RU2787632C2 - Bis-choline tetrathiomolybdate for treatment of wilson's disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to the treatment of Wilson’s disease. A method for the treatment of Wilson’s disease in a patient who needs it includes taking 15 mg of bis-choline tetrathiomolybdate once a day, while bis-choline tetrathiomolybdate is taken on an empty stomach. Other options of a method for the treatment of Wilson’s disease in a patient, methods for changing a scheme of taking bis-choline tetrathiomolybdate for a patient with Wilson’s disease, a method for taking bis-choline tetrathiomolybdate for the treatment of a patient with Wilson’s disease, and the use of a composition containing bis-choline tetrathiomolybdate in a method for the treatment of Wilson’s disease in a patient are also disclosed.

EFFECT: group of inventions provides improvement of Cu metabolism, reduction in a concentration of toxic Cu, and maintenance of a normal Cu concentration to improve symptomatology in patients, and it does not have side effects.

87 cl, 19 dwg, 12 tbl, 7 ex

Description

CROSS REFERENCES TO RELATED APPLICATIONS

[0001] The present application claims priority on U.S. Provisional Application No. 62/594,184, filed December 4, 2017; U.S. Provisional Application No. 62/646,553, filed March 22, 2018; U.S. Provisional Application No. 62/655,568, filed April 10, 2018; U.S. Provisional Application No. 62/669,095, filed May 9, 2018; U.S. Provisional Application No. 62/741,313, filed October 4, 2018, and U.S. Provisional Application No. 62/750,595, filed October 25, 2018, the contents of each of which are hereby incorporated by reference in their entirety and in every way.

BACKGROUND OF THE INVENTION

[0002] Wilson's disease (WV) is an autosomal recessive disease, which is based on a violation of copper (Cu) metabolism. Mutations in the ATP7B gene lead to insufficient synthesis of copper-transporting ATPase-2, which, in turn, leads to impaired Cu incorporation into ceruloplasmin, impaired excretion of Cu with bile, an increase in the concentration of "free" and albumin-bound Cu, and accumulation of Cu in the liver. , brain and other tissues, resulting in organ damage and dysfunction. The prevalence of BV is estimated at 1 in 30,000 population, which corresponds to approximately 10,000 people in the United States and approximately 15,000 people in the European Union.

[0003] Typical clinical manifestations of BV are found in adolescence and older adolescence. Genetic screening and establishing genotype-phenotype correlations are complicated by the many combined mutations of the ATP7B gene; most people with BV are compound heterozygotes. The initial signs and symptoms of BV are predominantly liver (~40%), neurological (~40%), or psychopathological (~20%) symptoms, but patients often develop a combined liver injury and neuropsychiatric disorder. Among patients who are not receiving treatment or receiving inadequate treatment, there is a progressive morbidity; mortality is usually due to decompensated liver cirrhosis and liver failure. Liver transplantation is the only effective treatment for acute liver failure associated with BV; other causes of death in VWD include malignant liver tumors and neurological impairment with severe malnutrition.

[0004] In the human body, the liver is one of the main Cu deposition organs. In healthy individuals, intracellular Cu homeostasis is tightly regulated. Cu enters cells via the copper transporter CTR1, then from CTR1 is transferred to copper chaperones, such as copper chaperones for antioxidant 1, cytochrome c oxidase, and superoxide dismutase. Copper bound to the chaperone is delivered to a specific cuproenzyme. In case of accumulation of excess Cu, excess Cu binds to metallothionein (MT) in the form of monovalent Cu (Cu+) via Cu-containing thiolate bridges on the numerous cysteine residues in MT, resulting in detoxification of copper by reducing its redox potential.

[0005] In patients with VV, Cu excretion is impaired due to lack of ATPase-2. This leads to the accumulation of Cu, mainly in the liver and brain, but also in other organs. Within the buffering capacity of MT, there is no apparent toxicity of Cu, since MT strongly binds Cu. However, beyond the buffering capacity of MT with respect to Cu, free Cu ions appear, and an excess amount of free intracellular Cu leads to the appearance of pro-oxidant properties, resulting in an increased risk of tissue/organ damage with subsequent clinical manifestation. It is assumed that Cu toxicity in BV is due to free or labile bound Cu, which does not form strong bonds with MT due to excess Cu.

[0006] The goals of treatment for BV are to compensate for impaired Cu excretion caused by a lack of ATPase-2. Currently, conventional chelating drugs D-penicillamine (CUPRIMIN® / CUPRIMINE®, Valeant Pharmaceuticals / Valeant Pharmaceuticals, DEPEN® / DEPEN®, Meda Pharmaceuticals / Meda Pharmaceuticals) and trientine (SIPRIN® / SYPRINE®, Aton Pharma, Inc./ Aton Pharma, Inc.), which non-specifically chelate Cu and improve urinary Cu excretion. In addition, zinc (Zn), which prevents the absorption of Cu from food, is mainly used for maintenance therapy. Zinc impairs Cu absorption by inducing MT in the gastrointestinal tract (GIT).

[0007] Of particular importance is the control of the disease in patients with neurological symptoms diagnosed with VWD. More than a third of patients with neurological symptoms do not improve after 4 years of chelator therapy. Failure to respond to chelation therapy in the presence of neurological symptoms may indicate irreversible damage to the nervous system. In addition, a recent study demonstrated that approximately 50% of patients had residual neurological symptoms despite years of treatment with a Cu controlling agent. Exacerbation of neurological symptoms at the beginning of treatment was reported in approximately 25% of patients treated with penicillamine and trientine, and in this population the proportion of patients who did not recover reached 50%. It is believed that the mechanism of this "paradoxical" aggravation of neurological symptoms is realized due to the mobilization of Cu from the liver, which leads to an increase in the concentration of Cu in the blood and the central nervous system, and the appearance of a neurological disorder. This theory is supported by non-clinical data.

[0008] Due to the development of adverse events and treatment failure, there has been a high incidence of discontinuation of treatment with currently available drugs for the treatment of BV. Adverse event profiles and complex drug regimens are responsible for low adherence to treatment and high rates of treatment failure, which is a serious problem in a lifelong disease such as BV.

[0009] Tetrathiomolybdate in the form of ammonium salt has been shown to help control Cu concentration and improve liver function even after a single dose. Most clinical and non-clinical studies on the safety and toxicity of tetrathiomolybdate-based treatments have been conducted using the ammonium cation as the counterion.

[0010] The absorption (absorption) of an orally administered drug may be affected by food taken before or after taking the active substance. Food can affect drug absorption (absorption) through several mechanisms. Food can influence absorption (absorption) by interacting with the active substance or pharmaceutical composition in the gastrointestinal tract by stimulating bile flow, changing the pH value in the gastrointestinal tract, accelerating visceral blood flow, or by delaying gastric emptying. Thus, food intake may affect the bioavailability of the active substance for about 2 hours before or about 1 hour after taking the active substance.

[0011] However, it is difficult to predict de novo whether food intake will affect a particular active ingredient or pharmaceutical composition. In addition, even if this effect exists, there may be an increase or decrease in the bioavailability of the active substance or pharmaceutical composition taken after a meal, compared with an equivalent dose on an empty stomach. In cases where food intake has a significant effect (i.e., eating before or after a dose causes a significant increase or decrease in the absorption (absorption) of the drug compared to taking the drug on an empty stomach), the pharmaceutical compositions taken after a meal are not bioequivalent to those the same pharmaceutical compositions taken on an empty stomach.

