies and antigen-binding fragments thereof of present ion, the dy or antigen binding fragment thereof has one or more of the following characteristics: - mes statin resistance in mammals, especially in rodents such as hamster - increase in LDLR expression in mammals, particularly in rodents such as hamster - decreases serum LDL-C in s such as hamster - synergistic decrease of LDL-C in conjunction with HlVlG—CoA reductase inhibitor administration, ularly in s such as hamster, wherein the HlVlG—CoA reductase inhibitor is preferably Atorvastatin.

In red embodiments, the antibody or the antigen-binding fragment thereof is characterized by one or more of the following: (i) capable of reducing serum total cholesterol at least about 25 to about 35% and sustaining the reduction over at least a 24 day period relative to a predose level, ably the reduction in serum total cholesterol is at least about 30-40%, (ii) capable of reducing serum LDL cholesterol at least about 65-80% and sustaining the reduction over at least a 24 day period relative to a predose level, (iii) capable of reducing serum triglyceride at least about 25-40% relative to predose level, (iv) achieves one or more of (i)-(iii) t reducing serum HDL cholesterol or reducing serum HDL cholesterol no more than 5% relative to predose level, (v) achieves one or more of ii) with little or no measurable effect on liver function, as determined by ALT and AST measurements.

In preferred embodiments, the antibody or the antigen-binding fragment thereof is characterized by one or more of the following: (i) capable of reducing serum LDL cholesterol at least about 40-70% and sustaining the reduction over at least a 60 or 90 day period relative to a predose level, (ii) capable of reducing serum triglyceride at least about 25-40% relative to predose level; (iii) does not reduce serum HDL cholesterol or reduces serum HDL terol no more than % relative to predose level.

In one embodiment, the antibody or the antigen-binding fragment thereof is characterized as binding an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID ). In a more specific embodiment, the antibody or n-binding fragment binds an epitope comprising one or more of amino acid residues at positions 23 8, 153, 159 and 343 of hPCSK9 (SEQ ID NO:75 5). In a more specific embodiment, the antibody or fragment thereof is characterized as binding an epitope which does not comprise an amino acid residue at positions 1O 192, 194, 197 and/or 237 of SEQ ID NO:755.

In one embodiment, the dy or the antigen-binding fragment thereof is characterized as binding an epitope comprising amino acid residue 366 of hPCSK9 (SEQ ID NO:755). In a more specific embodiment, the dy or antigen-binding fragment binds an epitope comprising one or more of amino acid residues at positions 147, 366 and 380 of hPCSK9 (SEQ ID NO:75 5). In a more specific embodiment, the antibody or n-binding nt of an antibody is characterized as binding an e which does not comprise an amino acid residue at position 215 or 238 of SEQ ID NO:755.

In one embodiment, the antibody or the antigen-binding fragment thereof comprises a heavy chain le region (HCVR) selected from the group consisting of SEQ ID N02, 18, 22, 26, 42, 46, 50, 66, 70, 74, 90, 94, 98, 114, 118, 122, 138, 142, 146, 162, 166, 170, 186, 190, 194, 210, 214, 218, 234, 238, 242, 258, 262, 266, 282, 286, 290, 306, 310, 314, 330, 334, 338, 354, 358, 362, 378, 382, 386, 402, 406, 410, 426, 430, 434, 450, 454, 458, 474, 478, 482, 498, 502, 506, 522, 526, 530, 546, 550, 554, 570, 574, 578, 594, 598, 602, 618, 622, 626, 642, 646, 650, 666, 670, 674, 690, 694, 698, 714, 718, 722, 738 and 742, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In one embodiment, the HCVR comprises an amino acid sequence selected from the group consisting of SEQ ID NO:50, 66, 70, 74, 90, 94, 122, 138, 142, 218, 234, 238, 242, 258, 262, 314, 330 and 334. In a more specific embodiment, the HCVR comprises SEQ ID NO:9O or 218.

In one embodiment, the antibody or the antigen-binding nt thereof further comprises a light chain variable region (LCVR) selected from the group consisting of SEQ ID NO:10, 20, 24, 34, 44, 48, 58, 68, 72, 82, 92, 96, 106, 116, 120, 130, 140, 144, 154, 164, 168, 178, 188, 192, 202, 212, 216, 226, 236, 240, 250, 260, 264, 274, 284, 288, 298, 308, 312, 322, 332, 336, 346, 356, 360, 370, 380, 384, 394, 404, 408, 418, 428, 432, 442, 452, 456, 466, 476, 480, 490, 500, 504, 514, 524, 528, 538, 548, 552, 562, 572, 576, 586, 596, 600, 610, 620, 624, 634, 644, 648, 658, 668, 672, 682, 692, 696, 706, 716, 720, 730, 740 and 744, or a substantially r sequence thereof haVing at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In one embodiment, the LCVR comprises an amino acid sequence ed from the group consisting of SEQ ID NO: 58, 68, 72, 82, 92, 96, 130, 140, 144, 226, 236, 240, 250, 260, 264, 322, 332 and 336. In a more specific embodiment, the LCVR comprises SEQ ID NO:92 or 226.

In specific ments, the antibody or the antigen-binding fragment thereof ses a HCVR and LCVR LCVR) sequence pair selected from the group consisting of SEQ ID NO: 2/10, 18/20, 22/24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72, 74/82, 90/92, 94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144, 146/154, 162/164, 166/168, 8, 186/188, 190/192, 2, 210/212, 214/216, 218/226, 234/236, 238/240, 242/250, 258/260, 262/264, 266/274, 282/284, 286/288, 290/298, 306/308, 310/312, 2, 2, 334/336, 6, 354/356, 358/360, 362/370, 378/380, 382/384, 386/394, 402/404, 406/408, 410/418, 426/428, 430/432, 434/442, 2, 454/456, 458/466, 474/476, 478/480, 0, 498/500, 502/504, 506/514, 522/524, 526/528, 530/538, 546/548, 550/552, 554/562, 570/572, 574/576, 578/586, 594/596, 598/600, 602/610, 618/620, 622/624, 626/634, 642/644, 646/648, 650/658, 666/668, 670/672, 674/682, 690/692, 694/696, 6, 6, 718/720, 722/730, 738/740 and 742/744.

In one embodiment, the HCVR and LCVR sequence pair comprises one of SEQ ID NO: 50/5 8, 66/68, 70/72, 74/82, 90/92, 94/96, 122/130, 138/140, 142/144, 218/226, 234/236, 238/240, 242/250, 258/260, 262/264, 314/322, 330/332 and 334/336. In preferred embodiments, the antibody or antigen-binding fragment thereof comprises an HCVR amino acid sequence as shown in SEQ ID NO: 90 and an LCVR amino acid sequence as shown in SEQ ID NO: 92. In another preferred embodiment, the antibody or antigen-binding fragment thereof comprises an HCVR amino acid sequence as shown in SEQ ID NO: 218 and an LCVR amino acid sequence as shown in SEQ ID NO: 226.

In preferred embodiments, the antibody or the antigen-binding fragment thereof comprises a heavy chain CDR3 (HCDR3) domain selected from the group consisting of SEQ ID 11Ct8,32,56,80,104,128,152,176,200,224,248,272,296,320,344,368,392,416,440,464, 488,512,536,560,584,608,632,656,680,704énu1728,orasubManfiaHysnnflarsequence f having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and a light chain CDR3 (LCDR3) domain ed from the group consisting of SEQ ID NO:16, 40, 64, ,136,160,184,208,232,256,280,304,328,352,376,400,424,448,472,496,520, 544, 568, 592, 616, 640, 664, 688, 712 and 736, or substantially similar sequences thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In one embodiment, the HCDR3/LCDR3 sequence pair is selected from the group consisting of SEQ ID NO:56/64, 80/88, 128/136, 224/232, 248/256 and 320/328. In more preferred embodiments, the dy or the antigen-binding nt thereof comprises a HCDR3 domain as shown in SEQ ID NO: 80 and a LCDR3 domain as shown in SEQ ID NO: 88. In another preferred embodiment, the dy or the antigen-binding fragment thereof comprises a HCDR3 domain as shown in SEQ ID NO: 224 and a LCDR3 domain as shown in SEQ ID NO: 232.

In a further embodiment, the antibody or the antigen-binding fragment thereof further comprises a heavy chain CDRl (HCDRl) domain selected from the group consisting of SEQ ID 11Ct4,28,52,76,100,124,148,172,196,220,244,268,292,316,340,364,388,412,436,460, 484,508,532,556,580,604,628,652,676,700znu1724,orasubmanfiaflysnnflarsequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, a heavy chain CDR2 (HCDR2) domain selected from the group consisting of SEQ ID N06, 30, 54, 78, 102,126,150,174,198,222,246,270,294,318,342,366,390,414,438,462,486,510,534, 558, 582, 606, 630, 654, 678, 702 and 726, or a substantially r sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, a light chain CDRl (LCDRl) domain selected from the group consisting of SEQ ID NO: 12, 36, 60, 84, 108, 132, 156,180,204,228,252,276,300,324,348,372,396,420,444,468,492,516,540,564,588, 612, 636, 660, 684, 708 and 732, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence ty, and a light chain CDR2 ) domain selected from the group consisting of SEQ ID NO:14, 38, 62, 86, 110, 134, 158, 182, 206,230,254,278,302,326,350,374,398,422,446,470,494,518,542,566,590,614,638, 662, 686, 710 and 734, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In one embodiment, the heavy and light ’] chain CDR sequences comprise a sequence selected from the group consisting of SEQ ID NO:52, 54, 56, 60, 62, 64, 76,78, 80, 84, 86, 88, 124, 126, 128, 132, 134, 136, 220, 222, 224, 228, 230, 232, 244, 246, 248, 252, 254, 256, and 316, 318, 320, 324, 326, 328. In more specific embodiments, the CDR sequences se SEQ ID NO: 76, 78, 80, 84, 86, 88, or 220, 222, 224, 228, 230, 232. In preferred embodiments, the antibody or antigen-binding nt thereof comprises heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86 and 88. In another preferred embodiment, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 220, 222, 224, 228, 230 and 232. 1O In a related embodiment, the antibody or antigen-binding fragment thereof ses heavy and light chain CDR domains contained within heavy and light chain sequence pairs selected from the group ting of SEQ ID NO: 2/ 10, 18/20, 22/24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72, 74/82, 90/92, 94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144, 4, 162/164, 166/168, 170/178, 186/188, 190/192, 194/202, 210/212, 214/216, 218/226, 234/236, 0, 242/250, 258/260, 262/264, 266/274, 282/284, 8, 290/298, 8, 310/312, 314/322, 330/332, 334/336, 338/346, 354/356, 358/360, 362/370, 378/380, 382/384, 386/394, 402/404, 406/408, 410/418, 426/428, 2, 434/442, 450/452, 454/456, 458/466, 474/476, 0, 482/490, 498/500, 502/504, 506/514, 522/524, 8, 530/538, 546/548, 550/552, 554/562, 570/572, 6, 578/586, 594/596, 598/600, 602/610, 618/620, 622/624, 626/634, 642/644, 646/648, 650/658, 666/668, 670/672, 674/682, 690/692, 694/696, 698/706, 714/716, 718/720, 722/730, 0 and 742/744. In one embodiment, the CDR sequences are contained within HCVR and LCVR selected from the amino acid sequence pairs of SEQ ID NO: 50/58, 66/68, 70/72, 74/82, 90/92, 94/96, 122/130, 138/140, 142/144, 218/226, 234/236, 238/240, 242/250, 258/260, 262/264, 314/322, 330/332 and 334/336. In more specific embodiments, the CDR sequences are comprised within CVR sequences ed from SEQ ID NO: 90/92 or 218/226. In preferred embodiments, the antibody or the antigen-binding fragment thereof comprises the heavy and light chain CDRs of an HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. In another preferred ment, the antibody or the antigen- binding fragment thereof comprises the heavy and light chain CDRs of an HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 218/226.

In one specific embodiment, the antibody or the antigen-binding fragment f ses the heavy chain variable region (HCVR), of SEQ ID NO:9O or a ntially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. .

In one specific embodiment, the antibody or the antigen-binding fragment thereof further comprises the light chain variable region (LCVR) of SEQ Id NO 92 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

In specific ments, the antibody or the antigen-binding fragment thereof comprises 1O HCVR amino acid sequence as shown in SEQ ID NO: 90 and an LCVR amino acid sequence as shown in SEQ ID NO: 92.

In specific embodiments, the antibody or the antigen-binding fragment thereof ses a heavy chain CDR3 (HCDR3) domain of SEQ ID NO: 80 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence ty, and/or a light chain CDR3 (LCDR3) domain of SEQ ID NO: 88, or substantially similar sequences thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In one embodiment, the HCDR3/LCDR3 sequence pair is SEQ ID NO:80/88 . In more preferred embodiments, the antibody or the antigen-binding fragment thereof comprises a HCDR3 domain as shown in SEQ ID NO: 80 and a LCDR3 domain as shown in SEQ ID NO: 88.

In a further specific embodiment, the antibody or the n-binding fragment thereof further comprises the heavy chain CDRl (HCDRl) domain of SEQ ID NO: 76, or a substantially similar sequence f having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or the heavy chain CDR2 (HCDR2) domain of SEQ ID NO: 78 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or a light chain CDRl (LCDRl) domain of SEQ ID NO: 84or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or a light chain CDR2 ) domain of SEQ ID NO: 86, or a substantially r sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In one embodiment, the heavy and light chain CDR sequences comprise a sequence selected from the group ting of SEQ ID NO: 76, 78, 80, 84, 86, 88. In preferred embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86 and 88.

In another specific embodiment, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR domains contained within the heavy and light chain sequence pair of SEQ ID NO:, 90/92.

A particularly red ment concerns an antibody sing HCVR/LCVR sequences SEQ ID Nos: 90/92 and/or CDR sequences SEQ ID Nos: 76, 78, 8O and/or CDR sequences SEQ ID NO:s 84, 86, 88. r particularly red embodiment concerns an antibody comprising the HCVR/LCVR sequences SEQ ID Nos: 90/92 and the CDR sequences SEQ ID Nos: 76, 78, 80 and the CDR sequences SEQ ID NO:s 84, 86, 88 (“3l6P”).

In one embodiment, the antibody or n-binding fragment thereof comprises an HCVR encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1, 17,21,25,41,45,49,65,69,73,89,93,97,113,117,121,137,141,145,161,165,169,185, 3,209,213,217,233,237,241,257,261,265,281,285,289,305,309,313,329,333, 337,353,357,361,377,381,385,401,405,409,425,429,433,449,453,457,473,477,481, 497,501,505,521,525,529,545,549,553,569,573,577,593,597,601,617,621,625,641, 9,665,669,673,689,693,697,7l3,7l7,72l,737;nu174l,orasubManfiaHyidenficd sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereof. In one embodiment, the HCVR is encoded by a nucleic acid sequence selected from the gyoupcoanfingofSEIQDDIflO:49,65,69,73,89,93,l2l,l37,l4l,2l7,233,237,24l,257 261, 3 13, 329 and 333. In more specific embodiments, the HCVR is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO: 89 and 217.

In one embodiment, the antibody or fragment thereof further comprises an LCVR encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO: 9, 19, 23, 33,43,47,57,67,71,81,91,95,105,115,119,129,139,143,153,163,167,177,187,191, 1,215,225,235,239,249,259,263,273,283,287,297,307,311,321,331,335,345, 355,359,369,379,383,393,403,407,417,427,431,441,451,455,465,475,479,489,499, 503,513,523,527,537,547,551,561,571,575,585,595,599,609,619,623,633,643,647, 657,667,67l,68l,69l,695,705,715,7l9,729,739and743,orasubfianfiaflyidenficd sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereof. In one embodiment, the LCVR is encoded by a c acid sequence selected from the group consisting of SEQ ID NO: 57, 67, 71, 81, 91, 95, 129, 139, 143, 225, 235, 239, 249, 259, 263, 321, 331 and 335. In more specific embodiments, the LCVR is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO: 91 and 225.

In one embodiment, the antibody or antigen-binding fragment thereof comprises an HCDR3 domain encoded by a nucleotide sequence selected from the group consisting of SEQ ID N07, 31, 55, 79, 103, 127, 151, 175, 199, 223, 247, 271, 295, 319, 343, 367, 391, 415, 439, 463, 487, 511, 535, 559, 583, 607, 631, 655, 679, 703 and 727, or a substantially identical sequence haVing at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereof, and a ’10 LCDR3 domain encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 15, 39, 63, 87, 111, 135, 159, 183, 207, 231, 255, 279, 303, 327, 351, 375, 399, 423, 447, 471, 495, 519, 543, 567, 591, 615, 639, 663, 687, 711 and 735, or a substantially identical sequence haVing at least 90%, at least 95%, at least 98%, or at least 99% ce identity thereof. In one embodiment, the HCDR3 and LCDR3 comprise a sequence pair encoded by the ’15 nucleic acid sequence of SEQ ID NO: 55/63, 79/87, 5, 1, 247/255 and 319/327, respectively. In more ic embodiments, the HCDR3 and LCDR3 comprise a sequence pair encoded by the nucleic acid sequence of SEQ ID NO: 79/87 and 223/231.

In a further embodiment, the antibody or antigen-binding fragment thereof further comprises: an HCDRl domain encoded by a nucleotide sequence selected from the group ting of SEQ ID NO: 3, 27, 51, 75, 99, 123, 147, 171, 195, 219, 243, 267, 291, 315, 339, 363, 387, 411, 435, 459, 483, 507, 531, 555, 579, 603, 627, 651, 675, 699 and 723, or a substantially identical sequence haVing at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereof, an HCDR2 domain encoded by a nucleotide sequence selected from the group consisting of SEQ ID N05, 29, 53, 77, 101, 125, 149, 173, 197, 221, 245, 269, 293, 317, 341, 365, 389, 413, 437, 461, 485, 509, 533, 557, 581, 605, 629, 653, 677, 701 and 725, or a ntially cal sequence haVing at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereof, an LCDRl domain d by a nucleotide sequence ed from the group consisting of SEQ ID NO: 11, 35, 59, 83, 107, 131, 155, 179, 203, 227, 251, 275, 299, 323, 347, 371, 395, 419, 443, 467, 491, 515, 539, 563, 587, 611, 635, 659, 683, 707 and 731, or a substantially identical sequence haVing at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereof, and an LCDR2 domain encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 13, 37, 61, 85, 109, 133, 157, 181, 205, 229, 253, 277, 301, 325, 349, 373, 397, 421, 445, 469, 493, 517, 541, 565, 589, 613, 637, 661, 685, 709 and 733, or a substantially identical sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereof. In one embodiment, the heavy and light chain CDR sequences are d by the nucleic acid sequences of SEQ ID NO: 51, 53, 55, 59, 61, 63, 75, 77, 79, 83, 85, 87, 123, 125, 127, 131, 133, 135, 219, 221, 223, 227, 229, 231, 243, 245, 247, 251, 253, 255, and 315, 317, 319, 323, 325, 327. In more specific embodiments, the heavy and light chain CDR ces are d by the nucleic acid sequences of SEQ ID NO: 75, 77, 79, 83, 85, 87, and 219, 221, 223, 227, 229, 231. 1O In a further embodiment, the antibody or n-binding fragment thereof comprises an HCDR3 and an LCDR3, wherein HCDR3 comprises an amino acid sequence of the formula X1 - XZ-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17 _X18_X19_X20 (SEQ ID NO:747), wherein X1 is Ala, X2 is Arg or Lys, X3 is Asp, X4 is Ser or Ile, X5 is Asn or Val, X6 is Leu or Trp, X7 is Gly or Met, X8 is Asn or Val, X9 is Phe or Tyr, X10 is Asp, X11 is ’15 Leu or Met, X12 is Asp or absent, X13 is Tyr or absent, X14 is Tyr or absent, X15 is Tyr or absent, X16 is Tyr or absent, X17 is Gly or absent, X18 is Met or absent, X19 is Asp or absent, and X20 is Val or absent, and LCDR3 comprises an amino acid sequence of the formula X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 - X9 (SEQ ID NO:750), wherein X1 is Gln or Met, X2 is Gln, X3 is Tyr or Thr, X4 is Tyr or Leu, X5 is Thr or Gln, X6 is Thr, X7 is Pro, X8 is Tyr or Leu, and X9 is Thr.

