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NZ763275B2 - Rnai agents and compositions for inhibiting expression of angiopoietin-like 3 (angptl3), and methods of use - Google Patents
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NZ763275B2 - Rnai agents and compositions for inhibiting expression of angiopoietin-like 3 (angptl3), and methods of use - Google Patents

Rnai agents and compositions for inhibiting expression of angiopoietin-like 3 (angptl3), and methods of use

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Publication number
NZ763275B2
NZ763275B2 NZ763275A NZ76327518A NZ763275B2 NZ 763275 B2 NZ763275 B2 NZ 763275B2 NZ 763275 A NZ763275 A NZ 763275A NZ 76327518 A NZ76327518 A NZ 76327518A NZ 763275 B2 NZ763275 B2 NZ 763275B2
Authority
NZ
New Zealand
Prior art keywords
angptl3
pharmaceutical composition
rnai agents
composition
pharmaceutically acceptable
Prior art date
Application number
NZ763275A
Other versions
NZ763275A (en
Inventor
Zhen Li
So Wong
Rui Zhu
Original Assignee
Arrowhead Pharmaceuticals Inc
Filing date
Publication date
Application filed by Arrowhead Pharmaceuticals Inc filed Critical Arrowhead Pharmaceuticals Inc
Priority claimed from PCT/US2018/050848 external-priority patent/WO2019055633A1/en
Publication of NZ763275A publication Critical patent/NZ763275A/en
Publication of NZ763275B2 publication Critical patent/NZ763275B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/3521—Methyl
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    • C12N2310/3533—Halogen

Abstract

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, able to inhibit Angiopoietin-like 3 (also called ANGPTL3, ANGPL3, angiopoietin-like protein 3) gene expression, and compositions that include ANGPTL3 RNAi agents. Also disclosed are methods of use of ANGPTL3 RNAi agents and compositions. The ANGPTL3 RNAi agents disclosed herein may be conjugated to targeting ligands to facilitate the delivery to cells, including to hepatocytes. Pharmaceutical compositions that include one or more ANGPTL3 RNAi agents, optionally with one or more additional therapeutics, are described. Deliver}' of the ANGPTL3 RNAi agents in vivoprovides for inhibition of ANGPTL3 gene expression, and can result in lower triglycerides and. or cholesterol levels in the subject. The RNAi agents can be used in methods of treatment of ANGPTL3 -related diseases and disorders, including cardiometabolic diseases such as hypertriglyceridemia and hyperlipidemia.

Claims (16)

CLAIMS :
1. An RNAi agent for inhibiting expression of an ANGPTL3 gene, sing: an antisense strand that consists of the modified nucleotide sequence of (5' ? 3') usAfscsUfgAfuCfaAfaUfaUfgUfuGfaGfsc (SEQ ID NO:2), and a sense strand that consists of the sequence of (5' ? 3') (NAG37)s(invAb)sgcucaacaUfAfUfuugaucaguas(invAb) (SEQ ID NO:300); wherein a is 2'-O-methyl ine; c is 2'-O-methyl cytidine; g is 2'-O-methyl guanosine; u is 2'-O-methyl uridine, Af is 2'-fluoro adenosine, Cf is 2'-fluoro cytidine; Gf is 2'-fluoro guanosine; Uf is 2'-fluoro uridine; s is a phosphorothioate linkage; (invAb) is an inverted abasic ibose residue; and (NAG37)s has the following chemical structure:
2. A pharmaceutically able salt of the RNAi agent of claim 1.
3. The pharmaceutically acceptable salt of claim 2, wherein the pharmaceutically acceptable salt is a sodium salt.
4. A pharmaceutical composition comprising the RNAi agent of claim 1 and a pharmaceutically acceptable excipient.
5. The pharmaceutical composition of claim 4, wherein the pharmaceutically able ent comprises saline.
6. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable excipient comprises water for injection.
7. The pharmaceutical composition of claim 6, further comprising a pharmaceutically acceptable buffering agent.
8. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable excipient comprises buffered saline.
9. The pharmaceutical composition of claim 4, n the pharmaceutical composition is packaged in a pre-filled syringe.
10. The ceutical composition of claim 4, wherein the pharmaceutical composition is packaged in a vial.
11. Use of the composition of any one of claims 4-10 in the ation of a medicament for the treatment of an ANGPTL3-related disease or disorder.
12. The use of claim 11, wherein the e is a metabolic disease.
13. The use of claim 11, wherein disease is hypertriglyceridemia, obesity, hyperlipidemia, abnormal lipid and/or cholesterol metabolism, atherosclerosis, type II diabetes mellitus, cardiovascular disease, coronary artery e, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, homozygous and/or heterozygous familial hypercholesterolemia, or statin resistant holesterolemia .
14. Use of the composition of any one of claims 4-10 in the preparation of a medicament for lowering triglyceride levels in a subject.
15. Use of the composition of any one of claims 4-10 in the preparation of a medicament for lowering the total cholesterol levels in a subject.
16. Use of the composition of any one of claims 4-10 in the preparation of a medicament for lowering low density lipoprotein (LDL) terol levels in a subject. OE:O\PA\/
NZ763275A 2018-09-13 Rnai agents and compositions for inhibiting expression of angiopoietin-like 3 (angptl3), and methods of use NZ763275B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201762558819P 2017-09-14 2017-09-14
US201762583919P 2017-11-09 2017-11-09
US201862651284P 2018-04-02 2018-04-02
US201862694976P 2018-07-07 2018-07-07
PCT/US2018/050848 WO2019055633A1 (en) 2017-09-14 2018-09-13 Rnai agents and compositions for inhibiting expression of angiopoietin-like 3 (angptl3), and methods of use

Publications (2)

Publication Number Publication Date
NZ763275A NZ763275A (en) 2025-08-29
NZ763275B2 true NZ763275B2 (en) 2025-12-02

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