[0012] The lack of bioequivalence can have serious clinical consequences. For example, as a result of taking a pharmaceutical composition with food, the concentration of the active substance in the blood plasma can be alarmingly high, which can lead to the development of clinical side effects. In other cases, administration of the pharmaceutical composition on an empty stomach may provide an effective dose, while administration of the composition after a meal may provide sub-therapeutic plasma concentrations of the active substance, as a result of which the dose obtained is not effective.

[0013] Accordingly, there is a need to provide treatments for Wilson's disease that are effective in improving Cu metabolism, reducing toxic "free" Cu, and maintaining normal Cu levels to improve symptoms in patients without the side effects associated with currently available treatments.

DISCLOSURE OF THE INVENTION

[0014] The present invention relates to methods for treating Wilson's disease with bischoline tetrathiomolybdate. In some embodiments, the bis-choline tetrathiomolybdate has the structure:

[0015] In some embodiments, the invention relates to methods for treating Wilson's disease in a patient by taking 15 mg of bischoline tetrathiomolybdate once a day or daily. In some embodiments, the invention relates to methods for treating Wilson's disease in a patient by taking 30 to 90 mg of bischoline tetrathiomolybdate daily. In some embodiments, the invention relates to methods for treating Wilson's disease in a patient by taking 30 to 90 mg of bischoline tetrathiomolybdate daily when the patient has one or more of the following: NCM _adjusted value greater than 2.3 µmol/L, concentration alanine aminotransferase (ALT) less than 80 IU/ml, hemoglobin concentration greater than 8 g/dl, platelet count greater than 30,000/μl, or neutrophil count greater than 1000/μl, or 1 × 10 ³ /μl.

[0016] In some embodiments, the invention relates to methods of modifying the dosing regimen of bischoline tetrathiomolybdate for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment by reducing the daily dose of bischoline tetrathiomolydate or by increasing the daily dose of bischoline tetrathiomolydate.

[0017] In one aspect, the present invention further provides methods for decreasing or increasing the daily dose of bis-choline tetrathiomolybdate for a patient with an abnormal test result, including optionally stopping treatment for a period.

[0018] In another aspect, the present invention provides pharmaceutical compositions containing bis-choline tetrathiomolybdate for the treatment of Wilson's disease in a patient. In another aspect, the present invention provides kits for the treatment of Wilson's disease, containing at least three sets of pharmaceutical dosage units and instructions for use.

[0019] In another aspect, the present invention provides methods for treating Wilson's disease in a patient in need thereof, comprising fasting bischoline tetrathiomolybdate. In certain aspects, bis-choline tetrathiomolybdate is administered as an enteric-coated dosage form.

[0020] In another aspect, the present invention relates to methods for treating Wilson's disease in a patient in need thereof, comprising taking bis-choline tetrathiomolybdate for about 24 weeks or longer, about 36 weeks or longer, about 48- weeks or more, about 60 weeks or more, about 72 weeks or more, about 84 weeks or more, about 92 weeks or more, about 120 weeks or more, about 132 weeks or longer, or about 144 weeks or longer.

[0021] In some embodiments, the invention relates to a pharmaceutical composition containing 15 mg of bischoline tetrathiolybdate for use in the treatment of Wilson's disease in a patient in need thereof. In some embodiments of the invention, a pharmaceutical composition containing 15 mg of bis-choline tetrathiomolybdate is suitable for administration once a day. In some embodiments, the pharmaceutical composition is suitable for administration once every second day. In some embodiments, the pharmaceutical composition is a sustained release pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of an enteric coated tablet.

[0022] In some embodiments of the invention, the patient has a decrease in the NCM _corrected , measured after 24 weeks of admission, in comparison with the patient's _adjusted MCM, measured before admission, for example, a decrease in the NCM _corrected by 20%, 35%, 50% or 75% when measured after 24 weeks of administration compared to the patient's _adjusted NCM measured before administration.

[0023] In some embodiments of the invention, the patient has a decrease in the NCM _corrected , measured after 48 weeks of admission, in comparison with the patient's _adjusted MCM, measured before admission, for example, a decrease in the NCM _corrected by 20, 35, 50 or 75% when measured after 48 weeks of intake compared to the patient's _adjusted NCM measured before intake.

[0024] In some embodiments of the invention, the patient has a decrease in the NCM _corrected , measured after 72 weeks of admission, in comparison with the patient's _adjusted MCM, measured before admission, for example, a decrease in the NCM _corrected by 20, 35, 50 or 75% when measured after 72 weeks of intake compared to the patient's _adjusted NCM measured before intake.

[0025] In some embodiments, the invention relates to a pharmaceutical composition containing bis-choline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient in need thereof, characterized in that 30, 45, 60, 75 or 90 mg of bis-choline tetrathiomolybdate is taken daily and the patient has one or more of the following:

a) the NCM _corrected value is greater than 2.3 µmol/L;

b) concentration of alanine aminotransferase (ALT) - less than 80 IU/ml;

c) hemoglobin concentration exceeds 8 g/dl;

d) the number of platelets exceeds 30,000/µl; or

e) the number of neutrophils exceeds 10 ³ /µl.

[0026] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is reduced if said patient has a measured alanine aminotransferase (ALT) concentration at least twice the ALT concentration measured at the start of treatment with bischoline tetrathiomolybdate. In some embodiments, for a patient receiving a dose of 15 mg of bis-choline tetrathiomolybdate once daily, the dose is reduced to 15 mg of bis-choline tetrathiomolybdate every second day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day.

[0027] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is reduced if said patient has a measured alanine aminotransferase (ALT) concentration at least twice the upper limit of normal (ULN). In some embodiments, for a patient receiving a dose of 15 mg of bis-choline tetrathiomolybdate once daily, the dose is reduced to 15 mg of bis-choline tetrathiomolybdate every second day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day. In some embodiments, the ULN is 30-45 IU/mL. In some embodiments, the ULN is 34 IU/mL. In some embodiments, the ULN is 40 IU/mL.

[0028] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is reduced if said patient has a measured the hemoglobin concentration is 70% or less of the hemoglobin concentration measured at the start of treatment with bischoline tetrathiomolybdate. In some embodiments of the invention, for a patient receiving a dose of 15 mg of bis-choline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bis-choline tetrathiomolybdate every second day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day.

[0029] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is reduced if said patient has a a platelet count that is 70% or less of the platelet count determined at the start of treatment with bischoline tetrathiomolybdate. In some embodiments, for a patient receiving a dose of 15 mg of bis-choline tetrathiomolybdate once daily, the dose is reduced to 15 mg of bis-choline tetrathiomolybdate every other day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day.

[0030] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is reduced if said patient has a a neutrophil count that is 70% or less of the neutrophil count determined at the start of treatment with bischoline tetrathiomolybdate. In some embodiments, for a patient receiving a dose of 15 mg of bis-choline tetrathiomolybdate once daily, the dose is reduced to 15 mg of bis-choline tetrathiomolybdate every other day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day.

[0031] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is canceled if said patient has a measured an alanine aminotransferase (ALT) concentration greater than five times the ALT concentration measured at the start of treatment with bischoline tetrathiomolybdate, and once the indicated patient has a measured ALT concentration that is two times lower than the ALT concentration measured at the start of treatment with bischoline tetrathiomolybdate, treatment resume at a dose of 15 mg of bischoline tetrathiomolybdate every second day for a patient who received a dose of 15 mg of bischoline tetrathiomolybdate every second day before discontinuation of bischoline tetrathiomolybdate, or at a dose of 15 mg/day of bischoline tetrathiomolybdate for a patient who received bis-hol before cancellation and tetrathiomolybdate dose of 15-90 mg of bischoline tetrathiomolybdate once a day.