In a further embodiment, the antibody or antigen-binding nt thereof further comprises an HCDRl sequence of the formula X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 (SEQ ID NO:745), n X1 is Gly, X2 is Phe, X3 is Thr, X4 is Phe, X5 is Ser or Asn, X6 is Ser or Asn, X7 is Tyr or His, and X8 is Ala or Trp, a HCDR2 sequence of the formula X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 (SEQ ID NO:746), n X1 is Ile, X2 is Ser or Asn, X3 is Gly or Gln, X4 is Asp or Ser, X5 is Gly, X6 is Ser or Gly, X7 is Thr or Glu, and X8 is Thr or Lys, a LCDRl sequence of the formula X1 ' X7 — X2 — X3 — X4 — X5 — X6 — X8 — X9 — X10 — X“ — X12 (SEQ ID NO:748) wherein X1 is Gln, X2 is Ser, X3 is Val or Leu, X4 is Leu, X5 is His or Tyr, X6is Arg or Ser, X7 is Ser or Asn, X8 is Asn or Gly, X9 is Asn, X10 is Arg or Asn, X11 is Asn or Tyr, and X12 is Phe or absent, an LCDR2 sequence of the formula X1 - X2 - X3 (SEQ ID NO:749) wherein X1 is Trp or Leu, X2 is Ala or Gly, and X3 is Ser.

In a further embodiment, the antibody or antigen-binding fragment thereof is a human anti-PCSK9 dy or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR) d by nucleotide sequence ts derived from VH, DH and JH germline sequences, and a light chain variable region (LCVR) encoded by nucleotide sequence segments derived from VK and JK germline sequences, n the germline sequences are (a) VH gene segment 3-23, DH gene t 7-27, JH gene segment 2, VK gene segment 4-1 and JK gene segment 2, or (b) VH gene segment 3-7, DH gene t 2-8, JH gene segment 6, VK gene t 2-28 and JK gene segment 4.

In preferred embodiments, the antibody or antigen-binding fragment thereof binds to the same epitope on hPCSK9 as an antibody comprising heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86, and 88 or as shown in SEQ ID NOs: 220, 222, 224, 228, 230 and 232.

In preferred embodiments, the antibody or antigen-binding fragment thereof competes for binding to hPCSK9 with an antibody comprising heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86, and 88 or as shown in SEQ ID NOs: 220, 222, 224, 228, 230 and 232.

The invention encompasses anti-PCSK9 antibodies having a modified glycosylation pattern. In some applications, modification to remove undesirable glycosylation sites may be useful, or e.g., removal of a fucose moiety to increase antibody dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) IBC 277:26733). In other applications, modification of osylation can be made in order to modify complement dependent cytotoxicity (CDC).

Some preferred sequences related to preferred antibodies for cing present invention: SEQ ID \0: 76: Gly Phe Thr Phe Asn Asn Tyr Ala SEQ ID \Oz78: Ile Ser Gly Ser Gly Gly Thr Thr SEQ ID \0: 80: Ala Lys Asp Ser Asn Trp Gly Asn Phe Asp Leu SEQ ID \0: 84: Gln Ser Val Leu Tyr Arg Ser Asn Asn Arg Asn Phe SEQ ID \0: 86: Trp Ala Ser SEQ ID NO: 88: Gln Gln Tyr Tyr Thr Thr Pro Tyr Thr SEQ ID NO: 90: Val Gln .eu Va' Glu Ser G'y Gly Ieu Val Gln Pro Gly 15 Ser Leu Arg reu Se: Cys A'a A'a Ser Phe Thr Phe Asn Ash 30 Ala Val Arg .ys Gly Leu Asp Trp Val Ser Thr Ile Ser G:_y Ser G'y G'y Thr Thr Asn r-I yr Ala Asp Ser Val 1O 50 60 .ys G'y Arg Phe I:_e Ile Ser Arg Asp Ser Ser .4ys His F'Ihr .4eu 65 70 75 80 G'n Met Asn Ser Arg Ala Glu Asp r'lhr Ala r-I reu Val yr yr 85 90 95 Ala Lys Asp Ser Ash rp Gly Asn Phe Asp .4eu Trp Arg Gly Thr 100 105 "10 Leu Val Thr Val Ser Ser 2O SEQ ID NOz92: Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Va' Ser 10 Glu Arg Ala Thr Ile Asn Ser Gln Ser Val Leu 25 30 Ser Ash Asn Arg Asn Phe .eu G'y Trp Gln Gln Lys Pro 45 Pro Pro Asn .eu Leu I'e r"yr T: Ala F'Ihr Arg Glu Ser Val 50 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Asp Phe Thr 65 75 Ile Ser Ser .eu Gln A'a Glu Asp Val Val yr Tyr Thr r"hr Pro Tyr Thr Phe Gly Gln Leu "00 105 110 SEQ ID NO: 755 9): Met Gly r"hr Val Ser Ser Arg Arg Ser Trp Trp Leu Leu 10 15 T.u L u . u L U T u I u Ala Gly Ala Arg Gln 4O 20 25 Asp Glu Asp Gly Asp r"yr G'u G'u Leu Val Leu Ieu Ser Glu Glu Asp Gly Leu Ala Glu Ala P:o Glu His Gly Thr F'Ihr Thr Phe 45 His Arg Cys A:_a Lys Asp Leu Pro F'Ihr Val Val 65 70 75 80 Val .eu Lys G' 'u Thr His reu Ser Ser Glu Arg Arg .eu Gln A' a G— n Ala Ala Arg Arg yr Leu .ys Leu 50 100 105 "10 His Val Phe His 1y Leu Leu Pro Gly Ieu Val Met 115 120 125 T.eu T.eu Glu T.eu Ala T.eu T.ys T.eu -Iis Val Asp 130 135 140 Asp Ser Ser Val Phe Ala Gin Ser Ile ?ro Trp Asn 150 __55 Thr Pro Pro Ala Asp yr Gln Pro Asp Ser T.eu Val T.eu T.eu Ser Ile Ser 180 185 Ile Val Met Val Phe Asn 200 205 Pro Asp Phe His Arg Gln Ser Ser Thr Hi s .eu Ala Gl y Val Val Ser Ala 225 230 235 Val Ala Ser Met Arg Ser Leu Leu Asn Cys 245 250 255 Val Ser Gly Th : Leu Ile Glu Phe Ile 265 270 Va' Gln Pro Val Gly Pro Leu Leu 280 Ser Arg Va' Asn Gln Leu Ala Val T.eu Va' Phe Asp 305 310 320 Asp A; a Leu Ty: Ser Pro A; a Glu Ile Val Ala Asn Gln Gin Thr Leu Thr Asn Gly Val Asp _ Ala Pro Ile 360 Ile Gly Ser Asp Cys Ser Phe Val Gin Ser 370 375 380 Thr Ser Ala His Val Ile Ala Met Met Leu 385 390 395 400 Ser Ala Glu Leu Thr T.eu T.eu Gin Arg Leu Ile His Phe Ser Asp Val Ile Asn Phe Pro Glu 425 430 Gln Val Pro Asn T.eu Val Pro Pro Ser Thr 4o 435 440 445 His Ala Gln Leu Phe Thr Val Ser His 455 460 Pro Ala Thr Ala Val Ala Arg Ala Asp 475 480 45 Ser Ser Phe Ser Arg Ser Gly T.ys T.eu Val Arg His 505 510 Va' Ala Leu 50 520 525 Asn Va __ His Thr A; a Pro Ala Ala Thr Arg Val His Gln His Val Thr 550 555 560 55 Ser His Trp Glu Val Glu Asp Leu Thr His .4ys Pro 565 570 575 Val Leu Arg Pro Arg Gln Pro Asn Gin Val Gly -Iis Arg 580 585 590 Glu Ala Ser Ile His Ala Cys Cys His A; a Leu Glu Cys 595 600 605 Lys Val Lys G'u His G'y I'e ?ro Ala Pro Gln Glu GLn Val Thr Val 610 6n5 620 Ala Cys Glu GLu Gly Trp Thr neu Thr Gly Cys Ser ALa Leu Pro Gly 625 630 635 640 Thr Ser His Val Leu G'y A'a r‘ch ALa Val Asp Asn Thr Cys Val Va; 645 650 655 Arg Ser Arg Asp Val Ser Thr r"hr GLy Ser Thr Ser G'u G'y A'a Va' 660 665 6 Thr A'a Val A'a Ile Cys Cys Arg Ser Arg His Leu A'a G'n A'a Se: 675 680 685 Gln G'u Leu G'n Preparation of Human Antibodies Methods for generating human antibodies in transgenic mice are known (see for example, US 6,596,541, Regeneron Pharmaceuticals, VELOCIMIVIUNETM). The VELOCIMIVIUNETM logy involves generation of a transgenic mouse having a genome sing human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. The DNA encoding the variable regions of the heavy and light chains of the antibody are isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing the fully human antibody. In specific ment, the cell is a CHO cell.

Antibodies may be therapeutically useful in blocking a ligand-receptor interaction or ting receptor component interaction, rather than by killing cells through fixation of complement and participation in complement-dependent xicity (CDC), or killing cells through dy-dependent cell-mediated cytotoxicity (ADCC). The constant region of an antibody is thus ant in the ability of an antibody to fix complement and mediate cell- dependent cytotoxicity. Thus, the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.

Human antibodies can exist in two forms that are associated with hinge geneity. In one form, an antibody molecule comprises a stable four-chain construct of approximately 150- 160 kDa in which the dimers are held er by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody).

These forms have been extremely difficult to separate, even after affinity purification.

The frequency of appearance of the second form in various intact IgG isotypes is due to, but not d to, ural differences associated with the hinge region isotype of the antibody.

A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30: 105) to levels typically observed using a human IgG1 hinge. The instant invention encompasses antibodies having one or more ons in the hinge, CH2 or CH3 region which may be desirable, for example, in tion, to improve the yield of the desired antibody form.

Generally, a VELOCIMlVIUNETM mouse is challenged with the n of interest, and lymphatic cells (such as B-cells) are recovered from the mice that s antibodies. The lymphatic cells may be fused with a a cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce dies specific to the antigen of interest. DNA encoding the variable regions of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain. Such an antibody protein may be produced in a cell, such as a CHO cell. Alternatively, DNA encoding the antigen-specific chimeric antibodies or the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes.

Initially, high affinity chimeric antibodies are isolated having a human variable region and a mouse constant region. As described below, the dies are characterized and selected for desirable characteristics, including y, selectivity, epitope, etc. The mouse nt regions are replaced with a desired human constant region to generate the fully human antibody of the invention, for example wild-type or modified IgGl or IgG4 (for example, SEQ ID NO:75 l, 752, 753). While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.

Epitope Mapping and d Technologies To screen for antibodies that bind to a particular epitope (e.g., those which block binding of IgE to its high affinity receptor), a e cross-blocking assay such as that described Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY) can be performed. Other methods include e scanning mutants, peptide blots (Reineke (2004) Methods Mol Biol 248:443-63) (herein specifically orated by reference in its entirety), or peptide cleavage analysis. In on, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Protein Science 9: 487-496) (herein specifically incorporated by reference in its entirety).

The term "epitope" refers to a site on an antigen to which B and/or T cells respond. B- cell epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from uous amino acids are typically retained on re to denaturing solvents, whereas epitopes formed by ry folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.

Modification-Assisted Profiling (MAP), also known as Antigen Structure-based Antibody ng (ASAP) is a method that categorizes large numbers of monoclonal antibodies (mAbs) directed against the same n according to the rities of the binding profile of each antibody to chemically or enzymatically modified antigen surfaces (US 2004/0101920, herein specifically incorporated by reference in its entirety). Each category may reflect a unique epitope either distinctly different from or partially overlapping with epitope represented by another category. This logy allows rapid filtering of genetically identical mAbs, such that terization can be focused on genetically distinct mAbs. When applied to hybridoma screening, MAP may facilitate identification of rare hybridoma clones that produce mAbs having the desired characteristics. MAP may be used to sort the anti-PCSK9 mAbs of the ion into groups of mAbs g ent epitopes.

In various embodiments, the anti-hPCSK9 antibody or antigen-binding fragment of an antibody binds an epitope within the catalytic domain, which is about 153 to 425 of SEQ ID NO:755), more specifically, an epitope from about 153 to about 250 or from about 250 to about 425, more specifically, the antibody or antibody fragment of the invention binds an epitope within the fragment from about 153 to about 208, from about 200 to about 260, from about 250 to about 300, from about 275 to about 325, from about 300 to about 360, from about 350 to about 400, and/or from about 375 to about 425.

In s embodiments, the anti-hPCSK9 antibody or antigen-binding fragment of an antibody binds an epitope within the propeptide domain (residues 31 to 152 of SEQ ID NO:755), more specifically, an epitope from about residue 31 to about residue 90 or from about residue 90 to about residue 152, more cally, the antibody or antibody nt of the invention binds an e within the nt from about residue 31 to about residue 60, from about residue 60 to about residue 90, from about residue 85 to about residue 110, from about residue 100 to about residue 130, from about residue 125 to about residue 150, from about residue 135 to about 1O residue 152, and/or from about residue 140 to about residue 152.

In some embodiments, the anti-hPCSK9 antibody or antigen-binding fragment of an antibody binds an epitope within the C-terminal domain, (residues 426 to 692 of SEQ ID NO:755), more specifically, an epitope from about residue 426 to about residue 570 or from about residue 570 to about residue 692, more specifically, the antibody or antibody fragment of the invention binds an epitope within the nt from about residue 450 to about residue 500, from about residue 500 to about residue 550, from about residue 550 to about residue 600, and/or from about residue 600 to about residue 692.

In some ments, the antibody or antibody fragment binds an epitope which includes more than one of the enumerated es within the catalytic, propeptide or C-terminal domain, and/or within two or three different domains (for example, es within the catalytic and C-terminal domains, or within the propeptide and catalytic domains, or within the tide, catalytic and C-terminal domains.

In some embodiments, the dy or antigen-binding fragment binds an epitope on hPCSK9 comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:755). Experimental results (see US 2010/0166768) showed that when D238 was mutated, the KD of mAb 316P exhibited >400-fold reduction in binding affinity (~1 x109 M to ~410 x109 M) and Tm decreased >3 0-fold (from ~37 to ~1 min). In a specific embodiment, the mutation was D23 8R. In specific embodiments, the antibody or antigen-binding fragment of the invention binds an epitope of hPCSK9 comprising two or more of amino acid residues at positions 153, 159, 238 and 343.

As shown before (see US 2010/0166768), a mutation in amino acid residue 153, 159 or 343 resulted in about a 5- to 10-fold decrease in affinity or similar shortening in Tm. In specific embodiments, the mutation was S153R, E159R and/or D343R.

In some embodiments, the antibody or antigen-binding fragment binds an epitope on hPCSK9 comprising amino acid residue 366 of hPCSK9 (SEQ ID NO:755). mental results (see US 2010/0166768) showed that when E366 was mutated, the affinity of mAb 3OON exhibited about d decrease (~O.7 xlO'9 M to ~36 xlO'9 M) and a similar shortening in Tm (from ~120 to ~2 min). In a specific embodiment, the mutation is E366K.

The present invention includes anti-PCSK9 antibodies that bind to the same epitope as any of the specific exemplary antibodies described herein. Likewise, the present invention also includes CSK9 antibodies that compete for binding to PCSK9 or a PCSK9 fragment with any of the c exemplary antibodies described .

One can easily determine whether an antibody binds to the same epitope as, or competes for binding with, a reference anti-PCSK9 dy by using routine methods known in the art. For example, to determine if a test antibody binds to the same epitope as a reference anti- PCSK9 antibody of the invention, the reference antibody is allowed to bind to a PCSK9 protein or peptide under saturating ions. Next, the y of a test antibody to bind to the PCSK9 molecule is assessed. If the test antibody is able to bind to PC SK9 following saturation binding with the reference anti-PCSK9 antibody, it can be concluded that the test antibody binds to a different epitope than the reference anti-PCSK9 antibody. On the other hand, if the test antibody is not able to bind to the PCSK9 molecule following saturation g with the reference anti- PCSK9 antibody, then the test antibody may bind to the same epitope as the epitope bound by the reference anti-PCSK9 antibody of the invention.

To determine if an antibody competes for binding with a nce CSK9 antibody, the above-described binding methodology is performed in two orientations: In a first orientation, the reference antibody is allowed to bind to a PCSK9 molecule under saturating conditions followed by assessment of g of the test antibody to the PCSK9 molecule. In a second orientation, the test antibody is allowed to bind to a PCSK9 molecule under saturating conditions followed by assessment of binding of the nce antibody to the PCSK9 molecule. If, in both orientations, only the first (saturating) antibody is capable of g to the PCSK9 molecule, then it is concluded that the test antibody and the reference antibody compete for binding to PCSK9. As will be appreciated by a person of ordinary skill in the art, an antibody that competes for binding with a reference antibody may not necessarily bind to the identical epitope as the nce antibody, but may sterically block binding of the reference antibody by binding an overlapping or adjacent epitope.

Two antibodies bind to the same or overlapping epitope if each competitively ts (blocks) binding of the other to the antigen. That is, a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as ed in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 1990 50: 1495- 1O 1502). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two dies have overlapping epitopes if some amino acid mutations that reduce or ate binding of one antibody reduce or eliminate binding of the other.

Additional routine experimentation (e.g., peptide mutation and binding es) can then be d out to confirm whether the observed lack of g of the test antibody is in fact due to binding to the same epitope as the reference antibody or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, surface n resonance, flow cytometry or any other tative or qualitative dy-binding assay available in the art.

In a specific embodiment, the invention comprises an anti-PCSK9 antibody or antigen binding fragment of an dy that binds an PCSK9 n of SEQ ID NO:755, wherein the binding between the antibody or fragment thereof to PCSK9 and a variant PCSK9 protein is less than 50% of the binding between the antibody or fragment and the PCSK9 protein of SEQ ID NO:755. In one specific embodiment, the variant PCSK9 protein comprises at least one mutation of a residue at a position selected from the group consisting of 153, 159, 238 and 343.

In a more specific embodiment, the at least one mutation is S153R, E159R, D23 8R, and/or D343R. In another specific embodiment, the variant PCSK9 protein comprises at least one mutation of a residue at a position selected from the group ting of 366. In one specific embodiment, the variant PCSK9 protein comprises at least one mutation of a residue at a position selected from the group consisting of 147, 366 and 380. In a more specific embodiment, the mutation is S147F, E366K and V3 80M.

Immunoconjugates The invention encompasses a human anti-PCSK9 monoclonal antibody ated to a therapeutic moiety (“immunoconjugate”), such as a cytotoxin, a chemotherapeutic drug, an immunosuppressant or a radioisotope. Cytotoxin agents include any agent that is detrimental to cells. Examples of suitable cytotoxin agents and chemotherapeutic agents for g immunoconjugates are known in the art, see for example, WO 05/103081.

Bispecifics 1O The antibodies of the present invention may be monospecific, bispecific, or multispecific. pecific mAbs may be specific for ent epitopes of one target polypeptide or may contain n-binding domains specific for more than one target polypeptide. See, e.g., Tutt et al. (1991) J. Immunol. 147:60-69. The human anti-PCSK9 mAbs can be linked to or co- expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be onally linked (e.g., by chemical coupling, genetic fusion, noncovalent ation or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment, to produce a bispecific or a multispecific dy with a second binding specificity.

An exemplary bi-specific antibody format that can be used in the context of the present ion involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces g of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference.

In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering, H43 5R by EU numbering). The second CH3 may further comprise a Y96F modification (by HVIGT, Y43 6F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V821 (by lMGT, D3 56E, L358M, N384S, K392N, V397M, and V4221 by EU) in the case of IgG1 antibodies, N44S, K52N, and V821 (IMGT, N3 848, K3 92N, and V4221 by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V821 (by IMGT, Q355R, N3 848, K392N, V397M, R409K, E419Q, and V4221 by EU) in the case of IgG4 antibodies. Variations on the bi- specific antibody format described above are contemplated within the scope of the present invention.

Bioequivalents The anti-PCSK9 antibodies and dy fragments of the present invention encompass proteins having amino acid ces that vary from those of the described mAbs, but that retain the ability to bind human PCSK9. Such variant mAbs and antibody fragments comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence, but exhibit ical activity that is essentially equivalent to that of the described mAbs. Likewise, the anti-PCSK9 antibody-encoding DNA sequences of the present invention encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to the disclosed sequence, but that encode an anti-PCSK9 antibody or antibody nt that is essentially bioequivalent to an anti-PC SK9 antibody or antibody fragment of the invention. Examples of such variant amino acid and DNA sequences are discussed above.

Two antigen-binding proteins, or antibodies, are considered bioequivalent if, for example, they are ceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar mental ions, either single does or multiple dose. Some antibodies will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be ered bioequivalent because such ences in the rate of absorption are ional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignif1cant for the particular drug product d. In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

In one ment, two antigen-binding proteins are ivalent if a patient can be switched one or more times between the reference product and the ical product without an expected increase in the risk of adverse effects, ing a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such ing.

In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism or mechanisms of action for the ion or conditions of use, to the extent that such mechanisms are known.

Bioequivalence may be demonstrated by in vivo and in vitro methods. Bioequivalence 1O measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time, (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo ilability data, (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its ) is measured as a function of time, and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or ivalence of an antibody.

Bioequivalent variants of anti-PCSK9 antibodies of the invention may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For e, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to t formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation.

Treatment Population The invention provides therapeutic methods for treating a human patient in need of a composition of the invention. While modifications in lifestyle and conventional drug treatment are often successful in reducing cholesterol levels, not all patients are able to achieve the recommended target cholesterol levels with such approaches. Various conditions, such as familial hypercholesterolemia (FH), appear to be resistant to lowering of LDL-C levels in spite of sive use of conventional y. Homozygous and heterozygous familial hypercholesterolemia (hoFH, heFH) is a condition associated with premature atherosclerotic vascular disease. However, patients diagnosed with hoFH are largely unresponsive to conventional drug therapy and have d treatment s. Specifically, treatment with statins, which reduce LDL-C by inhibiting cholesterol synthesis and upregulating the hepatic LDL receptor, may have little effect in patients whose LDL receptors are non-existent or defective. A mean LDL-C reduction of only less than about 20% has been recently reported in ts with genotype-confirmed hoFH treated with the maXimal dose of statins. The addition of ezetimibe 10 mg/day to this regimen resulted in a total reduction of LDL-C levels of 27%, which is still far from optimal. se, many patients are statin non-responsive, poorly controlled 1O with statin therapy, or cannot tolerate statin therapy, in general, these patients are unable to e cholesterol control with ative treatments. There is a large unmet medical need for new treatments that can address the short-comings of current treatment options.

Specific populations ble by the therapeutic methods of the invention include subjects indicated for LDL apheresis, subjects with PCSK9-activating mutations (gain of function mutations, “GOF”), subjects with heterozygous Familial Hypercholesterolemia , subjects with primary hypercholesterolemia who are statin intolerant or statin uncontrolled, and subjects at risk for developing hypercholesterolemia who may be tably treated. Other indications include ipidemia and dyslipidemia associated with secondary causes such as Type 2 diabetes mellitus, tatic liver diseases (primary biliary cirrhosis), nephrotic syndrome, hypothyroidism, obesity, and the prevention and treatment of sclerosis and cardiovascular diseases. However, depending on the severity of the afore-mentioned diseases and conditions, the treatment of subjects with the antibodies and antigen-binding fragments of the invention may be contraindicated for n diseases and conditions.

Therapeutic Administration and Formulations The invention provides therapeutic compositions comprising the anti-PCSK9 antibodies or antigen-binding fragments thereof of the present invention. The administration of therapeutic compositions in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide ed transfer, delivery, nce, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for e, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as CTINTM), DNA ates, anhydrous absorption pastes, oil-in-water and in-oil emulsions, emulsions carbowax (polyethylene s of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci l 52:23 8-3 11.

The dose may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. When the antibody of the present invention is used for treating various conditions and diseases associated with PCSK9, ing hypercholesterolemia, disorders associated with LDL and apolipoprotein B, and lipid metabolism disorders, and the like, in an adult patient, it is advantageous to intravenously administer the antibody of the present invention normally at a single dose of about 0.01 to about mg/kg body weight, more preferably about 0.02 to about 7, about 0.03 to about 5, or about 0.05 to about 3 mg/kg body weight. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. s delivery systems are known and can be used to administer the pharmaceutical composition of the ion, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells e of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of uction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral or l routes. If the dy of present invention is stered per injection, subcutaneous injection is preferred. Oral or peroral administration is preferred for the HlVlG—CoA inhibitor, e.g. the statin. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.

The pharmaceutical composition can be also delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249: 533, Treat et al. (1989) in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez Berestein and Fidler (eds.), Liss, New York, pp. 353-365, Berestein, ibid., pp. 317-327, see lly ibid.).

In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra, Sefton (1987) CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used, see, Medical Applications of lled Release, Langer and Wise (eds.), CRC Pres, Boca Raton, Florida (1974). In yet another embodiment, a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose (see, e. g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138, 1984).

The injectable preparations may include dosage forms for intravenous, aneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable ations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the dy or its salt described above in a sterile aqueous medium or an oily medium tionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic on containing glucose and other ary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene , polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-SO (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule. A pharmaceutical composition of the present invention can be red subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen ry device can be reusable or disposable. A reusable pen delivery device generally utilizes a eable cartridge that contains a pharmaceutical ition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can y be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen ry device can then be reused. In a disposable pen ry device, there is no replaceable cartridge. Rather, the disposable pen 12’] delivery device comes prefllled with the ceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical ition of the present invention. Examples e, but certainly are not limited to AUTOPENTM (Owen Mumford, Inc., Woodstock, UK), DISETRONICTM pen (Disetronic Medical Systems, Burghdorf, Switzerland), HUTVIALOG MIX M pen, HUMALOGTM pen, HUMALIN 70/30TM pen (Eli Lilly and Co., Indianapolis, IN), NOVOPENTM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIORTM (Novo k, Copenhagen, Denmark), BDTM pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPENTM, OPTIPEN PROTM, OPTIPEN STARLETTM, and OPTICLIKTM (sanofl-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen ry devices having ations in subcutaneous delivery of a pharmaceutical composition of the present invention include, but certainly are not limited to the SOLOSTARTM pen (sanof1-aventis), the FLEXPENTM (Novo Nordisk), and the KWIKPENTM (Eli Lilly).

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients.

Such dosage forms in a unit dose include, for example, s, pills, capsules, ions (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 4 to about 500 mg or from about 5 to about 500 mg per dosage form in a unit dose, especially in the form of injection, it is preferred that the aforesaid dy is contained in about to about 100 mg or about 5 to 400 mg (such as from about 50 to about 200 mg per 1 ml injection solution) and in about 10 to about 250 mg or to about 500 mg for the other dosage forms.

The invention provides eutic methods in which the antibody or antibody fragment of the invention is useful to treat hypercholesterolemia associated with a variety of conditions involving hPCSK9. The anti-PCSK9 antibodies or antibody fragments of the invention are particularly useful for the treatment of hypercholesterolemia and the like. Combination therapies may include the CSK9 antibody of the invention with, for example, one or more of any agent that (l) induces a cellular depletion of cholesterol synthesis by inhibiting 3-hydroxy methylglutaryl (HIVIG)—coenzyme A (CoA) reductase, such as statin, atorvastatin, simvastatin, pitavastatin, statin, fluvastatin, lovastatin, pravastatin; (2) inhibits cholesterol uptake and or bile acid re-absorption; (3) increase lipoprotein catabolism (such as niacin); and activators of the LXR transcription factor that plays a role in cholesterol elimination such as 22- hydroxycholesterol or fixed combinations such as ezetimibe plus simvastatin; a statin with a bile resin (e.g., cholestyramine, colestipol, colesevelam), a fixed combination of niacin plus a statin (e.g., niacin with lovastatin); or with other lipid lowering agents such as omegafatty acid ethyl esters (for example, omacor).

RED ASPECTS OF PRESENT INVENTION In the following, some preferred aspects and embodiments of present invention will be : ASPECTS D TO PATIENT POPULATIONS — A) l. A method for treating a disease or ion in which PCSK9 expression or activity causes an impact comprising administering a therapeutic amount of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/keXin type 9) to a subject in need thereof, wherein the subject in need thereof falls into one or more of the following groups of subjects: (i) subjects having a serum LDL cholesterol (LDL-C) level of at least 100 mg/dL; [at least 130 mg/dL, at least 160 mg/dL / at least 200 mg/dL]; (ii) subjects having a serum HDL-C level of less than 40 mg/dL; (iii) subjects having a serum cholesterol level of at least 200 mg/dL [240 mg/dL]; (iv) subjects having a serum triacylglycerol level of at least 150 mg/dL [at least 200 mg/dL; at least 500 mg/dL]; wherein said triacylglycerol level is determined after fasting for at least 8 hours; (v) ts being at least 35 years old [at least 40 /50 /55 /60 / 65 / 70 years old]; (vi) subjects younger than 75 years [65 / 60 / 55 / 50 / 45 / 40 years]; (vii) subjects having a BMI of25 [26/27/28/29/30/31 /32 /33 /34/35/36/37 /38 /39] or more; (viii) male subjects; (ix) female subjects; (X) subjects in which the administration of said antibody or antigen-binding fragment thereof leads to a reduction in the serum LDL-C level by at least 30 mg/dL [40 mg/dL; 50 mg/dL; 60 mg/dL; 70 mg/dL] relative to predose level; or (xi) subjects in which the administration of said antibody or antigen-binding fragment f leads to a reduction in the serum LDL-C level by at least 20% [30%; 40%; 50%; 60%] relative to predose level.

A method for treating a disease or condition in which PCSK9 expression or activity causes an impact comprising 1O administering a therapeutic amount of an antibody or an n-binding fragment thereof which specifically binds hPCSK9 (human tein convertase subtilisin/kexin type 9) to a subject in need thereof, wherein the subject in need thereof does not fall into one or more of the following groups of ts: (i) smokers; (ii) persons being 70 years old or older; (iii) persons suffering from hypertension; (iv) women who are pregnant; (v) women who are trying to become nt; (vi) women who are breast-feeding; (vii) s who have or ever had a disease affecting the liver; (viii) persons who had any unexplained abnormal blood tests for liver function; (ix) persons who drink excessive amounts of alcohol; (x) persons having kidney problems; (xi) persons suffering from hypothyroidism; (xii) persons suffering from muscle disorders; (xiii) persons having encountered previous muscular problems during treatment with lowering medicine; (xiv) persons having serious problems with their breathing; (xv) persons taking one or more of the following medicines: medicines altering the way the immune systems works (e.g. ciclosporin or antihistamines); antibiotics or antifungal medicines (e.g. erythromycin; clarithromycin; ketoconazole; itraconazole; rifampicin; fusidic acid); nes regulating lipid levels (e.g. gemf1brozil; colestipol); calcium channel blockers (e.g. verapamil; zem); medicines regulating the heart rhythm (digoxin; amiodarone); protease tors used in the treatment of HIV (e.g. nelf1navir); in; oral contraceptives; antacids or St. John’s Wort; or (xvi) persons drinking more than 0.1 L of grapefruit juice per day; (xvii) persons having a body mass index (BMI) of more than 40; (xviii) persons having a body mass index (BMI) of less than 18; (xix) persons suffering from type 1 diabetes or type 2 diabetes; (xx) persons positive for hepatitis B or hepatitis C; or (xxi) persons having a known sensitivity to monoclonal antibody therapeutics. 3. An antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/kexin type 9) for use in the treatment of a disease or condition in which PCSK9 sion or activity causes an ; wherein the antibody or antigen-binding fragment thereof is for administration to a t g at least into one of the following groups of subjects: (i) subjects having a serum LDL-C level of at least 100 mg/dL [at least 130 mg/dL / at least 160 mg/dL / at least 200 mg/dL]; (ii) subjects having a serum HDL-C level of less than 40 mg/dL; (iii) subjects having a serum cholesterol level of at least 200 mg/dL [240 mg/dL]; (W) subjects having a serum triacylglycerol level of at least 150 mg/dL [at least 200 mg/dL; at least 500 mg/dL]; wherein said triacylglycerol level is ined after fasting for at least 8 hours; (V) subjects being at least 35 years old [at least 40 /50 /55 /60 / 65 / s old]; (vi) ts younger than 75 years [65 /60 /55 /50 /45 /40 years]; 1O (vii) subjects having a BMI of25 [26/27/28 /29/30 /31 /32/33/34/35/36/37 /38 /39] or more; (viii) male ts; (iX) female subjects; (X) subjects in which the administration of said antibody or antigen-binding fragment thereof leads to a reduction in the serum LDL-C level by at least 20 mg/dL [30 mg/dL; 40 mg/dL; 50 mg/dL; 60 mg/dL; 70 mg/dL]; or (xi) subjects in which the administration of said antibody or antigen-binding fragment f leads to a reduction in the serum LDL-C level by at least 10% [20%; %; 40%; 50%; 60%].

An antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/keXin type 9) for use in the treatment of a disease or condition in which PCSK9 expression or activity causes an impact; wherein the antibody or antigen-binding fragment thereof is for stration to a subject who does not fall into one or more of the following groups of subjects: (i) smokers; (ii) persons being 70 years old or older; (iii) persons suffering from hypertension; (M women who are nt; (V) women who are trying to become pregnant; (vi) women who are breast-feeding; (vii) persons who have or ever had a disease affecting the liver; (viii) persons who had any unexplained abnormal blood tests for liver on; (iX) persons who drink excessive amounts of alcohol; 1O (X) persons having kidney problems; (xi) persons suffering from hypothyroidism; (xii) persons suffering from muscle disorders; (xiii) persons having encountered previous ar problems during treatment with lipid-lowering medicine; (xiv) persons having serious problems with their ing; (XV) persons taking one or more of the following medicines: medicines altering the way the immune systems works (e.g. ciclosporin or antihistamines); antibiotics or antifungal medicines (e.g. erythromycin; clarithromycin; ketoconazole; nazole; rifampicin; fusidic acid); medicines regulating lipid levels (e.g. gemf1brozil; ipol); calcium channel blockers (e.g. verapamil; diltiazem); medicines regulating the heart rhythm (digoxin; amiodarone); protease inhibitors used in the ent of HIV (e.g. nelf1navir); warfarin; oral contraceptives; antacids or St. John’s Wort; (xvi) persons drinking more than 0.1 L of grapefruit juice per day; (xvii) persons having a body mass index (BMI) of more than 40; (xviii) persons having a body mass index (BMI) of less than 18; (xix) persons ing from type 1 diabetes or type 2 diabetes; (xx) persons ve for hepatitis B or hepatitis C; or (xxi) persons having a known sensitivity to monoclonal antibody therapeutics.

The method of aspect I or 2 or the antibody of aspect 2 or 3; wherein the disease or ion in which PCSK9 expression or activity causes an impact is ameliorated; improved; inhibited or prevented with a PCSK9 antagonist.

The method or the antibody of any one of aspects 1 to 5; wherein the e or condition in which PCSK9 expression or activity causes an impact is selected from the group consisting of: hypercholesterolemia; hyperlipidemia; dyslipidemia; atherosclerosis and cardiovascular diseases.

The method or the antibody of any one of aspects 1 to 6; wherein the subject in need f is a subject indicated for LDL apheresis; a subject with PC SK9-activating mutations; a subject with heterozygous al Hypercholesterolemia; a subject with primary hypercholesterolemia who is statin uncontrolled; a subject at risk for developing hypercholesterolemia; a subject with hypercholesterolemia; hyperlipidemia; dyslipidemia; atherosclerosis or cardiovascular diseases.

The method or the antibody of any one of aspects 1 to 7; wherein the antibody or antigen- binding fragment thereof is a recombinant human antibody or nt thereof. 9. The method or the antibody of any one of aspects 1 to 8, wherein the antibody or the antigen-binding fragment thereof is characterized by one or more of the ing: (i) capable of reducing serum total cholesterol at least about 25 to about 35% and sustaining the reduction over at least a 24 day period ve to a predose level; (ii) capable of reducing serum LDL cholesterol at least about 65-80% and sustaining the reduction over at least a 24 day period relative to a predose level; (iii) capable of reducing serum ceride at least about 25-40% relative to predose level; (iv) achieves one or more of (i)-(iii) without reducing serum HDL cholesterol or reducing serum HDL cholesterol no more than 5% relative to predose level; (v) achieves one or more of (i)-(iii) with little or no measurable effect on liver function, as determined by ALT and AST measurements. 10. The method or the antibody of any one of aspects 1 to 9, wherein the antibody or the antigen-binding nt thereof comprises — a heavy chain CDR3 (HCDR3) domain selected from the group consisting of SEQ ID N08, 32, 56, 80, 104, 128, 152, 176, 200, 224, 248, 272, 296, 320, 344, 368, 392, 416, 440, 464, 488, 512, 536, 560, 584, 608, 632, 656, 680, 704 and 728; and — a light chain CDR3 ) domain selected from the group consisting of SEQ ID NO:16, 40, 64, 88, 112, 136, 160, 184, 208, 232, 256, 280, 304, 328, 352, 376, 400, 424, 448, 472, 496, 520, 544, 568, 592, 616, 639, 664, 688, 712 and 736. 11. The method or the antibody of any one of s 1 to 9, wherein the antibody or the antigen-binding fragment thereof comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 12. The method or the antibody of aspect 11, wherein the antibody or antigen-binding nt thereof comprises heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86, and 88. 13. The method or the antibody of aspect 12, wherein the antibody or antigen-binding 1O nt thereof comprises an HCVR amino acid ce as shown in SEQ ID NO: 90 and an LCVR amino acid sequence as shown in SEQ ID NO: 92. 14. The method or the antibody of any one of aspects 1 to 9, wherein the antibody or antigen- binding fragment f binds to the same epitope on hPCSK9 as an antibody comprising heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86, and 88.

. The method or the antibody of any one of aspects 1 to 9, wherein the antibody or antigen- binding fragment thereof competes for binding to hPCSK9 with an antibody comprising heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86, and 88. 16. The method or the antibody of any one of aspects 1 to 15, further comprising: administering a therapeutic amount of an HIVIG—CoA ase inhibitor to the subject in a dosage of between 0.05 mg to 100 mg. 17. The method or the antibody of aspect 16, wherein the HlVlG—CoA reductase inhibitor is a statin. 18. The method or the antibody of aspect 17, wherein the statin is ed from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin. 19. The method or the antibody of aspect 18, wherein the statin is — cerivastatin administered in a daily dosage of between 0.05 mg and 2 mg, — atorvastatin administered in a daily dosage of n 2 mg and 100 mg, — simvastatin administered in a daily dosage of between 2 mg and 100 mg, — pitavastatin administered in a daily dosage of between 0.2 mg and 100 mg, — rosuvastatin administered in a daily dosage of between 2 mg and 100 mg, — fluvastatin administered in a daily dosage of between 2 mg and 100 mg, — atin administered in a daily dosage of n 2 mg and 100 mg, or — tatin administered in a daily dosage of between 2 mg and 100 mg.

. An article of manufacture comprising (a) a packaging material, (b) an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9, and (C) a label or packaging insert contained within the packaging material indicating that patients receiving treatment with said antibody or antigen-binding fragment can be treated for a disease or condition selected from the group ting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases and further indicating that subjects falling into one or more groups of subjects as recited in aspect I can be treated. 21. An article of manufacture comprising (a) a packaging material; (b) an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9; and (C) a label or packaging insert contained within the packaging material indicating that patients receiving treatment with said antibody or n-binding fragment can be treated for a e or ion ed from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases and further indicating that the treatment of patients with said antibody or antigen-binding fragment thereof is indicated for patients belonging to one or more groups of subjects as d in aspect 2. 22. The article of manufacture according to aspect 20 or 21, wherein the antibody or antigen- binding fragment is an antibody or antigen-binding nt as specified in any of aspects 3 to 19. 23. The article of manufacture according to any of aspects 20 to 22, wherein the label or packaging insert contains reference to a method of treatment according to any of aspects 1, 2 or 5-19. 24. A method of testing the efficacy of an antibody or an antigen-binding nt thereof which specifically binds hPCSK9 for the treatment of a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases, said method comprising: treating a selected patient population with said antibody or antigen-binding fragment thereof, wherein each patient in said population has an LDL cholesterol (LDL-C) level of more than lOOmg/dL, and determining the efficacy of said antibody or antigen-binding nt thereof by determining the LDL-C level in the patient population before and after administration of said antibody or antigen-binding fragment thereof, wherein a reduction of the LDL-C level by at least 25% relative to a predose level in at least 75% of the patient population indicates that said antibody or n-binding fragment thereof is efficacious for the treatment of said disease or condition in said t population, wherein each patient falls into one or more groups of subjects as recited in aspect I.