[0032] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is canceled if said patient has a measured alanine aminotransferase (ALT) concentration exceeds 200 IU/ml, and as soon as the indicated patient's measured ALT concentration is half the ALT concentration measured at the beginning of treatment with bischoline tetrathiomolybdate, treatment is resumed at a dose of 15 mg of bischoline tetrathiomolybdate every second day for a patient who received before the withdrawal of bis-choline tetrathiomolybdate a dose of 15 mg of bis-choline tetrathiomolybdate every second day, or at a dose of 15 mg / day of bis-choline tetrathiomolybdate for a patient who received a dose of bis-choline tetrathiomolybdate before withdrawal of bis-choline tetrathiomolybdate 15-90 mg of bis-choline tetrathiomolybdate once a day day.

[0033] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is canceled if said patient has a measured hemoglobin concentration exceeds 8 g/dl, and once the indicated patient has a measured hemoglobin concentration equivalent to the hemoglobin concentration measured at the start of treatment with bischoline tetrathiomolybdate, treatment is resumed at a dose of 15 mg bischoline tetrathiomolybdate every second day for the patient who received up to discontinuation of bis-choline tetrathiomolybdate, a dose of 15 mg of bis-choline tetrathiomolybdate every second day, or at a dose of 15 mg / day of bis-choline tetrathiomolybdate for a patient who received a dose of 15-90 mg of bis-choline tetrathiomolybdate before the withdrawal of bis-choline tetrathiomolybdate choline tetrathiomolybdate once a day.

[0034] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is canceled if said patient is determined a platelet count of less than 30,000/µl, and as soon as the specified patient's platelet count is equivalent to the platelet count determined at the beginning of treatment with bischoline tetrathiomolybdate, treatment is resumed at a dose of 15 mg of bischoline tetrathiomolybdate every second day for a patient who received until the withdrawal of bis-choline tetrathiomolybdate, a dose of 15 mg of bis-choline tetrathiomolybdate every second day, or at a dose of 15 mg / day of bis-choline tetrathiomolybdate for a patient who received a dose of 15-90 mg bis before the withdrawal of bis-choline tetrathiomolybdate -choline tetrathiomolybdate one pa s per day.

[0035] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is canceled if said patient is determined neutrophil count less than 1.0 x 10 ³ /µl, and as soon as the indicated patient has a detectable neutrophil count equivalent to the neutrophil count determined at the beginning of treatment with bischoline tetrathiomolybdate, treatment is resumed at a dose of 15 mg of bischoline tetrathiomolybdate every second day for a patient who received before the withdrawal of bis-choline tetrathiomolybdate a dose of 15 mg of bis-choline tetrathiomolybdate every second day, or at a dose of 15 mg / day of bis-choline tetrathiomolybdate for a patient who received a dose of bis-choline tetrathiomolybdate before withdrawal of bis-choline tetrathiomolybdate 15-90 mg bis-choline tetrathiomolybdate o once a day.

[0036] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is canceled if said patient has a measured bilirubin concentration exceeds 2.4 mg/dl and alanine aminotransferase (ALT) concentrations exceed 120 IU/ml, and as soon as the indicated patient has a measured bilirubin concentration below the upper limit of normal, treatment is resumed at a dose of 15 mg of bischoline tetrathiomolybdate every second day for a patient who received before the withdrawal of bis-choline tetrathiomolybdate a dose of 15 mg of bis-choline tetrathiomolybdate every second day, or at a dose of 15 mg / day of bis-choline tetrathiomolybdate for a patient who received a dose of bis-choline tetrathiomolybdate before withdrawal of bis-choline tetrathiomolybdate 15-90 mg bis-choline tetrathiomolybdate once a day and.

[0037] In some embodiments, the invention relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in the treatment of Wilson's disease in a patient receiving treatment with bischoline tetrathiomolybdate, characterized in that the daily dose of bischoline tetrathiomolybdate is canceled if said patient has a measured bilirubin concentration is more than twice the upper limit of normal bilirubin, and the concentration of alanine aminotransferase (ALT) is more than three times the ALT ULN, and as soon as the indicated patient has a measured bilirubin concentration below the upper limit of normal, treatment is resumed at a dose 15 mg of bischoline tetrathiomolybdate every second day for a patient who received before the withdrawal of bischoline tetrathiomolybdate a dose of 15 mg of bischoline tetrathiomolybdate every second day, or at a dose of 15 mg / day of bischoline tetrathiomolybdate for a patient who received before the abolition of bis-choline tetrathiomolybdate dose, component 15-90 mg of bis-choline tetrathiomolybdate once a day.

[0038] In some embodiments, the invention relates to a composition containing bis-choline tetrathiomolybdate for use in a method of treating Wilson's disease in a patient. In some embodiments of the invention, the composition is defined according to any of the compositions disclosed in this application. In some embodiments of the invention, the composition is intended for use in any of the methods disclosed in this application. In some embodiments of the invention, the patient is defined as described in this application.

[0039] In some embodiments, the invention relates to a pharmaceutical composition of bis-choline tetrathiomolybdate for use in the treatment of Wilson's disease, characterized in that the composition is taken on an empty stomach. In some embodiments, the pharmaceutical composition contains 15 mg of bis-choline tetrathiomolybdate. In some embodiments, the pharmaceutical composition is an enteric-coated tablet.

[0040] In some embodiments, the invention relates to the aforementioned methods of treating Wilson's disease, comprising administering bischoline tetrathiomolybdate to patients with Wilson's disease and modifying the regimen of bischoline tetrathiomolybdate for patients with Wilson's disease characterized in that the patient has cirrhosis.

[0041] In some embodiments, the invention relates to the aforementioned methods of treating Wilson's disease, comprising taking bischoline tetrathiomolybdate to patients with Wilson's disease and changing the regimen of taking bischoline tetrathiomolybdate to patients with Wilson's disease, characterized in that the patient does not have cirrhosis.

[0042] In some embodiments, the invention relates to the aforementioned methods of treating Wilson's disease, comprising taking bischoline tetrathiomolybdate in patients with Wilson's disease and changing the regimen for taking bischoline tetrathiomolybdate in patients with Wilson's disease, characterized in that the patient has one or more phenotypes of Wilson's disease selected from general tremor; general gait; dystonia; mobility and coordination of limbs; and rigidity; preferably, when the patient has a phenotype of general tremor or mobility and limb coordination, or both phenotypes. In some embodiments, a) the general tremor phenotype comprises one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS) selected from: resting tremor; head tremor; postural tremor and tremor of the "wing flap" type (hands); postural tremor (legs); and jaw tremor; b) the phenotype of the general gait includes one or more neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: rising from a chair; body position - torsion dystonia, postural ataxia and parkinsonism; gait - dystonia of the legs, ataxia and parkinsonism; c) the dystonia phenotype includes one or more neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: oromandibular dystonia; cervical dystonia; dystonia of the arm and hand; torsion dystonia; and gait - dystonia of the legs; d) the mobility and coordination phenotype of the limbs includes one or more neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: finger tapping; quick alternating hand movements; handwriting finger-nose test and leg mobility; e) the rigidity phenotype includes one or more neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from neurological manifestations of the arms, legs, and neck.

[0043] In some embodiments, a) the overall tremor phenotype score on the UWDRS (Part III) is 30-45; b) the overall gait phenotype score on the UWDRS scale (part III) is 20-32; c) dystonia phenotype score on the UWDRS scale (part III) is 15-28; d) limb mobility and coordination phenotype score on the UWDRS scale (part III) is 20-36; and e) stiffness phenotype score on the UWDRS scale (part III) is 10-20.

[0044] In some embodiments, the invention relates to the aforementioned methods of treating Wilson's disease, comprising taking bischoline tetrathiomolybdate in patients with Wilson's disease and changing the regimen for taking bischoline tetrathiomolybdate in patients with Wilson's disease, characterized in that the patient has a neurological manifestation of the disease Wilson according to Part III of the Unified Wilson's Disease Symptoms Severity Rating Scale (UWDRS) is selected from handwriting, leg mobility, and a combination thereof. In some embodiments, the patient has a handwriting score on the UWDRS (Part III) scale of 2-4; the leg mobility score on the UWDRS (Part III) scale is 2-8 or the handwriting and leg mobility score on the UWDRS scale (Part III) is 4-12. In some embodiments of the invention, the patient experiences an improvement in one or more neurological manifestations of Wilson's disease on the UWDRS scale (Part III) after taking the composition. In some embodiments of the invention, the patient has a decrease in the score of one or more neurological manifestations on the scale UWDRS (Part III) by: a) 5-25 points for the phenotype of general tremor; b) 5-20 points for the general gait phenotype; c) 5-15 points for dystonia phenotype; d) 5-20 points for the limb mobility and coordination phenotype; and e) 5-15 points for the rigidity phenotype.

[0045] In some embodiments of the invention, the patient has a decrease in the score of one or more neurological manifestations on the UWDRS scale (Part III): handwriting score by 1-3 points; leg mobility score by 1-6 points; and handwriting and leg mobility score by 2-9 points.

[0046] In some embodiments, the invention relates to a composition described herein for use in the treatment of Wilson's disease, characterized in that the patient has one or more Wilson's disease phenotypes selected from general tremor; general gait; dystonia; mobility and coordination of limbs; and rigidity; preferably, when the patient has a phenotype of general tremor or mobility and limb coordination, or both phenotypes. In some embodiments, a) the general tremor phenotype comprises one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS) selected from: resting tremor; head tremor; postural tremor and tremor of the "wing flap" type (hands); postural tremor (legs); and jaw tremor; b) the phenotype of the general gait includes one or more neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: rising from a chair; body position - torsion dystonia, postural ataxia and parkinsonism; gait - dystonia of the legs, ataxia and parkinsonism; c) the dystonia phenotype includes one or more neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: oromandibular dystonia; cervical dystonia; dystonia of the arm and hand; torsion dystonia; and gait - dystonia of the legs; d) the mobility and coordination phenotype of the limbs includes one or more neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: finger tapping; quick alternating hand movements; handwriting finger-nose test and mobility of the legs of the mobility of the legs; e) the rigidity phenotype includes one or more neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from neurological manifestations of the arms, legs, and neck.

[0047] In some embodiments of the invention, a) the overall tremor phenotype score on the UWDRS scale (Part III) is 30-45; b) the overall gait phenotype score on the UWDRS scale (part III) is 20-32; c) dystonia phenotype score on the UWDRS scale (part III) is 15-28; d) limb mobility and coordination phenotype score on the UWDRS scale (part III) is 20-36; and e) stiffness phenotype score on the UWDRS scale (part III) is 10-20.

[0048] In some embodiments, the invention relates to a composition described herein for use in the treatment of Wilson's disease, characterized in that the patient has a neurological manifestation of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS) selected from handwriting, leg mobility and their combinations. In some embodiments, the patient has a UWDRS (Part III) handwriting score of 2-4; leg mobility score on the UWDRS (Part III) scale is 2-8 or handwriting and leg mobility score on the UWDRS scale (Part III) is 4-12. In some embodiments, the patient experiences an improvement in one or more of the neurological manifestations of Wilson's disease on the UWDRS scale (Part III) after taking the composition. In some embodiments of the invention, the patient has a decrease in the score of one or more neurological manifestations on the scale UWDRS (Part III) by: a) 5-25 points for the phenotype of general tremor; b) 5-20 points for the general gait phenotype; c) 5-15 points for dystonia phenotype; d) 5-20 points for the limb mobility and coordination phenotype; and e) 5-15 points for the rigidity phenotype.

[0049] In some embodiments of the invention, the patient has a decrease in the score of one or more neurological manifestations on the UWDRS scale (Part III): handwriting score by 1-3 points; leg mobility score by 1-6 points and handwriting and leg mobility score by 2-9 points.

[0050] In some embodiments, the invention relates to a composition described herein for use in the treatment of Wilson's disease, characterized in that the patient has cirrhosis.

[0051] In some embodiments, the invention relates to a composition described herein for use in the treatment of Wilson's disease, characterized in that the patient does not have cirrhosis.

[0052] Additional aspects and embodiments of the invention will be apparent from the following detailed description.

BRIEF DESCRIPTION OF GRAPHICS

[0053] FIG. 1 shows the characteristics of the study.

[0054] FIG. 2 shows changes in NCM concentrations _corrected over time. Changes from baseline are the end of the mean (SE) for 19-25 patients at each time point. One patient stopped treatment at week 23, but at a time interval that allowed him to include his measured NCM concentration _corrected as the value obtained at week 24. P-values are given in comparison to baseline.

[0055] FIG. 3 shows changes in the degree of disability and neurological status over time. Changes from baseline Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS Part II) scores (disability; A) and Part III (neurological manifestations; B) scores are the limit of mean (SE) for 21-28 patients.

[0056] FIG. 4 shows NCM concentrations _corrected for WTX101 treatment (WTX101 once daily).

[0057] FIG. 5 shows the dynamics of indicators of liver stability in the treatment of WTX101 (WTX101 once a day).

[0058] FIG. 6 shows changes in the degree of disability and neurological manifestations in the treatment of WTX101 (WTX101 once a day).

[0059] FIG. 7 shows the number of adverse events (AEs) reported during the main and additional periods.

[0060] FIGURES 8A- 8B show total plasma Mo concentrations (mean ± standard error) after a single dose of KO-coated WTX101 tablets (60 mg; 2×30 mg) on an empty stomach (Treatment A) and after a meal (Treatment B), and BO+PPI on an empty stomach (Treatment C). Data are presented in linear coordinates ( FIG. 8A ) and semi-logarithmic coordinates ( FIG. 8B ).

[0061] FIG. 9 shows the symptoms of neurological status on the scale UWDRS (Part III), which at least 50% of patients experienced at the beginning of treatment. Data are presented as a proportion of patients in the study population (N=28).

[0062]FIGURES 10A - 10B demonstrate the scores of neurological status items on the UWDRS scale (part III) in the study population. OnFIG. 10A items with a maximum score of 4 are presented. OnFIG. 10Aitems with a maximum score of 8 are presented.

[0063]FIGURES 11A - 11B show the number of patients in whom, at week 24, changes were detected in the points of neurological status on the UWDRS scale (part III) relative to the baseline. Data from all patients for the specified item are presented, including patients with zero scores at baseline (n=22 in each case). OnFIG. 11A items with a maximum score of 4 are presented. OnFIG. 11V items with a maximum score of 8 are presented.

[0064] FIG. 12 illustrates the distribution of patients in the extended study.

[0065] FIG. 13 shows NCM _correct concentrations measured in patients with cirrhosis and in patients without cirrhosis. NCM concentrations were not adjusted at the start of treatment as patients were not receiving WTX101. IE, baseline; NGN, lower limit of the normal reference range (0.8 µmol/L); ULN, upper limit of the normal reference range (2.3 µmol/L); NCM _correct , non-ceruloplasmin bound copper corrected for the amount of copper bound in the tetrathiomolybdate-copper-albumin complex; SEM, standard error of the mean.