. A method of testing the efficacy of an antibody or an antigen-binding fragment f which specifically binds hPCSK9 for the treatment of a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, idemia, atherosclerosis and cardiovascular diseases, said method comprising: determining the efficacy of an antibody or antigen-binding nt f that has been used for the treatment of a selected t population with said antibody or antigen-binding fragment thereof, wherein each patient in said population has an LDL cholesterol (LDL-C) level of more than lOOmg/dL by determining the LDL-C level in the patient population before and after stration of said antibody or antigen-binding fragment thereof, wherein a reduction of the LDL-C level by at least 25% ve to a predose level in at least 75% of the patient population indicates that said antibody or antigen-binding nt thereof is efficacious for the treatment of said disease or condition in said patient population; wherein each patient falls into one or more groups of subjects as recited in aspect I. 26. The method of aspect 25, wherein each t in said population has received a lipid lowering treatment by administration of a statin for at least 6 weeks prior to treatment with said antibody or antigen-binding fragment thereof. 1O 27. The method of any of aspects 24 to 26, wherein the dy or antigen-binding fragment is an antibody or antigen-binding fragment as specified in any of aspects 3 to 19. 28. The method of any of aspects 24 to 27, wherein the selected patient tion is or has been treated with a method of ent ing to any of aspects 1, 2 or 5-19. 29. A method for testing the y of a compound in lowering cholesterol levels in a subject, comprising the steps: (a) providing a rodent, (b) administering an antibody or an antigen-binding fragment thereof which specifically binds PCSK9 to the rodent, (c) administering a test compound to said rodent, (d) determining the effect of the test compound in the , wherein a lowering of the cholesterol level in the rodent as compared to the cholesterol level of a control animal indicates that the test compound is efficacious in lowering cholesterol levels in a subject, wherein the control animal is from the same species as said rodent, and wherein the control animal has not been challenged with the test compound.

ASPECTS RELATED TO PATIENT POPULATIONS — B) l. A method of treating a subject suffering from a disease or disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, the method comprising: (a) selecting a subject with a blood LDL-C level greater than 100 mg/dL, and (b) administering to said subject a composition comprising an antibody or antigen binding fragment thereof that specifically binds to human proprotein tase subtilisin/keXin type 9 (hPC 8K9), thereby ng cholesterol levels in the subject in need f. 2. The method of aspect I, wherein the disease or condition is selected from the group consisting of: hypercholesterolemia, hyperlipidemia, idemia, and atherosclerosis. 3. The method of aspect I, wherein the disease ion is primary hypercholesterolemia or familial hypercholesterolemia. 4. The method of aspect I, wherein the disease or ion is hypercholesterolemia which is uncontrolled by statins. 5. The method of aspect I, n the subject has a body mass indeX (BMI) of less than 18 kg/m2 or greater than 40 kg/mz. 6. The method of aspect I, wherein the subject was not previously cted to partake in a cholesterol-lowering diet. 7. The method of aspect I, wherein the subject has not previously taken a cholesterol- lowering drug except for atorvastatin. 8. The method of aspect 7, wherein the atorvastatin was administered at about 10 mg per day. 9 The method of aspect 7, wherein the cholesterol-lowering drug is selected from the group consisting of f1brates, bile acid resins, niacin, intestinal cholesterol absorption (ICA) blockers, and omega-3 fatty acids.

. The method of aspect 9, wherein the niacin is administered at greater than 500 mg per day. 11. The method of aspect 9, wherein the omega-3 fatty acids are administered at greater than 1000 mg per day. 12. The method of aspect 1, n the subject does not suffer from diabetes. 13. The method of aspect 12, wherein the diabetes is type 1 diabetes. 14. The method of aspect 12, n the diabetes is type 2 diabetes.

. The method of aspect 12, wherein the type 2 diabetes is treated with insulin. 16. The method of aspect 12, wherein the subject has a blood glycated hemoglobin concentration greater than or equal to 8.5%. 17. The method of aspect 1, wherein the subject is negative for hepatitis B and C e antigen. 18. The method of aspect 1, wherein the subject has a blood triglycerides concentration of greater than 350 mg/dL. 19. The method of aspect 1, wherein the subject has fewer than 1500 phils per cubic mm ofblood.

. The method of aspect 1, wherein the subject has fewer than 0 platelets per cubic mm ofblood. 21. The method of aspect 1, wherein the subject is female. 22. The method of aspect 21, wherein the subject is not pregnant. 23. The method of aspect 1, wherein the subject has a blood thyroid stimulating e concentration that is above the lower limit of normal and below the upper limit of normal. 24. The method of aspect 23, wherein the t has serum creatine of less than 1.4 of the upper limit of normal.

. The method of aspect 1, wherein the subject is a male. 26. The method of aspect 25, wherein the subject has serum creatine of less than 1.5 of the upper limit of normal. 27. The method of aspect 1, wherein the subject has an amount of aspartate transaminase that is less than two times the upper limit of normal. 28. The method of aspect 1, wherein the subject has an amount of alanine transaminase that is less than two times the upper limit of normal. 29. The method of aspect 1, wherein the antibody or antigen-binding fragment is stered in a dosage amount within the range of about 5 mg to about 500 mg.

. The method of aspect 29, wherein the antibody or antigen-binding fragment is administered in a dosage amount within the range of about 50 mg to about 300 mg. 31. The method of aspect 29, wherein the antibody is stered at between 200 and 300 mg every four weeks. 32. The method of aspect 29, wherein the antibody or antigen-binding fragment is administered in a dosage amount of about 150 mg. 33. The method of aspect 1, wherein the antibody or antigen-binding fragment thereof is administered to the subject every other week (E2W). 34. The method of aspect 1, wherein the antibody or antigen-binding fragment f is administered to the subject every fourth week (E4W). 1O 35. The method of aspect 1, wherein the antibody or the antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 36. The method of aspect 1, wherein the antibody or antigen-binding fragment ses a HCVR/LCVR amino acid ce pair as shown in SEQ ID NOs: 90/92. 37. The method of aspect 1, wherein the antibody or antigen-binding fragment thereof competes for binding to hPCSK9 with an antibody or antigen-binding nt comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 38. The method of aspect 1, wherein the antibody is administered subcutaneously. 39. The method of aspect 38, wherein the antibody is administered in the abdomen. 40. The method of aspect 1, further comprising administering a HIVIG—CoA ase inhibitor to the subject. 41. The method of aspect 40, wherein the HIVIG—CoA reductase inhibitor is administered in a dosage amount in the range of about 0.05 mg to 100 mg. 42. The method of aspect 41, wherein the HlVlG—CoA reductase inhibitor is a statin. 43. The method of aspect 42, wherein the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin. 44. The method of aspect 42, wherein the statin is atorvastatin administered at a dosage of 10 mg or 80 mg. 45. The method of aspect 44, wherein the statin is administered at about 10 mg per day and at 80 mg one day in an 8 week period. 46. A method of lowering terol levels in a subject in need thereof, sing: (a) ing a subject with a blood low density lipoprotein cholesterol (LDL-C) level greater than 100 mg/dL, and (b) administering to said subject a composition comprising an antibody or antigen binding fragment thereof that specifically binds to human proprotein convertase subtilisin/keXin type 9 (hPC 8K9), thereby ng cholesterol levels in the subject in need thereof. 47. The method of aspect 46, wherein the disease or condition is selected from the group consisting of: hypercholesterolemia, hyperlipidemia, dyslipidemia, and atherosclerosis. 48. The method of aspect 46, wherein the disease condition is primary hypercholesterolemia or familial holesterolemia. 49. The method of aspect 46, wherein the disease or condition is hypercholesterolemia which is rolled by statins. 50. The method of aspect 46, wherein the subject has a body mass index (BMI) of less than 18 kg/m2 or greater than 40 kg/mz. 51. The method of aspect 46, n the subject was not previously instructed to partake in a cholesterol-lowering diet. 52. The method of aspect 46, wherein the subject has not previously taken a cholesterol- lowering drug except for atorvastatin. 53. The method of aspect 52, wherein the atorvastatin was administered at about 10 mg per day. 54. The method of aspect 52, n the cholesterol-lowering drug is selected from the group consisting of fibrates, bile acid , niacin, intestinal cholesterol absorption (ICA) blockers, and 3 fatty acids. 55. The method of aspect 54, wherein the niacin is administered at greater than 500 mg per day. 56. The method of aspect 54, wherein the omega-3 fatty acids are administered at r than 1000 mg per day. 57. The method of aspect 46, wherein the subject does not suffer from diabetes. 58. The method of aspect 57, wherein the diabetes is type 1 diabetes. 59. The method of aspect 57, wherein the diabetes is type 2 diabetes. 60. The method of aspect 57, wherein the type 2 diabetes is treated with insulin. 61. The method of aspect 57, wherein the subject has a blood glycated hemoglobin concentration greater than or equal to 8.5%. 62. The method of aspect 46, wherein the subject is negative for hepatitis B and C surface antigen. 63. The method of aspect 46, wherein the subject has a blood triglycerides concentration of r than 350 mg/dL. 64. The method of aspect 46, wherein the subject has fewer than 1500 neutrophils per cubic mm ofblood. 65. The method of aspect 46, wherein the subject has fewer than 100,000 platelets per cubic mm ofblood. 66. The method of aspect 46, wherein the subject is female. 67. The method of aspect 66, wherein the subject is not pregnant. 68. The method of aspect 46, wherein the t has a blood thyroid stimulating hormone concentration that is above the lower limit of normal and below the upper limit of normal. 69. The method of aspect 68, n the subject has serum creatine of less than 1.4 of the upper limit of normal. 70. The method of aspect 46, wherein the t is a male. 71. The method of aspect 70, wherein the subject has serum creatine of less than 1.5 of the upper limit of normal. 72. The method of aspect 46, n the subject has an amount of aspartate transaminase that is less than two times the upper limit of normal. 73. The method of aspect 46, wherein the subject has an amount of alanine transaminase that is less than two times the upper limit of normal. 74. The method of aspect 46, wherein the antibody or antigen-binding fragment is administered in a dosage amount within the range of about 5 mg to about 500 mg. 75. The method of aspect 74, wherein the antibody or antigen-binding fragment is administered in a dosage amount within the range of about 50 mg to about 300 mg. 76. The method of aspect 74, n the antibody is administered at between 200 and 300 mg every four weeks. 77. The method of aspect 74, wherein the antibody or antigen-binding fragment is administered in a dosage amount of about 150 mg. 78. The method of aspect 46 wherein the antibody or n-binding fragment thereof is administered to the subject every other week (E2W). 79. The method of aspect 46, wherein the antibody or antigen-binding fragment thereof is stered to the subject every fourth week (E4W). 80. The method of aspect 46 wherein the antibody or the n-binding nt comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 81. The method of aspect 46, wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 82. The method of aspect 46, wherein the antibody or antigen-binding fragment thereof es for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 83. The method of aspect 46, wherein the antibody is stered subcutaneously. 84. The method of aspect 38, wherein the antibody is administered in the abdomen. 85. The method of aspect 46, further comprising administering a HlVIG—CoA reductase inhibitor to the subject. 1O 86. The method of aspect 85, n the HlVIG—CoA reductase inhibitor is stered in a dosage amount in the range of about 0.05 mg to 100 mg. 87. The method of aspect 86, n the HlVIG—CoA reductase inhibitor is a statin. 88. The method of aspect 87, wherein the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin. 89. The method of aspect 88, wherein the statin is atorvastatin administered at a dosage of 10 mg or 80 mg. 90. The method of aspect 89, wherein the atorvastatin is administered at about 10 mg per day and at 80 mg one day in an 8 week period. 18200137V1 ASPECTS RELATED TO DOSAGE REGIMENS — A) A method for treating a disease or condition in which PCSK9 expression or activity causes an , comprising: — administering a therapeutic amount of an dy or an n-binding fragment f which cally binds hPCSK9 (human proprotein convertase subtilisin/kexin type 9) to a subject in need thereof, wherein the antibody or antigen- binding fragment thereof is administered in a dosage amount ranging from 5 mg to 500 mg, and — administering a therapeutic amount of an HlVlG—CoA reductase inhibitor to said subject, wherein the CoA reductase inhibitor is administered in a dosage amount ranging from 0.05 mg to 100 mg.

An antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/kexin type 9) for use in the treatment of a disease or condition in which PCSK9 expression or activity causes an impact, wherein the antibody or antigen-binding fragment thereof is for administration in a dosage amount g from 5 mg to 500 mg, wherein the antibody or antigen-binding fragment thereof is further for administration in combination with an HlVlG—CoA reductase inhibitor at a dosage amount ranging from 0.05 mg to 100 mg.

The method of aspect I or the antibody of aspect 2, wherein the disease or condition in which PCSK9 expression or ty causes an impact is ameliorated, improved, inhibited or prevented with a PCSK9 antagonist. 4. The method or the antibody of any one of aspects 1-3, wherein the disease or condition in which PCSK9 expression or activity causes an impact is selected from the group consisting of: holesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular es.

. The method or the antibody of anyone of aspects 1 to 4, wherein the subject in need thereof is a subject indicated for LDL apheresis, a subject with PC SK9-activating mutations, a subject with zygous Familial Hypercholesterolemia, a subject with primary hypercholesterolemia who is statin uncontrolled, a subject at risk for developing hypercholesterolemia, a subject with hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis or cardiovascular diseases. 6. The method or the antibody of any one of aspects 1 to 5, wherein the HlVlG—CoA reductase inhibitor is administered three times per day, twice per day, or once per day. 7. The method or the antibody of any one of s 1 to 6, wherein the HlVlG—CoA reductase inhibitor is stered every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. 8. The method or the antibody of any one of aspects 1 to 6, wherein the HlVlG—CoA reductase inhibitor is administered every week, every other week, every third week, or every fourth week. 9. The method or the antibody of any one of aspects 1 to 8 wherein the CoA reductase inhibitor is administered in the g, at noon or in the evening.

. The method or the antibody of any one of aspects 1 to 9; wherein the HlVlG—CoA reductase inhibitor is a statin. ll The method or the antibody of aspect 10; wherein the statin is selected from the group consisting of cerivastatin; atorvastatin; simvastatin; pitavastatin; rosuvastatin; fluvastatin; lovastatin; and pravastatin. 12. The method or the antibody of aspect 11; n the statin is — statin administered in a daily dosage of between 0.05 mg and 2 mg; — atorvastatin administered in a daily dosage of between 2 mg and 100 mg; — tatin stered in a daily dosage of between 2 mg and 100 mg; — pitavastatin administered in a daily dosage of between 0.2 mg and 100 mg; — statin administered in a daily dosage of between 2 mg and 100 mg; — fluvastatin administered in a daily dosage of between 2 mg and 100 mg; — lovastatin administered in a daily dosage of between 2 mg and 100 mg; or — pravastatin administered in a daily dosage of between 2 mg and 100 mg; 13. The method or the antibody of any one of aspects 1 to 12; wherein the antibody or antigen-binding fragment thereof is administered to the subject every other week. 14. The method or the antibody of any one of aspects 1 to 13, wherein the dy or antigen-binding fragment thereof is administered in a dosage amount ranging from 50 mg to 300 mg. 15. The method or the dy of any one of aspects 1 to 14, wherein the antibody or antigen-binding fragment thereof is a recombinant human antibody or nt thereof. 16. The method or the antibody of any one of s 1 to 15, wherein the antibody or the antigen-binding fragment thereof is characterized by one or more of the following: 1O (i) capable of reducing serum total cholesterol at least about 25 to about 35% and sustaining the reduction over at least a 24 day period relative to a predose level, (ii) capable of ng serum LDL cholesterol at least about 65-80% and sustaining the reduction over at least a 24 day period ve to a predose level, (iii) capable of reducing serum triglyceride at least about 25-40% relative to predose level, (iv) achieves one or more of (i)-(iii) without reducing serum HDL cholesterol or reducing serum HDL cholesterol no more than 5% relative to predose level, (v) achieves one or more of (i)-(iii) with little or no measurable effect on liver function, as determined by ALT and AST measurements. 17. The method or the antibody of any one of aspects 1 to 16, wherein the antibody or the antigen-binding fragment thereof comprises — a heavy chain CDR3 (HCDR3) domain selected from the group consisting of SEQ ID N08, 32, 56, 80, 104, 128, 152, 176, 200, 224, 248, 272, 296, 320, 344, 368, 392, 416, 440, 464, 488, 512, 536, 560, 584, 608, 632, 656, 680, 704 and 728, and — a light chain CDR3 (LCDR3) domain selected from the group consisting of SEQ ID NO:16, 40, 64, 88, 112, 136, 160, 184, 208, 232, 256, 280, 304, 328, 352, 376, 400, 424, 448, 472, 496, 520, 544, 568, 592, 616, 639, 664, 688, 712 and 736. 18. The method or the antibody of any one of aspects 1 to 16, wherein the antibody or the antigen-binding fragment thereof comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 19. The method or the antibody of aspect 18, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86 and 88.

. The method or the antibody of aspect 19, wherein the dy or n-binding fragment thereof comprises an HCVR amino acid sequence as shown in SEQ ID NO: 90 and an LCVR amino acid sequence as shown in SEQ ID NO: 92. 21. The method or the antibody of any one of aspects 1 to 16, wherein the antibody or antigen-binding nt thereof binds to the same epitope on hPCSK9 as an antibody comprising heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86, and 88. 22. The method or the antibody of any one of aspects 1 to 16, wherein the antibody or n-binding nt thereof competes for binding to hPCSK9 with an antibody comprising heavy and light chain CDR amino acid sequences as shown in SEQ ID NOs: 76, 78, 80, 84, 86, and 88. 23. An e of manufacture comprising (a) a packaging material; (b) an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9; and (C) a label or packaging insert contained within the packaging material ting that patients receiVing treatment with said antibody or antigen-binding fragment can be treated for a disease or ion selected from the group consisting of hypercholesterolemia; hyperlipidemia; dyslipidemia; atherosclerosis and cardiovascular diseases. 24. An article of cture comprising (a) a packaging material; (b) an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9; and (C) a label or packaging insert contained within the packaging material indicating the treatment of patients with said antibody or antigen-binding fragment thereof together with the application of a statin.

. An e of manufacture comprising (a) a packaging material; (b) an antibody or an n-binding fragment thereof which specifically binds hPCSK9; and (C) a label or packaging insert indicating that the ent of patients with said antibody or antigen-binding fragment thereof er with a statin is contraindicated for patients belonging to one or more of the following groups: (i) smokers; (ii) persons being 70 years old or older; (iii) persons suffering from ension; (M women who are pregnant; (V) women who are trying to become pregnant; (vi) women who are breast-feeding; (vii) persons who have or ever had a disease affecting the liver; (viii) persons who had any unexplained abnormal blood tests for liver function; (iX) persons who drink excessive s of alcohol; 1O (X) persons having kidney problems; (xi) s suffering from hypothyroidism; (xii) s suffering from muscle disorders; (xiii) persons having encountered previous muscular problems during treatment with lipid-lowering medicine; (xiv) persons having serious problems with their breathing; (XV) persons taking one or more of the following medicines: medicines altering the way the immune systems works (e.g. ciclosporin or antihistamines); antibiotics or ngal medicines (e.g. erythromycin; clarithromycin; ketoconazole; itraconazole; rifampicin; fusidic acid); medicines regulating lipid levels (e.g. gemf1brozil; colestipol); calcium channel blockers (e. g. verapamil; zem); nes regulating the heart rhythm (digoxin; amiodarone); protease inhibitors used in the treatment of HIV (e.g. nelf1navir); warfarin; oral contraceptives; antacids or St. John’s Wort; or (xvi) persons drinking more than 0.1 L of grapefruit juice per day; (xvii) persons having a body mass index (BMI) of more than 40; (xviii) persons having a body mass index (BMI) of less than 18; (xix) persons suffering from type 1 diabetes or type 2 diabetes; (xx) persons positive for hepatitis B or hepatitis C; or (xxi) persons having a known sensitivity to monoclonal antibody therapeutics. 26. The article of manufacture according to one of aspects 23 to 25; wherein the antibody or n-binding fragment is an antibody or antigen-binding fragment as specified in any of s 2 to 22. 27. The article of manufacture according to one of aspects 23 to 26; wherein the label or ing insert contains reference to a method of treatment according to any of s 1; or 3-22. 28. A method of testing the efficacy of an dy or an antigen-binding fragment f which specifically binds hPCSK9 for the treatment of a disease or condition ed from the group consisting of hypercholesterolemia; hyperlipidemia; dyslipidemia; atherosclerosis and cardiovascular diseases; said method comprising: treating a selected patient population with said dy or antigen-binding fragment thereof; wherein each patient in said population has an LDL cholesterol (LDL-C) level of more than lOOmg/dL; and determining the y of said antibody or antigen-binding fragment thereof by determining the LDL-C level in the patient population before and after administration of said antibody or antigen-binding fragment thereof; wherein a reduction of the LDL-C level by at least 25% relative to a predose level in at least 75% of the patient population indicates that said antibody or antigen-binding nt thereof is efficacious for the treatment of said disease or condition in said patient population. 29. A method of testing the efficacy of an antibody or an antigen-binding nt thereof which specifically binds hPCSK9 for the treatment of a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis and cardiovascular diseases, said method comprising: determining the efficacy of an antibody or antigen-binding fragment thereof that has been used for the treatment of a selected patient population with said antibody or antigen-binding fragment thereof, wherein each patient in said population has an LDL cholesterol (LDL-C) level of more than lOOmg/dL by ining the LDL-C level in the t population before and after administration of said antibody or antigen-binding fragment thereof, wherein a reduction of the LDL-C level by at least 25% ve to a predose level in at least 75% of the patient population indicates that said antibody or antigen-binding nt thereof is efficacious for the treatment of said disease or condition in said patient population.