[0066] FIG. 14 shows ALT concentrations measured in patients with cirrhosis and in patients without cirrhosis. ALT, alanine aminotransferase; IE, baseline; SEM, standard error of the mean.

[0067] FIG. 15 shows the scores on the ICLS scale (severity of liver disease; score range, 6-40) in patients with cirrhosis and in patients without cirrhosis. IE, baseline; ICLR, End-Stage Liver Disease Model Scale; SEM, standard error of the mean.

[0068] FIG. 16 shows modified Nasser scores (prognostic index; score range, 0-20) in patients with cirrhosis and in patients without cirrhosis.

[0069] FIG. 17A shows albumin concentrations measured in patients with cirrhosis and in patients without cirrhosis. FIG. 17B shows the international normalization factor for patients with cirrhosis and for patients without cirrhosis. IE, baseline; MKN, international normalization factor; SEM, standard error of the mean.

[0070] FIG. 18 shows the clotting time in patients with cirrhosis and in patients without cirrhosis. IE, baseline; MKN, international normalization factor; SEM, standard error of the mean.

[0071] FIGURES 19 show scores on the UWDRS scale (Part II) (the degree of disability is determined by the patient's assessment of his daily activities; score range, 0-40) ( FIG. 19A ) and on the UWDRS scale (Part III) (neurological status is determined according to physician evaluation (score range; 0-143) ( FIG. 19B ) Higher scores indicate a more severe condition.

DETAILED DESCRIPTION OF THE INVENTION

[0072] Some aspects of the present invention are based on the surprising discovery that adverse events associated with the treatment of Wilson's disease can be reduced by taking a dosage form of bis-choline tetrathiomolybdate at a dosage of 15 mg or by changing the daily dose of bis-choline tetrathiomolybdate to control impaired liver function in the patient. As a rule, the ammonium salt of tetrathiomolybdate is taken in large doses, for example, from 90 to 220 mg per day. Brewer et al. Initial Therapy of Patients with Wilson's Disease with Tetrathiomolybdate. Arch. Neurol. 48:42-47 (1991). According to the present invention, administration of bis-choline tetrathiomolybdate at the same dosages or similar dosages to those of ammonium tetrathiomolybdate commonly known in the art is associated with the development of adverse events that the methods of the present invention reduce.

[0073] The present invention describes methods for administering a therapeutically effective dose of bischoline tetrathiomolybdate to a patient whose test results are abnormal following treatment with bischoline tetrathiomolybdate. Since abnormal liver function may indicate drug-induced liver damage (hepatotoxicity), it is important to determine whether abnormal liver function reflects liver damage or only indicates limited toxicity, which may disappear over time with continued use of the drug. According to the present invention, even patients with impaired liver function can continue taking bis-choline tetrathiomolybdate at the same dose or continue taking bis-choline tetrathiomolybdate at a reduced dose, optionally after temporarily stopping bis-choline tetrathiomolybdate. The advantage of this mode of administration is to maximize the time to receive the entire target dose of the drug and, therefore, the possibility of obtaining a beneficial therapeutic effect.

[0074] The methods of the present invention optionally include detecting abnormal liver function in a patient receiving bischoline tetrathiomolybdate and monitoring liver test results in a patient receiving a reduced dose of bischoline tetrathiomolybdate. In any of the methods described in this application, the concentration of ALT can be increased, for example, to a concentration in excess of 34 IU/ml or 64 IU/ml, or 170 IU/ml before dose reduction. Alternatively, the hemoglobin concentration may be reduced, or the platelet count may be reduced, or the neutrophil count may be reduced prior to dose reduction.

[0075] The methods of the present invention optionally include determining the concentration of copper in the body. Various methods are known in the art for determining the concentration of copper in the body. In one embodiment of the invention, the concentration of "free" copper in serum or plasma ultrafiltrate is determined using inductively coupled plasma mass spectrometry to assist in the diagnosis and control of Wilson's disease. In another embodiment of the invention, the concentration of "free" copper in the urine is determined. In another embodiment of the invention, the secretion of copper into the bile is assessed by determining the concentration of copper in the feces. In another embodiment of the invention, the concentration of copper in the hair is determined. In another embodiment, the serum free copper concentration is defined as the amount of unbound copper circulating in the blood, which is ceruloplasmin-free copper. It is clear that this is copper, which can easily accumulate in the liver and other organs. In a preferred embodiment, non-ceruloplasmin bound copper or NCM is determined by inductively coupled plasma mass spectrometry or other methods known in the art. In any of the methods described in this application, the NCM _adjusted index can be increased, for example, it can exceed 2.3 μmol/l.

[0076] Although the ranges of the aforementioned reference test results and concentrations in healthy individuals may vary depending on the research conditions and laboratory methods, it is generally known that in healthy people the following indicators are observed: ALT concentration is in the range of 6-34 U / l; 9-34 U/l or 6-41 U/l; the hemoglobin concentration is in the range of 11.6-16.4 g/dl, 13.6-18.0 g/dl, or 12.0-16.0 g/dl; the number of platelets - in the range of 140-400 x 10 ³ /µl; the number of neutrophils - in the range of 1.96-7.23 x 10 ³ /μl; bilirubin concentration - in the range of 0.2-1.2 mg / dl or 0.10-1.10 mg / dl. For more information on assay methods in clinical laboratory diagnosis and treatment of Wilson's disease, see the European Association for the Study of the Liver (EASL) Clinical Practice Guideline: Wilson's Disease; J. Hepatology 56:671-685 (2012), which are incorporated herein in their entirety.

[0077] In some embodiments, the invention relates to methods for treating Wilson's disease in a patient by taking 15 mg of bischoline tetrathiomolybdate once a day or once every other day. The single daily dose may be taken in the form of a single dose or two doses, optionally two equally divided doses, or three, four or five doses. The dose may be given orally or administered intravenously, intramuscularly, or by any other route known in the art.

[0078] In some embodiments, the invention relates to methods of treating Wilson's disease in a patient by daily administration of 30 to 90 mg of bischoline tetrathiomolybdate, characterized in that the patient has one or more of the following indicators: an NCM _adjusted value greater than 2, 3 µmol/l, alanine aminotransferase (ALT) concentration less than 80 IU/ml, hemoglobin concentration greater than 8 g/dl, platelet count greater than 30,000/μl, or neutrophil count greater than 1000/μl or 1 × 10 ³ /μl. The following indicators can be determined in a patient: the index of NCM _corrected exceeds 2.3 μmol / l and the concentration of alanine aminotransferase (ALT) is less than 80 IU / ml, or the index of NCM _corrected exceeds 2.3 μmol / l and the hemoglobin concentration exceeds 8 g / dl, or any combination of two or more of these may be defined. In some embodiments of the invention, one or more indicators will be defined. In one embodiment of the invention, the NCM _corrected index is determined. In another embodiment of the invention, two or more indicators are determined. In another embodiment of the invention, all indicators are determined.

[0079] In some embodiments, the invention relates to methods for treating Wilson's disease in a patient by taking 30 to 90 mg of bischoline tetrathiomolybdate daily when the patient has one or more of the following: NCM score_corrected exceeds 2.0; 2.1; 2.2; 2.3; 2.4; 2.5 µmol/l or exceeds the upper limit of normal (ULN) NCM_corrected; alanine aminotransferase (ALT) concentration less than 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 IU / ml or twice the upper limit of normal (ULN) ALT, hemoglobin concentration exceeds 6, 7, 8, 9, or 10 g/dL, platelet count greater than 20,000, 25,000, 30,000, 35,000, or 40,000/mcL, or neutrophil count greater than 0.5 x 10³; 1 x 10³; 1.5 x 10³; 2 x 10³ or 2.5 x 10³/µl. In some embodiments of the invention, a combination of two or more of these indicators can be determined in a patient. In some embodiments of the invention, one or more indicators will be defined. In another embodiment of the invention, the NCM index is determined_corrected. In some embodiments of the invention, two or more indicators are determined. In some embodiments of the invention, all indicators are determined.

[0080] In some embodiments, the invention relates to methods for altering the dosing regimen of bischoline tetrathiomolybdate for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment by increasing the daily dose of bischoline tetrathiomolybdate. In some embodiments of the invention, the dose of bis-choline tetrathiomolybdate is increased for a patient with certain test results. In some embodiments of the invention, the daily dose of bis-choline tetrathiomolybdate is increased in "steps" of 15 mg. In some embodiments of the invention, the daily dose is increased if the patient has one or more of the following: NCM score_corrected greater than 2.3 µmol/l, alanine aminotransferase (ALT) concentration less than 80 IU/ml, hemoglobin concentration greater than 8 g/dl, platelet count greater than 30,000/μl, or neutrophil count greater than 1000/μl or 1 × 10³/µl. In some embodiments of the invention, the daily dose is increased if the patient has one or more of the following: NCM score_corrected exceeds 2.0; 2.1; 2.2; 2.3; 2.4; 2.5 µmol/l or exceeds the upper limit of normal (ULN) NCM_corrected; alanine aminotransferase (ALT) concentration less than 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 IU / ml or twice the upper limit of normal (ULN) ALT, hemoglobin concentration exceeds 6, 7, 8, 9, or 10 g/dL, platelet count greater than 20,000, 25,000, 30,000, 35,000, or 40,000/mcL, or neutrophil count greater than 0.5 x 10³; 1 x 10³; 1.5 x 10³; 2 x 10³ or 2.5 x 10³/µl. The following indicators can be determined in a patient: NCM indicator_corrected exceeds 2.3 µmol/l and the concentration of alanine aminotransferase (ALT) is less than 80 IU/ml, or NCM indicator_corrected is greater than 2.3 µmol/l and the hemoglobin concentration is greater than 8 g/dl, or any combination of two or more of these may be determined. In some embodiments of the invention, one or more indicators will be defined. In one embodiment of the invention, the NCM index is determined_corrected. In another embodiment of the invention, two or more indicators are determined. In another embodiment of the invention, all indicators are determined. In some embodiments of the invention, the daily dose is increased in "steps" of 15 mg of bis-choline tetrathiomolybdate. In some embodiments, the daily dose is increased at the time of initiation of treatment, typically during the first 3, 4, 5, or 6 months of treatment with bischoline tetrathiomolybdate. In some aspects of the invention, the patient dose is increased once. In some aspects of the invention, the patient dose is increased twice. In some aspects of the invention, the patient dose is increased three or more times.

[0081] In some embodiments, the invention relates to methods for altering the dosing regimen of bischoline tetrathiomolybdate for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment by reducing the daily dose of bischoline tetrathiomolybdate. In some embodiments of the invention, the daily dose of bis-choline tetrathiomolybdate is reduced in "steps" of 15 mg. In another embodiment of the invention, the daily dose is reduced by taking a dose every second day. In another embodiment of the invention, the daily dose is reduced by taking 15 mg every second day, thus the patient receives an average of 7.5 mg of bis-choline tetrathiomolybdate per day.

[0082] In one aspect, the present invention further provides methods for reducing the daily dose of bis-choline tetrathiomolybdate for a patient with an abnormal test result. In some aspects of the invention, bischoline tetrathiomolybdate is temporarily discontinued if the patient exhibits certain abnormal test results and resumed, optionally at a lower dose, when the patient shows improvement in test results. In one embodiment, the study is a liver function study. Any liver function test known in the art may be used. In one embodiment, the concentration of alanine aminotransferase (ALT) or bilirubin is determined. In one embodiment of the invention, the study is an assessment of the degree of bone marrow depression mediated by prolonged and excessive removal of copper from the body, leading to cytopenia. In one embodiment of the invention, the study may be a study to determine the concentration of hemoglobin, platelet count or neutrophil count. In one embodiment, the invention takes into account the results of two or more studies. In one embodiment of the invention, multiple studies are used. In some embodiments of the invention, the dose is reduced if two consecutive test results are abnormal.

[0083] In some embodiments, for a patient with an abnormal test result, the daily dose of bischoline tetrathiomolybdate is reduced by 15 mg such that the dose for a patient who took 15 mg/day of bischoline tetrathiomolybdate until an abnormal the result of the study, will be reduced to 15 mg of bis-choline tetrathiomolybdate every second day; the dose for a patient who was taking 30 mg/day of bischoline tetrathiomolybdate prior to the detection of an abnormal test result will be reduced to 15 mg/day of bischoline tetrathiomolybdate; the dose for a patient who was taking 45 mg/day of bischoline tetrathiomolybdate prior to the detection of an abnormal test result will be reduced to 30 mg/day of bischoline tetrathiomolybdate; the dose for a patient who was taking 60 mg/day of bischoline tetrathiomolybdate prior to the detection of an abnormal test result will be reduced to 45 mg/day of bischoline tetrathiomolybdate; the dose for a patient who was taking 75 mg/day of bischoline tetrathiomolybdate prior to the discovery of an abnormal test result will be reduced to 60 mg/day of bischoline tetrathiomolybdate; the dose for a patient who was taking 90 mg/day of bischoline tetrathiomolybdate prior to the discovery of an abnormal test result will be reduced to 75 mg/day of bischoline tetrathiomolybdate. In some embodiments, the daily dose of bischoline tetrathiomolybdate for a patient with an abnormal test result is halved. In some embodiments, the dose of bis-choline tetrathiomolybdate for a patient with an abnormal test result who was taking a daily dose of 30-90 mg of bis-choline tetrathiomolybdate until an abnormal test result is detected is reduced to 15 mg of bis-choline tetrathiomolybdate once a day; and the dose of bis-choline tetrathiomolybdate for a patient with an abnormal test result who took 15 mg of bis-choline tetrathiomolybdate once a day until an abnormal test result is detected is reduced to 15 mg of bis-choline tetrathiomolybdate every second day.

[0084] In some embodiments, bischoline tetrathiomolybdate is temporarily discontinued if the patient demonstrates appropriate abnormal test results and resumed after the test results meet a certain threshold. In some embodiments of the invention, the reception is stopped if two consecutive results of the study deviate from the norm. In some embodiments of the invention, reception is resumed if two consecutive test results meet a certain threshold value. In some embodiments of the invention, the daily dose of bischoline tetrathiomolybdate is resumed at the same dose that was established prior to discontinuation. In some embodiments, the daily dose of bis-choline tetrathiomolybdate is resumed at a reduced dose as described above. In some embodiments of the invention, the daily dose is renewed at a dose of 15 mg of bis-choline tetrathiomolybdate. In some embodiments, the daily dose is resumed at 15 mg of bis-choline tetrathiomolybdate if the patient was taking a daily dose of 30-90 mg of bis-choline tetrathiomolybdate prior to the discovery of an abnormal test result. In some embodiments, the dose is restarted at 15 mg of bis-choline tetrathiomolybdate every second day if the patient was taking 15 mg of bis-choline tetrathiomolybdate daily prior to the discovery of an abnormal test result.