. The method of aspect 28 or 29, wherein each patient in said population has ed a lipid lowering treatment by administration of a statin for at least 6 weeks prior to ent with said antibody or antigen-binding fragment thereof. 31. The method of any of aspects 28 to 30, n the antibody or antigen-binding fragment is an antibody or n-binding fragment as specified in any of aspects 2 to 22. 32. The method of any of aspects 28 to 3 1, wherein the selected patient population is treated with a method of treatment according to any of aspects 1, or 3-22. 33. A package comprising an antibody or antigen-binding fragment thereof of one or more of aspects 2 to 22 and a label, said label comprising a d statement which informs the patient that the treatment of the antibody together with a statin is ted in one or more of the tions of aspect 4. 34. A package comprising an antibody or antigen-binding fragment thereof of one or more of aspects 2 to 22 and a label, said label comprising a printed statement which informs the patient that the treatment of the dy together with a statin is indicated for patients belonging to one or more of the following groups: (i) smokers; (ii) persons being 70 years old or older; (iii) s suffering from hypertension; (iv) women who are pregnant; (V) women who are trying to become pregnant; (vi) women who are breast-feeding; (vii) persons who have or ever had a disease affecting the liver; (viii) persons who had any unexplained abnormal blood tests for liver function; (ix) persons who drink excessive amounts of alcohol; (x) persons having kidney problems; (xi) persons suffering from hypothyroidism; (xii) persons suffering from muscle disorders; (xiii) persons having encountered previous muscular ms during treatment with lowering medicine; (xiv) persons having serious problems with their breathing; (XV) persons taking one or more of the following medicines: medicines altering the way the immune systems works (e.g. ciclosporin or antihistamines), otics or antifungal medicines (e.g. erythromycin, clarithromycin, ketoconazole, itraconazole, rifampicin, fusidic acid), medicines regulating lipid levels (e. g. gemf1brozil, colestipol), calcium channel rs (e.g. verapamil, diltiazem), medicines regulating the heart rhythm in, amiodarone), protease inhibitors used in the treatment of HIV (e.g. nelf1navir), warfarin, oral contraceptives, antacids or St. John’s Wort, or (xvi) persons drinking more than 0.1 L of grapefruit juice per day, (xvii) persons having a body mass index (BMI) of more than 40, (xviii) persons having a body mass index (BMI) of less than 18, (xix) s suffering from type 1 diabetes or type 2 diabetes, (XX) persons positive for hepatitis B or hepatitis C, or (xxi) persons having a known sensitivity to monoclonal antibody therapeutics.

. A method of regulating the LDL level in the blood comprising: — stering a therapeutic amount of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein tase subtilisin/kexin type 9) to a subject in need thereof, wherein the antibody or antigen- binding fragment thereof is stered in a dosage amount ranging from 5 mg to 500 mg, and — administering a therapeutic amount of an HlVlG—CoA reductase inhibitor to said subject, wherein the HlVlG—CoA reductase inhibitor is administered in a dosage amount ranging from 0.05 mg to 100 mg. 36. A method of preventing effects of a (persistently) increased LDL level in the blood comprising: — administering a therapeutic amount of an antibody or an antigen-binding fragment thereof which cally binds hPCSK9 (human proprotein convertase subtilisin/keXin type 9) to a t in need f, wherein the antibody or antigen- binding fragment thereof is administered in a dosage amount ranging from 5 mg to 500 mg, and — stering a therapeutic amount of an HlVlG—CoA reductase inhibitor to said subject, wherein the HlVlG—CoA reductase tor is administered in a dosage amount ranging from 0.05 mg to 100 mg. 37. A method of determining whether a ceutical compound is utilizable for rating, improving, inhibiting or preventing a disease or condition in which PCSK9 activity or expression has an impact comprising (a) administering to a subject a compound that specifically binds to PCSK9, preferably an antibody or antigen-binding fragment thereof 1cally binding to PCSK9, and (b) determining what fraction of PCSK9 in the blood is attached to the compound from (a).

ASPECTS RELATED TO DOSAGE REGIMENS — B) A method of treating a subject suffering from a disease or disorder characterized by elevated low-density lipoprotein terol (LDL-C) levels, the method comprising administering to the subject: (1) an dy, or antigen-binding fragment thereof, which specifically binds to human proprotein convertase subtilisin/keXin type 9 (hPCSK9), and (2) an HlVlG—CoA ase inhibitor, wherein the antibody or antigen-binding fragment thereof is administered at a dosage amount within the range of about 5 mg to about 500 mg, thereby treating the subject.

The method of aspect I, n the disease or condition is ed from the group 1O consisting of: hypercholesterolemia, hyperlipidemia, dyslipidemia, and atherosclerosis.

The method of aspect I, wherein the e condition is primary hypercholesterolemia or familial hypercholesterolemia.

The method of aspect I, wherein the e or condition is hypercholesterolemia which is uncontrolled by statins.

The method of aspect I, wherein the antibody or antigen-binding fragment is administered in a dosage amount within the range of about 50 mg to about 300 mg.

The method of aspect I, wherein the antibody or antigen-binding fragment is administered in a dosage amount of about 150 mg.

The method of aspect I, wherein the antibody or antigen-binding fragment thereof is administered to the subject every other week (EZW).

The method of aspect 1, wherein the antibody or n-binding fragment thereof is administered to the subject every fourth week (E4W).

The method of aspect 1, wherein the treatment reduces serum total terol at least about 25% to about 35% relative to a e level and sustains the reduction over at least a 24 day period.

. The method of aspect 1, wherein the treatment s serum total cholesterol at least about 65% to about 80% relative to a predose level and sustains the reduction over at least a 24 day period. 11. The method of aspect 1, wherein the treatment reduces serum triglyeride levels at least about 25% to about 40% relative to a e level. 12. The method of aspect 1, wherein the treatment reduced serum HDL cholesterol no more than 5% relative to a predose level. 13. The method of aspect 1, wherein the treatment has little or no measurable effect on liver function, as determined by ALT and AST measurements. 14. The method of aspect 1, wherein the antibody or the antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

. The method of aspect 1, wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 16. The method of aspect 1, wherein the antibody or antigen-binding fragment thereof competes for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 17. The method of aspect 1, wherein the HlVlG—CoA reductase inhibitor is administered in a dosage amount in the range of about 0.05 mg to 100 mg. 18. The method of aspect 1, wherein the HlVlG—CoA ase inhibitor is a statin. 19. The method of aspect 1, wherein the statin is selected from the group consisting of statin, atorvastatin, simvastatin, statin, rosuvastatin, fluvastatin, lovastatin, and pravastatin.

. The method of aspect 1, n the statin is atorvastatin administered at a dosage of 10 mg or 80 mg. 21. A method of enhancing the LDL-C lowering actiVity in a subject undergoing statin therapy, the method comprising administering to the subject an dy, or n- binding fragment thereof, which specifically binds to human proprotein convertase subtilisin/keXin type 9 (hPCSK9), wherein the antibody or antigen-binding fragment thereof is administered at a dosage amount within the range of about 5 mg to about 500 mg, thereby enhancing LCL-C lowering activity of the statin therapy in the subject. 22. The method of aspect 21, wherein the subject is resistant to the statin therapy prior to administration of the antibody. 23. The method of aspect 21, wherein the subject suffers from a disease or condition selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, and atherosclerosis. 24. The method of aspect 21, wherein the disease condition is primary hypercholesterolemia or familial holesterolemia.

. The method of aspect 21, wherein the antibody or n-binding fragment is administered in a dosage amount within the range of about 50 mg to about 300 mg. 26. The method of aspect 21, wherein the antibody or antigen-binding fragment is administered in a dosage amount of about 150 mg. 27. The method of aspect 21, wherein the antibody or antigen-binding fragment thereof is administered to the subject every other week (E2W). 28. The method of aspect 21, wherein the dy or n-binding fragment thereof is administered to the subject every fourth week (E4W). 29. The method of aspect 21, wherein the treatment reduces serum total cholesterol at least about 25% to about 35% relative to a predose level and sustains the ion over at least a 24 day period.

. The method of aspect 21, wherein the treatment reduces serum total cholesterol at least about 65% to about 80% relative to a predose level and sustains the reduction over at least a 24 day period. 31. The method of aspect 21, wherein the treatment reduces serum triglyeride levels at least about 25% to about 40% relative to a predose level. 32. The method of aspect 21, wherein the treatment d serum HDL cholesterol no more than 5% relative to a predose level. 33. The method of aspect 21, wherein the treatment has little or no measurable effect on liver function, as determined by ALT and AST ements. 34. The method of aspect 21, wherein the antibody or the antigen-binding fragment comprises 1the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92.

. The method of aspect 21, n the antibody or n-binding fragment comprises a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 36. The method of aspect 21, wherein the antibody or antigen-binding fragment thereof es for binding to hPCSK9 with an antibody or antigen-binding fragment comprising a CVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 37. The method of aspect 21, wherein the statin is ed from the group ting of cerivastatin, statin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, and pravastatin. 38. The method of aspect 21, wherein the statin is atorvastatin administered at a dosage of 10 mg or 80 mg. 39. A pharmaceutical unit dosage form comprising an antibody, or antigen-binding fragment thereof, which specifically binds to hPCSK9, and pharrnaceutically acceptable carrier, wherein the antibody or antigen-binding fragment is present in a dosage amount within the range of about 5 mg to about 500 mg. 40. The dosage form of aspect 39, wherein the antibody or antigen binding fragment is present in a dosage amount within the range of about 50 mg to about 300 mg. 41. The dosage form of aspect 39, wherein the antibody or antigen binding fragment is present in a dosage amount of about 150 mg. 42. The dosage form of aspect 39, wherein the antibody or the antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 43. The dosage form of aspect 39, wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 44. The dosage form of aspect 39, wherein the antibody or antigen-binding nt thereof competes for binding to hPCSK9 with an antibody or antigen-binding nt 1O comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 45. The dosage form of aspect 39, further comprising a HIVIG—CoA reductase inhibitor. 46. The dosage form of aspect 39, wherein the HIVIG—CoA ase inhibitor is present in a dosage amount in the range of about 0.05 mg to 100 mg. 47. The dosage form of aspect 39, wherein the HIVIG—CoA reductase inhibitor is a statin. 48. The dosage form of aspect 39, wherein the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, statin, rosuvastatin, fluvastatin, lovastatin, and tatin. 49. The dosage form of aspect 39, wherein the statin is atorvastatin present at dosage amount of 10 mg or 80 mg. 50. A kit for treating elevated low-density lipoprotein cholesterol (LDL-C) levels in a subject, the kit comprising (a) pharmaceutical unit dosage form comprising an antibody, or antigen-binding fragment thereof, which specifically binds to hPCSK9, and pharmaceutically acceptable carrier, wherein the antibody or antigen-binding fragment is present in a dosage amount within the range of about 5 mg to about 500 mg, and (b) a label or packaging insert with instructions for use. 51. The kit of aspect 50, wherein the label indicates that patients receiving treatment with said antibody or antigen-binding fragment can be d for a e or condition selected from the group consisting of holesterolemia, hyperlipidemia, dyslipidemia, and atherosclerosis and cardiovascular diseases. 52. The kit of aspect 51, wherein the disease or condition is y hypercholesterolemia or familial hypercholesterolemia. 53. The kit of aspect 51, wherein the disease or condition is hypercholesterolemia which is uncontrolled by s. 54. The kit of aspect 50, wherein the antibody or antigen-binding fragment is present in dosage amount within the range of about 50 mg to about 300 mg. 55. The kit of aspect 50, wherein the antibody or antigen-binding nt is present in a dosage amount of about 150 mg. 56. The kit of aspect 50, wherein the label or packaging insert indicates that the antibody or antigen-binding fragment f is administered to the subject every other week (E2W). 57. The kit of aspect 50, wherein the label or ing insert indicates that the antibody or antigen-binding fragment thereof is administered to the subject every fourth week (E4W). 58. The kit of aspect 50, wherein the dy or the antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 59. The kit of aspect 50, wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 60. The kit of aspect 50, wherein the antibody or antigen-binding fragment thereof competes for binding to hPCSK9 with an antibody or antigen-binding nt comprising a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 61. The kit of aspect 50, further comprising an HIVIG—CoA ase inhibitor. 62. The kit of aspect 61, wherein the inhibitor in a dosage amount in the range of about 0.05 mg to 100 mg. 63. The kit of aspect 50, wherein the HIVIG—CoA reductase inhibitor is a statin. 64. The kit of aspect 50; wherein the statin is selected from the group consisting of cerivastatin; atorvastatin; simvastatin; pitavastatin; rosuvastatin; fluvastatin; lovastatin; and pravastatin.

The kit of aspect 50; wherein the instructions indicate that the statin is atorvastatin administered at a dosage of 10 mg or 80 mg. 66. The kit of aspect 50; wherein the instructions indicate that treatment with the antibody or an is contraindicated for patients belonging to one or more of the following groups: (XXii) smokers; (XXiii) persons being 70 years old or older; (XXiv) persons ing from hypertension; (XXV) women who are pregnant; (xxvi) women who are trying to become pregnant; (xxvii) women who are breast-feeding; (XXViii) persons who have or ever had a e affecting the liver; (XXiX) persons who had any unexplained abnormal blood tests for liver function; (XXX) persons who drink ive amounts of alcohol; (XXXi) persons having kidney problems; (XXXii) persons suffering from yroidism; (XXXiii) s suffering from muscle disorders; (XXXiv)persons having encountered previous ar problems during treatment with lipid-lowering medicine; (XXXV) persons having serious problems with their breathing; (xxxvi)persons taking one or more of the following medicines: medicines altering the way the immune systems works (e.g. ciclosporin or antihistamines), antibiotics or antifungal medicines (e.g. erythromycin, hromycin, nazole, itraconazole, rifampicin, fusidic acid), medicines regulating lipid levels (e.g. gemf1brozil, colestipol), calcium channel blockers (e. g. verapamil, diltiazem), medicines regulating the heart rhythm (digoxin, 1O amiodarone), protease inhibitors used in the treatment of HIV (e.g. avir), warfarin, oral contraceptives, antacids or St. John’s Wort, or (xxxvii) persons drinking more than 0.1 L of grapefruit juice per day, (xxxviii) persons having a body mass index (BMI) of more than 40, )persons having a body mass indeX (BMI) of less than 18, (X1) persons suffering from type 1 diabetes or type 2 diabetes, (Xli) persons positive for hepatitis B or hepatitis C, or (Xlii) persons having a known sensitivity to monoclonal dy therapeutics.

ASPECTS RELATED TO COMPOSITIONS Pharmaceutical composition comprising about 40 to about 500 mg per dose of an antibody or an antigen-binding fragment f which specifically binds hPCSK9 (human proprotein convertase subtilisin/keXin type 9) together with a pharmaceutically able excipient or r.

Pharmaceutical composition according to aspect 1, comprising about about 50 mg to about 500mg, about 50 mg to about 300mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350mg, of about 400 mg, about 450 mg or about 500 mg of the antibody or antigen-binding fragment f.

Pharmaceutical composition according to one of the aspects 1 or 2 comprising about 150, 200 or 300 mg of the antibody or antigen-binding fragment thereof.

Pharmaceutical composition according to one of the aspects 1-3 comprising an effective dose of an antibody or an antigen-binding fragment thereof which specifically binds hPCSK9 (human proprotein convertase subtilisin/keXin type 9), wherein the dose is sufficient for sustained reduction of low-density lipoprotein (LDL-C) levels over a period of at least 14, at least 15, at least 16, at least 17, at 8, at least 19, at least 20, at least 1O 21, at least 22, at least 23 or at least 28 days after administration, together with a pharmaceutically acceptable excipient or carrier.

Pharmaceutical composition according to one of the aspects l-4, wherein the dose is sufficient for sustained reduction of LDL-C levels over a period of at least 14 days, 28 days or 1 month.

Pharmaceutical composition according to one of the aspects l-5 further sing an effective amount of an HlVlG—CoA ase inhibitor.

Pharmaceutical composition according to aspect 6, wherein the HlVlG—CoA reductase inhibitor is a statin, preferably selected from the list consisting or: cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, atin or tatin and is preferably atorvastatin.

Pharmaceutical composition according to aspect 6 or 7, comprising about 0.05 mg to about 100 mg, about 0,5 mg to about 100 mg, about 5 mg to about 90 mg, about 10 mg, about 20 mg, about 40 mg or about 80 mg of HlVlG—CoA ase inhibitor and ably about 10, about 20, about 40 or about 80 mg.

Pharmaceutical composition according to one of the aspects 6 to 8, comprising an effective dose of HlVlG—CoA ase inhibitor for lowering LDL-D levels by administration once per day.

. Pharmaceutical composition according to one of the aspects 1 to 9, wherein the antibody or antigen-binding fragment thereof has one or more of the following features: reduction of low-density lipoprotein (LDL-C) levels of at least about -25% to about -40% relative to a predose level with a sustained reduction over at least a 14 day-period upon administration to a subject, wherein the sustained ion is preferably at least -25% and more preferably at least -30% relative to a predose level, ularly if administered in a dose of about 40 to about 60 mg, preferably about 45 to about 55 mg and more preferably about 50 mg in a biweekly administration regime (every other week, E2W), 1O reduction of low-density lipoprotein (LDL-C) of at least about -50% to about - 65% relative to a predose level with a sustained reduction over at least a 14 day- period upon administration to a subject, wherein the sustained ion is preferably at least -40% and more preferably at least -45% relative to a e level, particularly if administered in a dose of about 100 mg EZW. reduction of low-density otein (LDL-C) of at least about -60 % to at least about -75% [e.g. at least about -60 %, at least about -65%, at least about -70 or at least about -75%] relative to a predose level with a sustained reduction over at least a 14 day-period upon administration to a subject, n the sustained reduction is preferably at least -55% and more preferably at least -60% relative to a e level, particularly when administered in a dose of about 150 mg E2W, ion of low-density lipoprotein (LDL-C) of at least about 40% to about 75% relative to a predose level with a sustained reduction over at least a 28 day period wherein the sustained reduction is preferably at least -3 5% and more preferably at least -40% relative to a predose level, particularly when administered in a dose of about 200 mg E4W reduction of low-density lipoprotein (LDL-C) of at least about -50 % to about - 75% relative to a predose level with a sustained reduction over at least a 28 day- period upon administration to a subject, n the ned reduction is preferably at least -40% and more preferably at least -45% relative to a predose level, particularly when administered in a dose of about 300 mg E4W, f increase of serum HDL cholesterol levels of at least 2%, at least 2.5%, at least, 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5% or at least 5.5% relative to a predose level upon administration to a t, particularly when admimistered in a dose of about 150 mg E2W, g. little or no measurable effect on troponin levels upon administration to a t, h. increase of one or more of: Total-Cholesterol levels, ApoB levels, non HDL-C levels, Apo-B/ApoA-l ratio, upon administration to a subject. ll. Pharmaceutical composition according to one of the aspects 1-9, n the antibody or antigen-binding fragment thereof is capable of overcoming statin resistance when administered to a subject with statin-resistant hypercholesterolemia. 12. Pharmaceutical composition according to one of the aspects l-lO, wherein the dy or antigen-binding fragment thereof comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92 substantially identical sequences having at least 98% or 99% identity therewith. l3. Pharmaceutical composition according to one of the aspects 1-1 1, wherein the antibody or antigen-binding nt thereof ses a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92 or a pair of substantially identical sequences having at least 98% or 99% identity therewith. l4. Pharmaceutical composition according to one of the aspects l-lO, wherein the antibody or antigen-binding fragment thereof es for binding to hPCSK9 with an antibody or antigen-binding fragment sing a HCVR/LCVR amino acid sequence pair as shown in SEQ ID NOs: 90/92. 15. ceutical composition according to one of the aspects l-l3, wherein the antibody or antigen-binding nt thereof binds an epitope comprising amino acid residue 238 ofhPCSK9 (SEQ ID NO:755). 16. Pharmaceutical composition according to one of the aspects 1-14, wherein the antibody or antigen-binding fragment f binds an epitope comprising one or more of amino acid residues at positions 238, 153, 159 and 343 of hPCSK9 (SEQ ID NO:755). 17. Pharmaceutical composition ing to one of the aspects 1-15, wherein the dy or antigen-binding fragment thereof binds an epitope which does not se an amino acid residue at positions 192, 194, 197 and/or 237 of hPCSK9 (SEQ ID NO:755). 18. Pharmaceutical composition according to one of the aspects 1-16 comprising the antibody or antigen-binding fragment thereof as dry formulation for dissolution such as a lyophilized powder, -dried powder or water free concentrate. 1O 19. Pharmaceutical composition according to one of the aspects 1-17 comprising the antibody or fragment thereof as liquid formulation, e. g. injection or infusion solution.