[0085] An abnormal test result can be determined based on the performance of established thresholds above or below which liver function or bone marrow function is considered normal. In an optional aspect, an upper limit of normal (ULN) is determined for the test result. In an optional aspect, a dose change is performed for a patient with two consecutive abnormal test results. Bischoline tetrathiomolybdate dosing regimen may be changed if the test result exceeds the ULN, or two times the ULN, or three times the ULN, or four times the ULN, or five times the ULN, or the test result exceeds the ULN by any multiple of ULN, or if the result determined by a liver function test is greater than any fractional multiple of ULN between one, two, three, four, or five times ULN. In one embodiment of the invention, the daily intake of bis-choline tetrathiomolybdate is reduced if the test result exceeds ULN by 2-5 times. In one embodiment of the invention, the daily intake of bis-choline tetrathiomolybdate is canceled if the test result exceeds the ULN by more than five times. In one embodiment of the invention, the study of liver function is the determination of the concentration of ALT. Optionally, bischoline tetrathiomolybdate is resumed if ALT concentration is two times lower than ULN. Optionally, the daily dose of bis-choline tetrathiomolybdate is resumed at a reduced dosage if the ALT concentration is two times lower than the ULN. In one embodiment of the invention, ULN and lower limit of normal (LN) ALT depend on the quantitation method used. In one embodiment, ALT ULN is 30-45 IU/mL or 30-33 IU/mL or 33-36 IU/mL or 36-39 IU/mL or 39-42 IU/mL or 42- 45 IU/ml. In one embodiment, the ALT ULN is 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 IU/ml, or any fractional number in range of specified values. In one embodiment, the ALT ULN is 34 IU/mL. In one embodiment, the ALT ULN is 40 IU/mL.

[0086] In yet another optional aspect, the daily dose of bischoline tetrathiomolybdate is changed if liver function tests are below baseline prior to taking bischoline tetrathiomolybdate. Optionally, the specified baseline is specific to the patient. Optionally, the specified baseline is determined according to the judgment of the physician. Optionally, the specified baseline is determined according to the results of clinical studies. Optionally, the dose is changed if the patient has two consecutive abnormal test results. In one embodiment, the cut-off value at which the dose of bis-choline tetrathiomolybdate is changed is 50%, or 60%, or 70%, or 80%, or 90% of baseline, or any percentage within the indicated range. In another embodiment of the invention, the threshold is 65%, or 70%, or 75% of baseline. In one embodiment of the invention, the threshold is 70% of baseline. In an optional aspect, the dose of bis-choline tetrathiomolybdate is changed if the patient's hemoglobin concentration is less than 70% of said patient's baseline hemoglobin concentration. In another optional aspect, the threshold is 70% of the original platelet count or 70% of the original neutrophil count.

[0087] In another aspect, the dose of bischoline tetrathiomolybdate is reduced or temporarily discontinued if the patient's measured hemoglobin concentration is less than 6, 7, 8, 9, or 10 g/dl. In another aspect, the dose of bis-choline tetrathiomolybdate is reduced or temporarily discontinued if the patient's measured hemoglobin concentration is less than 8 g/dL. In another aspect, the dose of bischoline tetrathiomolybdate is reduced or temporarily discontinued if the patient's platelet count is less than 20,000, 25,000, 30,000, 35,000, or 40,000/µl. In another aspect, the dose of bischoline tetrathiomolybdate is reduced or temporarily discontinued if the patient's platelet count is less than 30,000/µl. In another aspect, the dose of bis-choline tetrathiomolybdate is reduced or temporarily canceled if the patient's neutrophil count is less than 0.5 x 10 ³ ; 1 x 10 ³ ; 1.5 x 10 ³ ; 2 x 10 ³ or 2.5 x 10 ³ /µl. In another aspect, the dose of bis-choline tetrathiomolybdate is reduced or temporarily discontinued if the patient's neutrophil count is less than 1 x 10 ³ /µl. Optionally, the dose is changed if the patient has two consecutive abnormal test results.

[0088] In some embodiments, when a dose of bischoline tetrathiomolybdate has been temporarily discontinued, the dose is resumed if the patient has one or more of the following: hemoglobin concentration is or greater than 6, 7, 8, 9, or 10 g/dL ; the platelet count is greater than or equal to 20,000, 25,000, 30,000, 35,000 or 40,000/µl, and/or the neutrophil count is greater than or equal to 0.5 x 10 ³ ; 1 x 10 ³ ; 1.5 x 10 ³ ; 2 x 10 ³ or 2.5 x 10 ³ /µl. In some embodiments, when a dose of bischoline tetrathiomolybdate has been temporarily discontinued, the dose is resumed if the patient has one or more of the following: hemoglobin concentration is or greater than 8 g/dl; the platelet count is greater than or equal to 30,000/μl, and/or the neutrophil count is greater than or equal to 1 x 10 ³ /μl. In some embodiments, when a dose of bischoline tetrathiomolybdate has been temporarily discontinued, the dose is resumed if the patient has one or more of the hemoglobin concentration, platelet count, or neutrophil count values consistent with baseline values.

[0089] Those skilled in the art will appreciate that the listed liver function tests or indicators of bone marrow depression are not restrictive. Other studies of liver function or the degree of bone marrow suppression may be done. Can be developed and used new methods of studying the function of the liver or the degree of oppression of the bone marrow, instead of the methods disclosed in this application for the study of liver function.

[0090] In another aspect, the present invention provides methods for reducing the daily dose of bis-choline tetrathiomolybdate for a patient who is experiencing exacerbation of neurological symptoms. In one embodiment, the worsening of neurological symptoms is assessed using a UWDRS score (Part III). In one embodiment, baseline UWDRS (Part III) scores are set prior to initiation of bis-choline tetrathiomolybdate. In one embodiment, an aggravation of neurological symptoms is defined as an increase in the UWDRS (Part III) score from baseline by 1, 2, 3, 4, 5, 6, 7, or 8 points. In another embodiment, an aggravation of neurological symptoms is defined as an increase in the UWDRS (Part III) score from baseline by 4, 5, or 6 points. In another embodiment, worsening of neurological symptoms is defined as a 4-point increase in UWDRS (Part III) score from baseline with a baseline UWDRS (Part III) score of less than 20 points. In another embodiment, neurological worsening is defined as a 6-point increase in UWDRS (Part III) score from baseline with a baseline UWDRS (Part III) score of 20 or greater. In an optional aspect, the change is to eliminate bis-choline tetrathiomolybdate. In an optional aspect, the change is for the patient to take a modified dose of bis-choline tetrathiomolybdate in the absence of aggravation of neurological symptoms. In some aspect, the patient does not experience an aggravation of neurological symptoms if the UWDRS (Part III) score of said patient is unchanged. In one embodiment, the modified dose is a reduced dose. In some embodiments of the invention, the modified dose is half the daily dose that the patient took before the aggravation of neurological symptoms. In some embodiments of the invention, the modified dose is less than the daily dose that the patient took before the worsening of neurological symptoms, namely, 15 mg less than the daily dose that the patient took before the worsening of neurological symptoms. In some embodiments of the invention, the patient who received a dose of 15 mg of bis-choline tetrathiomolybdate once a day receives 15 mg of bis-choline tetrathiomolybdate every second day; a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day receives 15 mg of bischoline tetrathiomolybdate once a day; a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day receives 15-30 mg of bischoline tetrathiomolybdate once a day; a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day receives 30 mg of bischoline tetrathiomolybdate once a day; a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day receives 30-45 mg of bischoline tetrathiomolybdate once a day; or a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day receives 45 mg of bischoline tetrathiomolybdate once a day.