. Pharmaceutical composition according to one of the aspects 4-18 sing the HIVIG— CoA reductase inhibitor as peroral formulation, e. g. capsule or tabled, or as liquid formulation, e.g. suspension, dispersion or solution, e. g. for peroral administration, injection or infusion. 21. Injection on according to aspect 19, preferably comprising about 40 mg to about 200 mg or about 40 to about 200 mg, e.g. about 40 mg, about 50 mg, about 75 mg, at about 100 mg, about 150 mg or about 200 mg of the antibody or antigen-binding fragment thereof per 1 ml volume. 22. Dry formulation according to aspect 17, ably comprising about 40 mg to about 500 mg, 50 to about 500 mg, about 50 to about 400, about 50 to about 300 e.g. about 40 mg, about 50 mg, about 75 mg, at about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500mg and preferably about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg and even more preferably about 150 mg, about 200 mg or about 300 mg of the antibody or antigen-binding fragment thereof per dose. 23. Antibody or antigen binding fragment thereof as comprised in one of the pharmaceutical compositions according to one of the aspects 1-17. 24. Unit dosage form comprising the ceutical composition according to one of the aspects 1-20, the injection on according to aspect 21, the dry formulation according to aspect 22, or the antibody according to aspect 23.

. Unit dosage form ing to aspect 24, comprising about 40 mg, about 50 mg, about 75 mg, at about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg of the antibody or antigen- binding fragment thereof. 26. Unit dosage form ing to one of the aspects 24 or 25 comprising the dy or fragment thereof as dry formulation for dissolution in a hermetically sealed container such as a Vial, an ampoule or te. 27. Unit dosage form according to one of the s 24 or 25 comprising the antibody or fragment thereof as liquid formulation in a hermetically sealed container such as a Vial, a sachette, a pre-fllled syringe, a pre-fllled autoinjector or a cartridge for a reusable syringe or applicator. 28. Unit dosage form according to aspect 26 or 27, wherein the quantity of active ingredient is indicated on the hermetically-sealed container. 29. Article of manufacture comprising, the pharmaceutical composition according to one of the aspects 1-20, the liquid formulation according to aspect 21 or the dry formulation according to aspect 22, the antibody or antigen-binding fragment thereof according to aspect 23 or one or more unit dosage forms according to one of the aspects 24-28, and a container.

. Article of manufacture ing to aspect 29 comprising separate unit dosage forms the antibody according to aspect 23 and the HlVlG—CoA reductase inhibitor according to one of the aspects 5-9 or 20. 31. Article of manufacture according to aspect 30 comprising one or more of the following components: a. One or more unit dosage forms comprising the dy according to aspect 23, b. One or more unit dosage forms comprising the HlVlG—CoA ase inhibitor according to one of the aspects 6-9 or 20, c. Instructions for use, d. A device for application of the antibody such as a syringe. 32. Article of manufacture according to aspect 3 1, comprising suff1cient unit dosage forms of the antibody and preferably also of the HlVlG—CoA ase tor, for one single administration of antibody and HlVlG—CoA reductase inhibitor, for a two-week (i.e. 14- day) treatment with antibody and HVlG-CoA reductase inhibitor, for a four week (i.e, 28- day) ent with dy and HVlG-CoA reductase inhibitor or for a one-month treatment with antibody and HlVlG-CoA reductase inhibitor. 33. Article of manufacture according to aspect 32, comprising suff1cient unit dosage forms of antibody for a bi-weekly administration regime or a four-weekly administration regime or a monthly administration regime. 34. Article of manufacture according to aspect 32 or 33 comprising sufficient unit dosage forms of HlVlG—CoA reductase inhibitor for a daily administration regime.

. Pharmaceutical composition according to one of the aspects 1 to 20 or dy or antigen-binding fragment f according to aspect 21 for use in the treatment of a disease or condition in which PCSK9 sion or activity causes an impact, preferably for use in the lowering of elevated LDL-C (low density lipoprotein C) levels 36. Pharmaceutical composition or antibody or antigen-binding fragment f according to aspect 35, wherein the disease or condition is selected from the group consisting of: elevated total cholesterol levels, ed low-density lipoprotein (LDL-C) levels, holesterolemia, hyperlipidemia, dyslipidemia, and atherosclerosis, particularly primary hypercholesterolemia, familial hypercholesterolemia, or hypercholesteremia which is uncontrolled by statins 37. Pharmaceutical composition or antibody or antigen-binding fragment thereof according to aspect 35 or 36, wherein the composition, the antibody or n-binding fragment thereof is administered to the subject every other week (E2W), every fourth week (E4W) or once a month. 38. Pharmaceutical composition or antibody or n-binding fragment thereof according to one of the aspects 35-3 7, comprising co-administration of an HlVlG-CoA reductase inhibitor, preferably an CoA reductase inhibitor according to one of the aspects 7-9 or 20. 39. Pharmaceutical composition or antibody according to aspect 38, wherein the HlVlG—CoA reductase inhibitor is administered once a day and preferably every day. 40. Method for preparing a pharmaceutical composition according to one of the aspects 1-20 1O comprising mixing the antibody or antigen-binding fragment thereof and optionally the HlVlG—CoA reductase inhibitor with one or more pharmaceutical excipients or carriers. 41. Method for preparing a unit dosage form according to one of the aspects 24 to 28 comprising admeasuring an amount of the pharmaceutical composition according to one of the aspects 1-20, the antibody ing to aspect 21, the liquid formulation according to aspect 22 or the dry formulation according to aspect 23 comprising one or more doses of the dy and optionally of the CoA reductase inhibitor and tailor them as physically discrete units suitable as unitary dosages for human and/or animal subjects. 42. Method for preparing an article of cture ing to one of the aspects 29-34 comprising packaging the pharmaceutical composition according to one of the aspects 1- 20, the antibody according to aspect 21, the liquid formulation according to aspect 22, the dry formulation according to aspect 23 or one or more of the unit dosage forms of one of aspects 24 to 28 in a container.

EXAlVIPLES The following es are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not ed to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure cy with respect to numbers used but some experimental errors and deviations should be accounted for. Unless ted otherwise, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. 1O Study 1 This was a multicenter, randomized, double-blind, parallel-group, o-controlled, 12- week study to assess the efficacy and safety of antibody 316P in patients with an elevated low- density otein cholesterol (LDL-C) (Z 100 mg/dL or 2,59 mmol/L), when treated with atorvastatin (10mg, 20 mg, or 40 mg) at a stable dose for at least 6 weeks. The randomization was stratified by the dose of atorvastatin received prior to randomization. After the double-blind period patients were followed during an 8-week follow-up period. The primary objective of the study was to evaluate the effect of antibody 316P on LDL-C levels after 12 weeks of treatment in comparison with placebo in patients with LDL-C (Z 100 mg/dL or 2,59 mmol/L) on ongoing stable atorvastatin therapy.

The following doses/dose regimens were evaluated: 50mg, 100mg and 150mg every 2 weeks (E2W), 200 mg and 300 mg every 4 weeks (E4W) in comparison with placebo. t study comprised a total of 122 patients (20 in placebo, 19 in 50 mg E2W group, 20 in 100 mg E2W group, 20 in 150 mg E2W group, 22 in 200 mg E4W group, and 21 in 300 mg E4W group). Forty siX (37.7%) of these patients were randomized in the stratum atorvastatin 10 mg, 43 (35.2%) in the stratum atorvastatin 20 mg and 33 ) in the stratum atorvastatin 40 Patient selection Inclusion criteria: — Patients (patients ing a lipid lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg, 20 mg or 40 mg for at least 6 weeks prior to ing period or drug na'1've patients) with primary hypercholesterolemia likely to have low- density lipoprotein cholesterol (LDL-C) Z 100 mg/dL (Z 2.59 mmol/L) at the end of the run-in period on atorvastatin therapy (Week-l).

— Patients with primary hypercholesterolemia treated with atorvastatin at stable dose of 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening period and likely to have LDL-C Z 100 mg/dL (Z 2.59 mmol/L) at the screening Visit Week-l.

Exclusion criteria: — LDL-C < 100 mg/dL (< 2.59 mmol/L) at Week-l (V1): 0 After the run-in period on atorvastatin (10 mg, 20 mg, or 40 mg) for patients receiving a lipid lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg, 20 mg or 40 mg for at least 6 weeks prior to the screening period, or drug naive patients. 0 At the first Visit for patients who are being treated with stable dose of statin (10 mg, 20 mg, or 40 mg) for at least 6 weeks prior to ing Visit Week-l.

Use of a statin other than atorvastatin 10 mg, 20 mg, or 40 mg, or use of other lipid lowering drugs ing but not limited to fibrates, bile acid resins, niacin > 500 mg, intestinal cholesterol absorption (ICA) blockers, or omega-3 fatty acids at doses > 1000 mg during the screening period.

Body mass index (BMI) < 18 or > 40 kg/m2 at Week-7 or Week-1.

Patients not previously instructed on a terol-lowering diet.

Patients with type 1 diabetes.

Patients with type 2 diabetes treated with insulin.

Patients with type 2 diabetes and with an HbAlc 2 8.5% at Week-7 or Week-1 (considered poorly controlled).

Laboratory findings ed before randomization: 0 Positive test for tis B surface antigen and/or hepatitis C antibody. 0 Triglycerides (TG) > 350 mg/dL (> 3.95 mmol/L) at Week -7 or Week -1. o Neutrophils < 1,500/mm3 and/or platelets < 100,000/mm3. 0 Positive serum or urine pregnancy test in females of childbearing potential. 0 Abnormal sensitive TSH level (> ULN or < LLN) ing to the normal values of the Central Laboratory 0 ce of renal impairment as determined by: . Men: serum creatinine > 1.5 X ULN.

' Women: serum creatinine > 1.4 X ULN. 0 ALT or AST > 2XULN. o CPK > 3XULN (1 repeat lab is allowed).

— All contraindications to the protocol mandated background therapy (i.e. atorvastatin) or warning/precaution of use (when appropriate) as displayed in the respective National Product Labeling that was used for g these exclusion ia.

— Known sensitivity to monoclonal antibody therapeutics.

— Pregnant or breast-feeding women.

— Women of childbearing potential with no effective contraceptive method.

Patient population: Demographics and baseline teristics were generally r across treatment . The median age of patients was 58.0 years (28.7% of ts were 2 65 years of age) with patients aged 24-75 years. The mean range for baseline LDL-C and Total-C among treatment groups was similar and ranged between 3.214 mmol/L and 3.500 mmol/L for LDL-C and between 5.284 mmol/L and 5.521 mmol/L for Total-C. The BMI (kg/m2) was between 19.7 to 40.5 with a mean value of 29.04 and a median value of 28.4 (with 63.6% of the patients having a BMI of <30 and 36.4% of the patients having a BMI of >30). 80 (65.6%) of the 122 patients had hyperlipoproteinemia Type IIa (familiar hypercholesterinemia) according to Fredrickson fication, 41 (33.6%) type IIb (combined hyperlipidemia) and 1 (08%) type IV (endogenous hyperlipidemia). Overall 82% of the patients had received previous treatment with a lipid lowering agent, whereas 22% had not.

Duration of study period per subject: The duration of study participation depended on the status of the patient at screening: - For patients ing atorvastatin 10 mg, 20 mg or 40 mg at a stable dose for at least 6 weeks prior to screening, the study participation was approximately 21 weeks including a screening period of 1 week, a double-blind treatment period of 12 weeks and a follow-up period of 8 weeks.

- For patients receiving a lipid lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg, 20 mg or 40 mg for at least 6 weeks prior to screening, or drug naive patients, the study participation was approximately 27 weeks including a screening period of 7 weeks (including a run-in period of 6 weeks), a double-blind treatment period of 12 weeks, and a follow-up period of 8 weeks.

Active compounds: Antibody 3 l6P: dy 3 l6P is a fully human antibody comprising a HCVR as shown in SEQ ID NO: 90 and LCVR as shown in SEQ ID NO: 92 of the sequence listing. The CDR sequences are shown in SEQ ID NOs: 76, 78, and 80 (CDRl, CDR2, CDR3 of the heavy chain) as well as in SEQ ID NOs: 84, 86, and 88 (CDRl, CDR2, CDR3 of the light chain).

Antibody 3OON: Antibody 3OON is a fully human dy comprising a HCVR as shown in SEQ ID NO: 218 and LCVR as shown in SEQ ID NO: 226 of the sequence listing. The CDR sequences are shown in SEQ ID NOs: 220, 222, and 224 (CDRl, CDR2, CDR3 of the heavy chain) as well as in SEQ ID NOs: 228, 230, and 232 (CDRl, CDR2, CDR3 ofthe light chain).

Study arms: Arm 1: The first group of patients received two injections of 1 mL each of dy 3 l6P, administered subcutaneously in the abdomen, with a dose regimen at 50 mg, every two weeks, for a ent period of 12 weeks, Atorvastatin was administered once per day at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.

Arm 2: The second group of patients received two injections of 1 mL each of antibody 3 l6P, administered subcutaneously in the abdomen, with a dose regimen at 100 mg, every two weeks, for a treatment period of 12 weeks, Atorvastatin was administered once per day at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.

Arm 3: The third group of patients received two injections of 1 mL each of antibody 3 l6P, stered aneously in the abdomen, with a dose regimen at 150 mg, 1O every two weeks, for a treatment period of 12 weeks, Atorvastatin was administered once per day at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.

Arm 4: The fourth group of patients received two injections of 1 mL each of a placebo on, administered subcutaneously in the abdomen, every two weeks, for a treatment period of 12 weeks, Atorvastatin was administered once per day at stable dose of 10 mg, 20 mg, or 40 mg as background therapy.

Arm 5: The fifth group of patients received two injections of 1 mL each of antibody 3 l6P, administered subcutaneously in the abdomen, with a dose regimen at 200 mg, every four weeks, for a treatment period of 12 weeks, a placebo solution was administered alternating with the administration of antibody 3 l6P so that the patient has the same ion scheme as the ts in arms 1 to 4, i.e. the patient received two ions of 1 mL each of a placebo solution in weeks 2, 6, and 10 and two injections of 1 mL each of antibody 3 l6P in weeks 0, 4, 8, and 12, Atorvastatin was administered once per day at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.

Arm 6: The sixth group of patients received two injections of 1 mL each of antibody 3 l6P, administered subcutaneously in the abdomen, with a dose regimen at 300 mg, every four weeks, for a treatment period of 12 weeks, a placebo solution was administered alternating with the administration of 1O antibody 3 l6P so that the t has the same injection scheme as the patients in arms 1 to 4, i.e. the patient received two injections of 1 mL each of a o solution in weeks 2, 6, and 10 and two ions of 1 mL each of antibody 3 l6P in weeks 0, 4, 8, and 12, Atorvastatin wais administered once per day at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.

Primary and key secondary endpoints: The primary efficacy variable is the percent change in calculated LDL-C from baseline to Week 12, which is defined as: lOOX (calculated LDL-C value at Week 12 — calculated LDL-C value at baseline)/calculated LDL-C value at beseline.

In case of unavailable calculated LDL-C value at Week 12 as defined above, then the last calculated LDL-C value measured during the efficacy period and before the Week 12 time window will be used to impute the missing Week 12 calculated LDL-C value (Last ation d Forward [LOCF] procedure). ary efficacy endpoints are: The absolute change (mmol/L and mg/dL) from ne in calculated LDL-C to Week 12, defined as: (calculated LDL-C value at Week 12-calculated LDL-C value at ne), using same definitions and imputation rules as for the primary endpoint.

The percentage of patients with calculated LDL-C<70mg/dL (1.81 mmol/L) and <1OO mg/dL (2.59 ) at Week 12.

Percent change in ApoB from baseline to Week 12: same definitions and rules as for LDL-C, except for baseline value that will be the ApoB value measured at ransomization visit (Visit2) and before first IP injection, or, if missing, the last unscheduled value obtained from Visit 1(Week-1) up to before the first IP injection. 1O Percent and absolute (mmol/L and mg/dL) change in non HDL-C from baseline to Week12: same definitions and rules as for LDL-C. t and absolute (mmol/L and mg/dL) change in fasting Triglycerides from baseline to Week 12: same definitions and rules as for LDL-C, excluding measurements in not fasting patients or ements with missing fasting status.

Percent change in ApoA-l from baseline to week 12: same definitions and rules as for AboB.

Absolute change in the ration AboB/ApoA-l from baseline to Week12: same definitions and rules as for AboB.

Percent change in Lp(a) from baseline to Week12: same definitions and rules as for ApoB. In case of Lp(a) value below the detection limit, a value y between zero and the detection limit will be used for calculation Results: The y of 316P treatment on LDL-C level-lowering Table 1 — LDL-C in mmol/L (mg/dL) at Week 12 LDL Cholesterol Placebo 50mg 200 mg 100 mg 300 mg 150 mg mmol/L ) E2W E4W E2W E4W E2W Number of patients N=20 N=19 N=20 N=2 1 Baseline Mean 3.489 3.214 3.318 3.422 3.500 3.238 (134.7) (124.1) ) (132.1) (135.1) (125.0) 3.134 (121) 3.121 3.225 3.225 3.250 3.121 Median (120.5) (124.5) (124.5) (125.5) (120.5) Week 12 Mean 3.173 1.859 1.722 1.251 1.766 0.860 (122.5) (71.8) (66.5) (48.3) (68.2) (33.2) 3.121 1.813 1.567 1.101 1.632 0.984 Medlan (120.5) (70.0) (60.5) (42.5) (63.0) (38.0) Week 12 - change from baseline Mean -O.317 -1.355 -1.595 -2.171 -1.733 -2.378 (-12,2) (-52.3) (-61.6) ) (-66.9) (-91.8) Median -0.265 -1.295 -1.593 -2.117 -1.904 -2.363 (-10.3) (-50.0) (-61.5) (-81.8) (—73.5) (—91.3) Week 12 - % change from baseline Mean -6.08 -41.06 -47.23 -63.90 -48.29 -72.68 Median -6.92 -37.04 -49.46 -64.28 -51.98 -74.83 Statistically significant decreases in percent change from baseline in LDL-C at 12 weeks were observed in all groups compared to the placebo group. The greatest decrease was seen in the 100 mg E2W (-63.90%) and 150 mg E2W (-72.68%) groups compared with a slight decrease in the placebo group (-6.08%) (LS mean difference vs. placebo of -58.36% and -68.78%, respectively); these decreases observed after the first injection were maintained throughout the study and more particularly hout the interval period n the injections. Large ses from baseline in LDL-C at 12 weeks were also observed in the 200 mg and 300 mg E4W groups (-47.23% and 48.29%, respectively with a LS mean difference vs. o of -42.53% and — 42.26%) with also significant decreases of at least about -40% during the interval periods. Among 18 patients in the 150 mg E2W group, 17 had a LDL-C reduction from ne > 50% at week 12.

Effects of 316P treatment on other key efficacy endpoints Placebo 50 mg 200 mg 100 mg 300 mg 150 mg E2W E4W E2W E4W E2W Number of patients N=20 N=19 N=20 N=20 N=21 N=18 Cholesterol mmol/L Baseline Mean 5.521 5.286 5.305 5.386 5.416 5.388 Median 5.458 5.232 5.394 5.199 5.180 5.361 Week 12 Mean 5.378 3.974 3.709 3.288 3.778 2.922 Median 5.258 3.937 3.587 3.238 3.393 2.823 Week 12 change from ne Mean -0.143 -1.313 -1.596 -2.098 -1.638 -2.466 Median -0.188 -1.399 -1.716 -2.163 -2.020 -2.331 Week 12 % change from baseline Mean . -1.47 -24.21 -29.54 -38.97 -29.61 -45.21 Median -3.73 -23.34 -29.51 -40.21 -33.48 -45.03 Non-HDL Cholesterol (mmol/L) Week 12 % change from baseline Mean . 29 -35.23 -40.07 -54.78 -41.17 -63.71 Median -4.71 -36.62 -39.91 -55.91 -45.55 -65.94 Consistent results (decrease) were seen for Total-C, ApoB, non HDL-C . For HDL-C there was a trend of increase in all groups, similar pattern was seen for ApoA-l. Antibody 316P was well tolerated during the 12 weeks of treatment at all tested doses/dose regimens. cantly, no change in troponin levels was noted in all treatment groups.

Conclusion: The results of this study showed that dosage regimens with E2W or E4W application schemes and different dosages of anti-PCSK 9 antibody 3 l6P as used in this study are efficient and safe ies for lowering LDL-C levels in patients with hyperlipoproteinemia and or hyperlipidemia and thus for the treatment of hyperlipoproteinemia and/or hyperlipidemia. Best overall results were achieved using the 150mg E2W dosage regimen. However, taking into consideration the patient comfort in only obtaining antibody treatments once a month, also both E4W dosage regimens tested in present study provided very good s.

Study 2 This was a randomized, double-blind, 3-parallel-groups, placebo-controlled, fixed dose/ dose regimen, multicenter, 8-week study in subjects with primary hypercholesterolemia, aged 18-75 years. One aim of this study was to assess the efficacy and safety of 3 l6P in patients with an elevated LDL-C (Z 100 mg/dL or 2.59 mmol/L) treated with a stable dose of atorvastatin 10 mg.

During the screening period, patients had to be stabilized to atorvastatin 10 mg for at least 6 weeks, if they are not y. Then, after 1 onal screening week, patients were lly randomized via IVRS/IWRS in a l:l:l ratio to one of the 3 treatment groups (placebo for 3 l6P + atorvastatin 80 mg, 3 l6P 150 mg E2W + atorvastatin 80 mg, 3 l6P 150 mg E2W + atorvastatin mg) and treated in a double-blind manner for approximately 8 weeks. 3 l6P was administered every 2 weeks on site trough subcutaneous injection and atorvastatin was stered orally once daily in the evening at home. The double-blind treatment period was then followed by an 8- week follow-up period.

Approximately 90 patients (30 patients per treatment group) were recruited and randomized from imately 20 sites.

Objectives y Objective To evaluate the effect of 3 l6P on low-density lipoprotein cholesterol (LDL-C) levels compared with placebo when co-administered with 80 mg of atorvastatin after 8 weeks of ent in patients with LDL-C Z lOOmg/dL (Z 2.59 mmol/L) on statin 10 mg.

Secondary Objective The key secondary objectives presented in this KRM are: 0 To evaluate the effects of 3 l6P on other lipid levels in comparison with placebo, when co-administered with 80 mg of atorvastatin after 8 weeks of treatment 0 To evaluate the efficacy of 3 l6P when co-administered with a high dose of atorvastatin (80 mg) versus atorvastatin 10mg 0 To evaluate the safety and tolerability of 3 l6P when co-administered with 2 different doses of atorvastatin 0 To evaluate the effects of 3 l6P on other exploratory endpoints: g plasma glucose, glycated hemoglobin Alc (HbAlc), high-sensitivity tive n (hs-CRP).

Patient selection: Inclusion criteria: — ts (patients receiving a lipid lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening , or drug naive patients) with primary hypercholesterolemia likely to have low-density lipoprotein cholesterol (LDL-C) Z 100 mg/dL (Z 2.59 mmol/L) at the end of the run-in period on atorvastatin therapy (Week -l).

— Patients with primary hypercholesterolemia treated with stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening period and likely to have low-density lipoprotein terol (LDL-C) Z 100 mg/dL (Z 2.59 mmol/L) at the screening visit (Week -l).

Exclusion criteria: — LDL-C < 100 mg/dL (< 2.59 mmol/L) at Week -1 (V1): 0 After the run-in period on atorvastatin 10 mg for patients receiving a lipid lowering treatment other than atorvastatin/ or not at stable dose of statin 10 mg for at least 6 weeks prior to the screening period, or drug naive patients. 1O OR 0 At the first visit for ts who are being treated with atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening visit Week -1.

— Body mass index (BMI) < 18 or > 40 kg/m2 at Week -7 or Week -1.

— Patients not previously instructed on a terol-lowering diet.

— Use of a statin other than atorvastatin 10 mg, or use of other lipid lowering drugs including but not limited to fibrates, bile acid resins, niacin > 500 mg, intestinal cholesterol absorption (ICA) blockers, or omega-3 fatty acids at doses > 1000 mg during the screening period. — ts with type 1 diabetes.

— Patients with type 2 diabetes treated with insulin.

— Patients with type 2 diabetes and with an HbAlc 2 8.5% at Week -7 or Week -1 (considered poorly controlled).

— Laboratory findings measured before randomization: 0 Positive test for hepatitis B surface antigen and/or hepatitis C antibody. o Triglycerides (TG) > 350 mg/dL (> 3.95 mmol/L) at Week -7 or Week -1. o Neutrophils < mm3 and/or platelets < lOO,OOO/mm3. 0 Positive serum or urine pregnancy test in females of childbearing potential. 0 Abnormal sensitive TSH level (> ULN or < LLN) according to the normal values of the Central Laboratory. 0 Evidence of renal impairment as determined by: . Men: serum creatinine > 1.5 X ULN.

' Women: serum creatinine > 1.4 X ULN. 0 ALT or AST > 2XULN (1 repeat lab is allowed). o CPK > 3XULN (1 repeat lab is allowed).

— All indications to the protocol mandated background therapy (i.e., atorvastatin) or warning/precaution of use (when appropriate) as displayed in the respective National Product Labeling that was used for defining these exclusion criteria.

— Known sensitivity to monoclonal antibody therapeutics. — nt or breast-feeding women.

— Women of childbearing potential with no effective contraceptive method.

Duration of study period per subject: The duration of study participation will depend on the status of the patient at screening: - For patients ing atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening, the study participation will be approximately 17 weeks including a ing period of 1 week, a -blind treatment period of 8 weeks and a follow-up period of 8 weeks (see Fig. 5).

- For patients ing a lipid lowering treatment other than atorvastatin/ or not at stable dose of statin 10 mg for at least 6 weeks prior to screening, or drug naive ts the study participation will be approximately 23 weeks with a screening period of 7 weeks (including a run-in period of 6 weeks), a double-blind treatment period of 8 weeks and a follow-up period of 8 weeks (see Fig. 4).

Active compounds: Antibody 316P Antibody 3 l6P is a fully human antibody comprising a HCVR as shown in SEQ ID NO: 90 and LCVR as shown in SEQ ID NO: 92 of the sequence listing. The CDR sequences are shown in SEQ ID NOs: 76, 78, and 80 (CDRl, CDR2, CDR3 of the heavy chain) as well as in SEQ ID NOs: 84, 86, and 88 (CDRl, CDR2, CDR3 of the light chain).

Antibody 3OON Antibody 3OON is a fully human antibody comprising a HCVR as shown in SEQ ID NO: 218 and LCVR as shown in SEQ ID NO: 226 of the sequence listing. The CDR sequences are shown in SEQ ID NOs: 220, 222, and 224 (CDRl, CDR2, CDR3 of the heavy chain) as well as in SEQ ID NOs: 228, 230, and 232 (CDRl, CDR2, CDR3 of the light chain).

Study arms: Arm 1: The first group of patients receives one subcutaneous injection of 1 mL of antibody 3 l6P, stered in the abdomen every two weeks, with a dose regimen at 150 mg, for a double-blind treatment period of 8 weeks, Atorvastatin is administered once per day at a stable dose of 10 mg as background therapy.

Atorvastatin is administered at a dose of 80 mg once during the double-blind treatment period of 8 weeks.

Arm 2: The second group of patients receives one subcutaneous ion of 1 mL of a placebo solution, stered in the abdomen every two weeks, with a dose regimen at 150 mg, for a double-blind treatment period of 8 weeks; Atorvastatin is stered once per day at a stable dose of 10 mg as background 1O therapy.

Atorvastatin is administered at a dose of 80 mg (2 over-encapsulated atorvastatin 40mg tablets) once during the double-blind treatment period of 8 weeks.

Arm 3: The third group of patients receives one subcutaneous injection of 1 mL of dy 3 l6P, administered in the abdomen every two weeks, with a dose regimen at 150 mg, for a double-blind treatment period of 8 weeks, Atorvastatin is stered once per day at a stable dose of 10 mg as background therapy.

Atorvastatin is administered at a dose of 10 mg (l over-encapsulated atorvastatin lOmg tablet + 1 matching placebo tablet) once during the double-blind treatment period of 8 weeks.

Primary and Key Secondary Endpoints Primary Endpoints The primary efficacy variable is the percent change in calculated LDL-C from ne to Week 8, which is defined as: lOOX (calculated LDL-C value at Week 8 - calculated LDL-C value at baseline) / calculated LDL-C value at baseline.

In case of lable calculated LDL-C value at Week 8 as defined above, then the last calculated LDL-C value measured during the efficacy period and before the Week 8 time window was used to impute the missing Week 8 calculated LDL-C value (Last Observation Carried Forward [LOCF] procedure).

Key Secondary Endpoints The secondary efficacy variables are: The absolute change (mmol/L and mg/dL) from baseline in calculated LDL-C to Week 8, defined as: lated LDL-C value at Week 8 - ated LDL-C value at baseline) The percentage of patients with calculated LDL-C < 70 mg/dL (1.81 mmol/L) and < 100 mg/dL (2.59 mmol/L) at Week 8 Percent change in ApoB from baseline to Week 8 t and absolute (mmol/L and mg/dL) change in non HDL-C from baseline to Week8 Percent and absolute (mmol/L and mg/dL) change in total cholesterol from baseline to Week 8 Percent and absolute (mmol/L and mg/dL) change in HDL-C from baseline to Week 8 Percent and absolute (mmol/L and mg/dL) change in g Triglycerides from baseline to Week 8 Percent change in ApoA-l from baseline to Week 8 Absolute change in the ratio ApoB/ApoA-l from baseline to Week 8 0 Percent change in Lpg a) from baseline to Week 8.

Sample Size Calculation Assumptions The study was expected to enroll approximately 90 patients.

To detect a difference of 20% in LDL-C percent change from baseline to Week 8 n 3 l6P 150 mg + atorvastatin 80 mg group and Placebo for 3 l6P + atorvastatin 80 mg group, assuming a 5% rate of unevaluable primary endpoint, 30 ts by arm were estimated to result in 95% power, with a standard deviation of 20%, and using a two-sided t-test at the 0.05 significance level.

Calculations were made using nQuery Advisor 6.01. tical Methods Analysis populations y populations The primary efficacy analysis population is the modified intent-to-treat (mITT) population.

Modified intent-to-treat population Modified ITT (mITT) population: ized population with an evaluable primary endpoint.

The primary endpoint was evaluable when both of the following conditions are met: 0 bility of at least one calculated LDL-C value from the Visit 1 (Week -1) and up to before first 1P injection. 0 Availability of at least one calculated LDL-C value during the efficacy period and, within or before the Week 8 time window.

Patients in the mITT population were analyzed ing to the treatment group allocated by ization.

Per-protocol population Per-protocol (PP) population is a subset of the mITT tion, excluding patients: 1O 0 with important protocol deviations impacting LDL-C baseline or LDL-C assessment at Week 8, 0 receiving prohibited therapy potentially impacting lipids levels during the pre-treatment period or during the efficacy period before the primary endpoint assessment 0 with a poor compliance to 3 l6P IP administrations. 0 with a poor compliance to atorvastatin non 1P during the pre-treatment period or with non compliance to atorvastatin 1P during the 3 days preceding primary nt assessment.

Safety population Safety population is defined as the randomized tion who did actually receive at least one dose or partial dose of 3 l6P IP analyzed according to the treatment actually received. Patients treated without being randomized would not be considered as randomized and would not be ed in any populations. The safety experience of patients treated and not randomized would be reported separately. y efficacy analysis The percent change from baseline in calculated LDL-C at Week 8-LOCF as defined above was analyzed in the mITT population using an analysis of covariance (ANCOVA) model with treatment group as fixed effect and the baseline LDL-C as covariate. The ent group factor had three levels: placebo + atorvastatin 80 mg, 3 l6P 150 mg E2W + atorvastatin 10 mg and 3 l6P 150 mg E2W + atorvastatin 80 mg.

Throughout the ANCOVA model, the 3 l6P 150 mg E2W + atorvastatin 80 mg group was compared to the placebo + atorvastatin 80 mg group using appropriate contrast and the 95% confidence interval (CI) of the difference was provided. 1O No formal comparison with the 3 l6P 150 mg E2W + atorvastatin 10 mg group was performed: only 95% C1s for difference versus the other arms was provided.

Key secondary y analysis Continuous secondary efficacy variables were ed in the mITT tion using the same ANCOVA model as for the primary endpoint. For triglycerides and LP(a) known to have non Gaussian distribution, the rank-based ANCOVA method was used.

Binary secondary efficacy variables were analyzed in the mITT population using an exact conditional logistic sion model with treatment group and baseline LDL-C level as effects.

Safety analysis The safety is was based on reported adverse events (AEs) (if any) and other safety information, such as clinical laboratory data, vital signs, and ECG.

The TEAE period was defined as the time from first 1P injection to last 1P injection + 70 days (10 weeks).

AEs of interest included the following terms: 0 Possible ion site reaction (HLT “Injection site reactions”) 0 Possible allergic events (HLGT “Allergic conditions”) 0 Patients with LDL-C <25 mg/dL (if any) or LDL-C <15 mg/dL (if any).

Other assessments analysis Other ment nts defined below are exploratory variables. They include metabolic and inflammatory parameters: 0 Absolute change in HbAlc (%) from baseline to Week 8 0 Absolute change from baseline in fasting plasma glucose (mmol/L) to Week 8 0 Percent change from baseline in hs-CRP to Week 8.

Those endpoints were summarized in the m-ITT population by time points using descriptive statistics. The time profile (including LOCF value) of each parameter was also plotted by treatment group with the corresponding standard errors.

PCSA ion for hs-CRP was also summarized by treatment group using descriptive statistics.

Results Study 2 was a enter, randomized, double-blind, parallel-group, placebo-controlled, 8-week study conducted in the United States to assess the efficacy and safety of 3 l6P in patients with an ed low-density lipoprotein cholesterol (LDL-C) (Z 100 mg/dL or 2.59 mmol/L), treated with a stable dose of atorvastatin 10 mg for at least 6 weeks. After the 8-week double-blind period patients were followed during an 8-week follow-up period.

The primary objective of the study was to evaluate the effect of 3 l6P on LDL-C levels compared with placebo when co-administered with 80 mg of atorvastatin after 8 weeks of treatment in patients with LDL-C Z 100mg/dL (Z 2.59 mmol/L) previously on atorvastatin 10 mg. Evaluation of the efficacy of the inistration of 3 l6P with this high dose of atorvastatin (80 mg) compared with that of the co-administration of 3 l6P with atorvastatin 10mg was one of the secondary objectives. The dose regimen of 150 mg every 2 weeks (E2W) in comparison with placebo was evaluated.

Efficacy analyses were performed on 88 patients (29 in the placebo + atorvastatin 80 mg group, 29 in the 3 l6P 150 mg + atorvastatin 10 mg group, and 30 in the 3 l6P 150 mg + atorvastatin 80 mg group). aphics and ne characteristics were similar across the treatment groups. The median age of patients was 58.0 years (25.0% of patients were 2 65 years of age). The mean ne LDL-C and Total-C ranged between 3.101 mmol/L and 3.288 mmol/L, and between 5.447 mmol/L and 5.200 mmol/L, respectively.

Efficacy: A statistically significant decrease in percent change from baseline in LDL-C at 8 weeks was observed in the 3 l6P 150 mg + atorvastatin 80 mg group compared with the placebo + atorvastatin 80 mg group (LS mean ence of -55.8%, p < 0.0001). Because of the non- gaussian distribution and non neity of ce of the primary efficacy endpoint, a sensitivity analysis was also performed using rank-based analysis of covariance which showed similar results: effect size estimate of 3 l6P 150 mg + atorvastatin 80 mg vs placebo + atorvastatin 80 mg of -54.5%, p < 0.0001. Large decreases from baseline were seen in both treatments groups where 3 l6P 150 mg was co-administered with statin, with a median reduction of— 70.4 % for the 3 l6P 150 mg + atorvastatin 10 mg group, and of — 70.6 % for the 3 l6P 150 mg + statin 80 mg group compared with a median reduction of -26.9 % in the placebo + atorvastatin 80 mg group.

Consistent results were seen for Total-C, ApoB, non HDL-C and Apo-B/ApoA-l ratio. For HDL-C, an increase in the percent change from baseline was observed in both treatment groups where 3 l6P 150 mg was co-administered with atorvastatin 10 mg or 80 mg (LS mean + 2.6 %, and + 5.8 %, respectively) compared with a decrease in the o + atorvastatin 80 mg group (LS mean -3.6 %).

Safety: 3 l6P was well tolerated during the 8 weeks of treatment in all treatment groups. Significantly, no change in troponin levels was noted in all treatment groups.

Conclusion: There was a tically significant decrease in t change from baseline in LDL-C at 8 weeks in the 3 l6P 150 mg + statin 80 mg group as compared with the placebo + atorvastatin 80 mg group (LS mean difference of -55.8%; p < 0.0001). A similar magnitude of effect observed with 3 l6P was noted regardless of the dose of atorvastatin (10 mg or 80 mg) with a substantial decrease in LDL-C when co-administered to these 2 atorvastatin doses.

Consistent results were seen for Total-C, ApoB, non HDL-C and Apo-B/ApoA-l ratio. For HDLC, there was a trend of increase in both treatment groups where 3 l6P 150 mg was co- administered with atorvastatin 10 mg or 80 mg. 3 l6P 150 mg E2W was well tolerated during the 8 weeks of treatment in all treatment .

No particular safety signal was noted.

Efficacy of 3 l6P 150 mg E2W as well its good safety profile were confirmed in this study regardless of the dose of atorvastatin administered (10 mg or 80 mg).

Study 3 This is a randomized, double-blind, placebo-controlled, multiple ascending dose, multicenter clinical trial in subjects with primary hypercholesterolemia.

The objective of this study was to determine whether a fully human monoclonal antibody to PCSK9 (316P) is effective and safe as either a y or adjunctive agent to lower LDL-C in patients with zygous Familial Hypercholesterolemia (HeFH) or other forms of primary hypercholesteremia (nonFH). 61 adults with either documented HeFH (n=21) or nonFH (n=30), on diet plus stable atorvastatin therapy (atorvaRX) or nonFH (n=10) on diet alone ed in this al trial. Subjects on stable atorvastatin therapy had LDL-C 22.6 mmol/L and those on diet alone had LDL-C 234 mmol/L. 316P at doses of 50, 100 and 150 mg was administered subcutaneously (sc) at l, 29 and 43 days. The primary endpoint was the incidence and severity of treatment emergent adverse events (TEAE). The primary efficacy endpoint was percent and 1O absolute change in serum LDL-C from baseline to each visit. Additional endpoints ed apolipoprotein (apo) B, total terol, HDL-C, VLDL-C, and the ratio of apoB to apoAl. 109 patients were screened, and 61 ts were randomized (14 placebo, 47 316P) with 100% completing 148 +/-7 days of treatment and follow up. Compared to the nonFH cohort, the FH group was younger (mean 40 vs. 52 yrs), had more males (81% vs. 57%) and was on higher doses of atorvastatin (52% on 40 mg vs. 3%). Baseline LDL-C was 3.45, 2.88 and 4.46 mmol/L in the FH, nonFH atorvaRx and nonFH diet only groups, respectively. Treatment with 316P ed in mean % reductions in LDL-C on top of statins on day 57 of 35.6%, 50.2% and 57.5% at the 50, 100 and 150 mg doses, respectively, in the combined FH and nonFH populations.

Although no statistical analysis was performed, there did not appear to be differences in response between FH and nonFH or those on or not on statin therapy. Response to 316P is shown in Figures 1, 2 and 3. Favourable changes were observed in HDL-C and apoAl. No serious adverse events were seen and treatment was generally well-tolerated. No drug-related adverse effects were seen on liver function testing or other laboratory parameters.

This first multiple-dose, of-concept trial of a PC SK9 inhibitor, in FH and nonFH on stable statin therapy, shows that treatment with an anti-PCSK9 antibody, such as 316P, is a promising therapeutic option for patients with or without HeFH with ed cholesterol on statin therapy.

Study 4 This is an animal study on the cholesterol lowering effect of 3 l6P, a fully human PCSK9 blocking monoclonal antibody in male Syrian hamster Introduction The hepatic LDL receptor (LDLR) is the key component for terol homeostasis.

PCSK9 regulates hepatic LDLR levels by enhancing its degradation. The transcription of both the LDLR and PCSK9 is up-regulated by statins through SREBP-Z, thereby limiting the extent that statins can lower LDL-cholesterol (LDL-C) in humans and even more in rodents where statins are not effective in reducing LDL-C.

Objective The aim of this study was to investigate the effect of 3 l6P, a human monoclonal antibody to human PC 8K9, alone and in combination with statins on sion of the hepatic LDLR and the resulting s on serum LDL-C.

Results In hamster, a single s.c. injection of 3 l6P (1/3/10 mg/kg) resulted in a ependent decrease in LDL-C lasting more than 2 weeks. The maximal effect on LDL-C (-l7/-27/-60%) was seen within 7 days. PK data of 3 l6P are in line with the ependent effect on LDL-C.

Atorvastatin treatment up to the maximal tolerated dose has no effect on hepatic LDLR expression and did not se LDL-C. 3 l6P on top of Atorvastatin could overcome the statin resistance increased LDLR expression and decreased serum LDL-C. The combination treatment was more ive than single treatment with 3 l6P alone, although Atorvastatin alone has no effect.

Conclusion PCSK9 inhibition resulted in dose-related lowering in rs. However, when stered in combination with a normally ineffective dose of statin, a potentiated reduction in LDL-C was observed. These data suggest that neutralizing PCSK9 is ive in overcoming the statin-resistance observed in the hamster model. This data are in accordance with results in a human phase I study, where LDL-C reduction exceeded 60% and lasted for 30 days ing a single i.v. administration. This confirmed that the hamster is a suitable model to investigate drugs targeting PC 8K9.

Study 5 This is a randomized, double-blind, placebo-controlled, unbalanced (2:1, 3 l6Pzplacebo), parallel-group study with an open-label extension.

Obj ective(s) The primary objective of this study is to evaluate the long-term safety and tolerability of 3 l6P over the main treatment period in hypercholesterolemic patients at risk of cardiovascular disease not adequately controlled with their lipid lowering treatment.

Secondary objectives are 0 To evaluate the long-term safety and tolerability of 3 l6P over the whole study duration. 0 To te the effect of 3 l6P on low-density lipoprotein cholesterol (LDL-C) levels after 12 weeks of treatment in comparison with placebo. 0 To evaluate the long-term efficacy of 3 l6P on low density lipoprotein cholesterol (LDL- C) . 0 To evaluate the effect of 3 l6P on Total-Cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C), Apolipoprotein B (ApoB), HDL-C, Triglycerides (TG), Apolipoprotein A-l (ApoA-l), ratio ApoB/ApoA-l, and Lipoprotein a (Lp (a)) after 12 weeks of treatment in ison with placebo and after long term treatment 0 To te the development of anti-3 l6P dies. 0 To evaluate the pharmacokinetics (PK) of 3 l6P. 0 To explore the effect of 3 l6P on adjudicated cardiovascular events over the main treatment period in comparison with placebo and over the whole study duration.

Study Design Patients will be f1ed according to heterozygous familial hypercholesterolemia (heFH) population, prior y of myocardial infarction (M1) or stroke, high-intensity statin therapy (ie, atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily) and geographic region. Patients randomized to 3 l6P will receive 150 mg subcutaneous (sc) every 2 weeks. This ose regimen, assessed in the Phase 1 program, is also one of the doses/dose regimens being evaluated in the Phase 2 program. For the present study, the administration of 150 mg subcutaneous every 2 weeks has been ed as the dose/dose regimen providing the t systemic re to 3 l6P in the range of doses/regimens likely to be effective. This dose and regimen may be adjusted, if needed, to a different dose/dosing frequency during the course of the study, through a protocol amendment, when the full data set of dose/regimen finding data become available.

The study consists of: 0 A screening period of up to 2 weeks, including an intermediate visit during which the patient or another designated person (such as spouse, relative, etc...) will be trained to self1nj ect/inj ect with placebo. 0 A double-blind period of 18 months study treatment with 3 l6P or placebo for all ts.

— The main treatment period is defined for the purpose of the primary analysis and this period ends 12 months after the last patient in (LPI) is randomized, and includes patients with variable duration of double blind treatment between 12 months and 18 months. 0 An open-label period (OLP) which consists of study treatment with 3 l6P in patients who have ted the 18-month double-blind period. The OLP will be of variable duration and ends for all patients at 24 months after the LPI or at 39 months after the FPI, ver comes first. 0 A follow-up period (off-treatment) of 8 weeks after the end of the open-label period.

Patients will be instructed to be on a stable diet (NCEP-ATPIII TLC diet or equivalent) hout the entire study duration from screening. Statin dose as well as dose of other lipid- lowering treatment(s) (if applicable) should be stable throughout the whole study duration.

During the double-blind period, ation is allowed under certain conditions. During the open-label period, modification is based upon investigator’s judgment. es other than fenofibrate are not allowed during the study. The lipid parameters will be blinded during the double-blind period.

Study Population: Inclusion Criteria Either A or B below AND not adequately controlled with a maximally tolerated stable dose of statin for at least 6 weeks prior to the screening visit (Week -2) with or t other lipid lowering therapy (LLT).

A) Patients with heterozygous familial hypercholesterolemia (heFH) OR B) Patients with non-familial hypercholesterolemia (non-FH) with established coronary heart disease (CHD) or CHD risk equivalents Note: All background LLT, including therapy other than statins, should be at a stable dose for at least 6 weeks prior to the screening visit (week -2).

The only statins which are permissible at study inclusion are simvastatin, atorvastatin, and rosuvastatin taken daily.

Patients are eligible for the study if they are on maximally tolerated statin even if this is not ntensity statin. Maximally tolerated statin is defined as any daily dose of simvastatin, atorvastatin, and rosuvastatin that is maximally tolerated. ntensity statin is defined as atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily.

If patient is not on high-intensity statin during screening, then the reason needs to be documented (ie, myalgias, liver enzyme alities, etc.).

If Screening (Week -2 visit) LDL-C is 2160 mg/dL (4.14 mmol/L), patients should have been offered another LLT in the past in addition to their maximally ted statin. In addition, if patients are on maximally tolerated statin therapy only, then reason needs to be documented, such patients are still eligible for the study and are not excluded.

Daily doses above simvastatin 80 mg, atorvastatin 80 mg or rosuvastatin 40 mg are not allowed for study inclusion. tatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without ce of muscle injury (myopathy) and should not be started in new ts, including patients already taking lower doses of the drug.

Prescriptions of other LLT should be in accordance with the national product label.

Key Exclusion Criteria LDL-C <70 mg/dL (<l.8 mmol/L) at the screening visit (Week-2).

TG >350 mg/dL (>395 mmol/L) at the screening visit (Week-2) - Use of fibrates other than fenofibrate within 6 weeks prior to screening visit (Week -2) or plan to receive it.

Total expected number of patients: Approximately 2100 randomized (1400:700, 3 l6P:placebo) Study Treatment(s) Investigational Medicinal Product(s): Antibody 3 l6P and placebo for 3 l6P Antibody 3 l6P is a fully human antibody sing a HCVR as shown in SEQ ID NO: 90 and LCVR as shown in SEQ ID NO: 92 of the sequence g. The CDR sequences are shown in SEQ ID NOs: 76, 78, and 80 (CDRl, CDR2, CDR3 of the heavy chain) as well as in SEQ ID NOs: 84, 86, and 88 (CDRl, CDR2, CDR3 of the light chain).

Alternatively, the study can be carried out with antibody 3OON (= back-up compound) instead of antibody 3 l6P. Antibody 3OON is a fully human dy comprising a HCVR as shown in SEQ ID NO: 218 and LCVR as shown in SEQ ID NO: 226 of the sequence listing. The CDR sequences are shown in SEQ ID NOs: 220, 222, and 224 (CDRl, CDR2, CDR3 of the heavy chain) as well as in SEQ ID NOs: 228, 230, and 232 (CDRl, CDR2, CDR3 of the light chain).

Formulation Prefilled es: 3 l6P lSOmg/mL, or placebo for 3 l6P.

Route(s) of administration: - Subcutaneous (SC) - ion volume: lmL in total for the dose of 150 mg - One injection of 1 mL subcutaneous over the abdomen, thigh, or outer area of upper arm (ie, deltoid region).

Dose regimen: Dose of 150 mg every 2 weeks Primary and Secondary Endpoint(s) Primary Endpoint: Safety ters (adverse events [including adjudicated cardiovascular events], laboratory data, vital signs, and ECG) assessed throughout the main treatment period.

Main Secondary Endpoints: - Safety parameters (adverse events [including adjudicated vascular events], laboratory data, vital signs, and ECG) assessed throughout the whole study duration - The percent change in LDL-C from baseline to Week 12 (as main time point).

- Anti-3 l6P antibodies - Serum 3 l6P concentrations Assessment Schedule t’s assessments in the screening period: - On-site : Week -2 (screening visit), Week -1 (Injection training visit).

Patient’s assessments in the double-blind period: - On-site : Week 0 (randomization Visit = baseline), Week 4, Week 8, Week 12, Week 16, Week 24, Week 36, Week 52/Month 12, Week 64/Month 15, Week 78/Month 18 (end of double blind period).

- Phone calls: Week 2*, Week 20, Week 28, Week 32, Week 40, Week 44, Week 48, Week 56, Week 60, Week 68, Week 72 and Week 76. >“Note: Week 2 could become an on-site Visit for further injection training with the patient’s scheduled injection from the -blind study ent kit allocated by IVRS, as needed. 1O Patient’s assessments in the open-label period: - On-site Visits: Every 12 weeks after the end of the double-blind period Visit and until the end of open label period Visit.

- Phone calls: Every 4 weeks between on-site Visits.

Note: During the course of the study, through the ongoing safety reViews, the Data Monitoring Committee (DMC) will assess the adequacy of the Visit frequency and corresponding procedures for the open-label period and make appropriate endations.

Patient’s assessments in the follow-up period: - On-site Visit: 8 weeks after the end of open label period Visit.

Statistical Considerations For safety ment, a sample size of 2100 patients (randomization ratio 2: 1, ie, 316P: 1400 and placebo: 700) will allow to have long term safety data in a broad database. With this sample size, 1050 and 364 ts are expected to be exposed to 316P for a minimum of 12 months and 18 months, respectively, at the time of the primary analysis (12 months after the last patient in). Moreover, with 1400 patients treated with 316P, adverse events with a rate 20.002 will be detected with 95% confidence.

The stratification s include heFH population, prior history of M1 or stroke, high- intensity statin and region (North America, n Europe, Eastern Europe, Rest of World).

Summary of safety variables will be performed based on the safety population. The safety population consists of the randomized population who did actually receive at least one dose or partial dose of Investigational Medicinal Product (HVIP) analyzed according to the treatment actually ed. 1O Descriptive statistics will be used for the summary of safety variables from this study. For adverse events, in addition to y tables presented with crude rates, the table of all TEAEs will be provided using patient-year ed incidence rates. If any clinically significant signal is detected and need further characterization or for adverse event or Potentially Clinically Significant Abnormality (PCSA) of interest, a time-to-event analysis will be med using Kaplan-Meier ology. Moreover, the frequency of adverse event or PCSA of interest over time will be provided. The primary safety analysis will be done on the safety events that can be attributed to the administration of double blind ent during the main treatment period. ary safety analyses will be conducted on the safety events observed during the double- blind period and the open-label period.

The efficacy analysis population will be the modified intent at (mITT) population, defined as the ITT population (i.e., randomized population) with an evaluable LDL-C endpoint.

This endpoint will be considered as evaluable when both of the following ions are met: - The ne LDL-C value is available.

- At least one LDL-C value collected in the main efficacy period is available.

The main efficacy period will be defined as: - The time from the first HVIP injection (excluding training injection) up to 21 days after the last 1MP injection for patients who permanently discontinue the IMP before Week 12.

- The time from the first HVIP injection (excluding training injection) up to Week 12 for patients who were treated at least 12 weeks.

Patients in the mITT population will be analyzed according to the treatment group allocated by randomization.

The percent change in LDL-C from ne to Week 12 (main ary endpoint) and at other time points throughout the study (other secondary endpoints) will be analyzed using an analysis of ance (ANCOVA) model with treatment group and each stratification factor (heFH population, prior history ofM1 or stroke, high-intensity statin, ) as fixed effect and the baseline LDL C as covariate. The treatment group factor will have 2 levels: placebo and 1O 316P. Throughout the ANCOVA model, the 316P group will be compared to placebo using appropriate contrast, and the 95% CI of the difference will be provided.

In case of missing Week 12 LDL-C on ent value, the last-observation-carried- forward (LOCF) principle will be used.

Duration of Study Period (per patient) The study duration for each patient is variable. The m study duration includes up to 2 weeks of screening period, 18 months study treatment during double blind period, up to 21 months of 316P treatment in the open label period (depending on when patient randomized into study and duration of recruitment) and 8 weeks of follow up period. Thus, the maximum study duration is up to ~ 42 months for the first patient randomized into the study and up to ~ 27 months for the last patient randomized into the study.

Study 6 A randomized, -blind, multi-dose, placebo controlled, 75-patient trial in patients with heterozygous familial hypercholesterolemia . In this trial, ts must meet the World Health Organization criteria for heFH, be on a stable daly statin regimen for at least 6-weeks before entering the trial, and have serum LDL-C levels 2 100mg/dL. Patients were permitted to be taking ezetimibe in addition to a daily statin. The primary endpoint of the study is the change in LDL cholesterol from baseline compared to placebo over the 12-week study period.

An interim analysis of study 6 in heterozygous familial hypercholesterolemia patients with elevated cholesterol (LDL-CZlOOmg/dL) on stable doses of statins with or without ezetimibe trated that patients treated with 3 l6P every two or four weeks achieved significantly r mean LDL-C reductions at lZ-weeks compared to patients treated with placebo. Patients treated with different doses of 3 l6P achieved mean LDL-C reductions of approximately 30% to greater than 60% from baseline at lZ-weeks compared to a 10% reduction with placebo (p<0.01), which was the y endpoint of the study. The m analysis was conducted when all patients completed the primary endpoint at 12-weeks.

THE

Claims (19)

CLAIMS 1. DEFINING THE INVENTION ARE As FOLLOWS :
1. I . A phannaceutical composition comprising 40 ing, 50 ing, 75 ing, 100 ing, 150 ing, 200 ing, 250 ing, 300 ing, 350mg, 400 ing, 450 ing or 500mg of an antibody or an antigen-binding fragment thereof which specifically binds human proprotein convertase subtilisin/kexin type 9 (hPCSK9) together with a pharmaceuticalIy acceptable excipient or carrier, wherein the antibody or antigen-binding nagi:nent thereof comprises the three heavy chain CDRs set forth in SEQ ID Nos: 76, 78, and 80 and the three Iig}It chain CDRs set forth in SEQ ID Nos: 84,86, and 88
2. 2. The ceutical composition of claim I, wherein the antibody or antigen- 10 binding fragment thereof ses the heavy chain variable region (HCVR) amino acid ce and the 11g}It chain variable region (LCVR) amino acid sequence set forth in SEQ ID Nos: 90 and 92, respectively.
3. 3. The phannaceutical composition of claim I or 2, comprising about 75 ing of the antibody or n-binding fragment f. 15
4. 4. The phannaceutical composition of claim I or 2, sing about 150 ing of the dy or antigen-binding fragment thereof.
5. 5. The phannaceutical composition of claim I or 2, comprising about 300 ing of the antibody or antigen-binding fragment thereof.
6. 6. The phannaceutical composition of any one of the previous claims comprising the 20 dy or antigen-binding fragment thereof as a liquid fomiulation, wherein the liquid ation is an injectable solution of the antibody or antigen-binding fragment thereof per I inI volume.
7. 7. The phannaceutical composition of claim 6, wherein the injectable solution comprises 75 ing of the antibody or antigen-binding fragment thereofper I inI volume. 25
8. 8. The phannaceutical composition of claim 6, wherein the injectable solution comprises 150 ing of the antibody or antigen-binding fragilent thereofper I inIvolume.
9. 9. The phannaceutical composition of claim 6, wherein the able solution comprises 300 ing of the antibody or antigen-binding fragment thereof per I inI volume.
10. 10. The phamiaceutical composition of claim I or 2 being comprised in a unit dosage fonn, wherein the unit dosage fonn ses about 40 ing, 50 ing, 75 ing, 100 ing, 150 ing, 200 ing, 250 ing, 300 ing, 350 ing, 400 ing, 450 ing, or 500 ing of the antibody or antigen-binding fragment thereof.
11. I I . The phannaceutical composition of claim I O, wherein the unit dosage fonn comprises 75 ing of the antibody or antigen-binding nt thereof
12. 12. The phannaceutical composition of claim I O, wherein the unit dosage fomi 10 comprises 150 ing of the antibody or antigen-binding fragilent thereof.
13. 13. The phannaceutical ition of claim 10, wherein the unit dosage fonn ses 300 ing of the antibody or antigen-binding fragilent thereof.
14. 14. The ceutical composition of any one of claims I-13, wherein the phannaceutical composition is in a hemietically sealed container selected from the group 15 consisting of a vial, a sachet, a pre-filled syringe, a pre-filled autoinjector, a cartridge for a reusable syringe, and an applicator.
15. 15. The phannaceutical composition of any one of claims I-14, wherein the antibody or antigen-binding fragment thereof binds an e comprising one or more of amino acid residues at positions 238,153,159, and 343 ofhPCSK9 (SEQ ID N0:755) 20 16. The pharmaceutical composition of any one of claims I-15, wherein the antibody or n-binding fragment thereof is capable of achieving one or more of the following in a subject: a) reduction of LDL-C of at least -60 % to at least -75% relative to a predose level with a sustained reduction over at least a 14 day-period when fonnulated at a dose of 25 150 ing that is suitable for administration every two weeks; b) reduction of LDL-C of at least -50 % to -75% relative to a e level with a sustained reduction over at least a 28 day-period when fonnulated at a dose of 300 ing that is suitable for administration every four weeks; c) se of serum HDL cholesterol levels of at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5% or at least 5.5% ve to a predose level when fonnulated at a dose of 150 ing that is suitable for administration every two weeks; co increase of one or more of: total-cholesterol levels, ApoB , non
16. HDL-C levels, and Apo-B/ApoA- I ratio. 10
17. 17. A phannaceutical composition comprising 75 ing of an antibody or an antigenbinding fragment thereof which specifically binds hPCSK9, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence and the light chain variable region (LCVR) amino acid sequence set forth in SEQ ID Nos : 90 and 92, respectively, and wherein the antibody or antigen- 15 binding fragilent f is in a I inI injectable on.
18. 18. A phannaceutical composition comprising 150 ing of an antibody or an antigenbinding nt thereof which specifically binds hPCSK9, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) amino acid sequence and the Iiglit chain variable region (LCVR) amino acid ce set 20 forth in SEQ ID Nos: 90 and 92, respectively, and wherein the antibody or antigenbinding fragment thereof is in a I inI injectable solution.
19. 19. A phannaceutical composition comprising 300 ing of an antibody or an antigenbinding fragment thereof which specifically binds hPCSK9, wherein the antibody or antigen-binding fragment thereof ses the heavy chain variable region (HCVR) 25 amino acid sequence and the Iiglit chain variable region (LCVR) amino acid sequence set forth in SEQ ID Nos: 90 and 92, tively, and wherein the antibody or antigen- binding fragment thereof is in a I inI injectable solution. 20 The phannaceutical composition according to any one of the previous claims, ntially as hereinbefore described.