[0091] In some embodiments, the invention relates to increasing or decreasing the dose of bis-choline tetrathiomolybdate in a fixed "step". In one embodiment, the method comprises administering to the patient a first dose of about 15 to about 90 mg of bischoline tetrathiomolybdate per day for a period of time, followed by a second dose for a second period of time that is at least approximately 15 mg of bis-choline tetrathiomolybdate per day less than the value of the first dose of bis-choline tetrathiomolybdate. In one embodiment, the second dose is 15 mg every other day. Dose size and daily dose may be used interchangeably. The dose size may include one, two, three, four, five or more doses taken at different times or at the same time of day. The dose may optionally be a tablet or two tablets. Optionally, the dose may be a tablet, capsule, or other dragee. Optionally, the dose may be in liquid form.

[0092] In some embodiments, the first dose is 15 mg or 30 mg or 45 mg or 60 mg or 75 mg or 90 mg. In an optional aspect, the value of the first dose may exceed 90 mg. In some embodiments, the second dose is 15 mg or 30 mg or 45 mg or 60 mg or 75 mg or 90 mg. In an optional aspect, the value of the second dose may exceed 90 mg. One of skill in the art will appreciate that the dosage values listed are not limiting. Optionally, the dose may be adjusted depending on the weight of the subject. Optionally, the dose may be adjusted by determining the bioavailability of the drug, for example, by determining the serum tetrathiomolybdate concentration following administration of bischoline tetrathiomolybdate. Optionally, the dose may be adjusted by determining the patient's serum copper concentration. Optionally, the dose may be adjusted by determining the NCM _adjusted .

[0093] In one embodiment, the first dose is 90 mg, the second dose is 15 mg. In one embodiment, the first dose is 90 mg, the second dose is 75 mg. In some embodiments, the first dose is 90 mg, or 75 mg, or 60 mg, or 45 mg, the second dose is 15 mg less than the first dose. In one embodiment, the second dose is 30 mg less than the first dose. In some embodiments, the bischoline tetrathiomolybdate treatment is discontinued between the first and second doses. In one embodiment of the invention, the treatment is canceled if the results of the studies deviate from the norm. In one embodiment of the invention, the treatment of the patient with a second dose is carried out after receiving the results of studies corresponding to the norm.

[0094] In another aspect, the present invention relates to pharmaceutical compositions for the treatment of Wilson's disease in a patient, containing bis-choline tetrathiomolybdate. Some pharmaceutical compositions containing bis-choline tetrathiomolybdate are described in US Pat. No. 7,189,865, which is incorporated herein by reference in its entirety. A general description of pharmaceutical compositions is given in Remington: The Science and Practice of Pharmacy, 22nd edition (2012).

[0095] In some embodiments, the pharmaceutical composition contains bis-choline tetrathiomolybdate and a second active pharmaceutical ingredient. In one embodiment, the second active pharmaceutical ingredient is zinc. The zinc may be provided in the form of zinc acetate or zinc sulfite. In one embodiment, the second active pharmaceutical ingredient is a tetrathiomolybdate salt other than a bischoline salt. Optionally, the second active pharmaceutical ingredient is ammonium tetrathiomolybdate. In another embodiment of the invention, the second active pharmaceutical ingredient is a copper chelator. In an optional embodiment of the invention, the second active pharmaceutical ingredient is 2,3,2-tetramine or D-penicillamine.

[0096] In some embodiments, the compositions and methods of the invention relate to tetrathiomolybdate salts other than tetrathiomolybdate bischoline salt. In some embodiments, the tetrathiomolybdate salt is a salt of tetrathiomolybdate and any pharmaceutically acceptable counterion. Non-limiting and illustrative counterions include ammonium, choline, and acetylcholine. The counterion can be, for example, a positively charged organic acid. The dose is adjusted depending on the molecular weight of the salt.

[0097] In another aspect, the present invention provides kits for the treatment of Wilson's disease, containing at least three sets of pharmaceutical dosage units and instructions for use. In one embodiment of the invention, the kit contains tablets in an amount sufficient for a 7-day, 30-day or 90-day course of treatment with instructions for use. In one embodiment of the invention, the instructions for use indicate the study of liver functions and thresholds at which it is necessary to increase or decrease the number of pharmaceutical dosage units or fractional doses of pharmaceutical dosage units that must be taken each day. In one embodiment, the kit further comprises zinc tablets. In one embodiment, the kit further comprises a copper chelator other than bis-choline tetrathiomolybdate. In another aspect, the present invention provides compositions for use in any of the methods of the present invention. In another aspect, the present invention provides compositions for use in the manufacture of a medicament for use in any of the methods of the present invention.

[0098] For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dosage forms, for example, tablets (both swallowable and chewable tablets), capsules, or gel capsules, manufactured by conventional methods using pharmaceutically acceptable excipients and carriers. such as binders (for example, pregelatinized corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.), fillers (for example, lactose, microcrystalline cellulose, calcium phosphate, etc.), lubricants (for example, magnesium stearate, talc, silicon dioxide, and the like), disintegrants (eg, potato starch, sodium starch glycolate, and the like), wetting agents (eg, sodium lauryl sulfate), and the like. Such tablets may also be coated by methods well known in the art.

[0099] The dose taken may be adjusted depending on the age, weight and condition of the patient, as well as depending on the route of administration, dosage form, regimen and desired result. In some embodiments, the subject is dosed incrementally until the desired endpoint is reached.

[00100] The compositions described above may be taken in dosage forms as described above, as a single dose or in divided doses from one to four times a day.

[00101] Dosage units can be produced, including tablets, capsules and caplets of various sizes, for example, the total weight of which can be from about 2 to 10,000 mg and which contain one or both active substances in the ranges described above, the rest of the dosage unit in according to standard pharmaceutical practice is a physiologically acceptable carrier of other substances. These pills can certainly be at risk in order to receive fractional doses. The composition of gelatin capsules may be similar.

[00102] In some embodiments of the invention, bis-choline tetrathiomolybdate is provided in the same dosage unit in the form of a divisible dosage unit. For example, in some embodiments, the scored tablet may provide a dosage unit. Under the supervision of a physician or other specialist, the subject may take one part of the dosage unit, with one part providing the desired dose for a given interval. At the next interval, the patient may be informed to take two or more portions of the dosage unit, with two or more portions providing the desired dose for that interval.

[00103] Liquid dosage forms can also be produced by dissolving or suspending a single active ingredient or a combination of active ingredients in a standard pharmaceutically acceptable liquid carrier to provide the desired dosage of 1-4 teaspoons.

[00104] A patient's dosage regimen may include one to four doses per day.

[00105] Some aspects of the invention are based on the unexpected discovery that, compared with fasting bischoline tetrathiomolybdate, absorption (absorption) of bischoline tetrathiomolybdate is reduced by 60-75% when taken after a meal. In one aspect of the invention, a patient suffering from Wilson's disease takes bis-choline tetrathiomolybdate on an empty stomach. In some embodiments, the bis-choline tetrathiomolybdate is taken after an overnight fasting period. In some embodiments, bischoline tetrathiomolybdate is taken on an empty stomach, after a fasting period of about 1, 2, 3, 4, 5, 6, 7, or 8 hours. In some embodiments, the bischoline tetrathiomolybdate is administered as an enteric-coated dosage form.

[00106] All of the features described herein (including any appended claims, abstract, and drawings) and/or all steps of any method thus disclosed may be combined with any of the above aspects in any combination, except for combinations where at least some of such features and/or steps are mutually exclusive. Namely, any of the active substances and compositions described in this application can be used in any of the described methods of treatment. Any and all such combinations are expressly considered to be within the scope of the invention.

[00107] In the context of this application, the following terms have the following meanings.

[00108] "Bis-choline tetrathiomolybdate" means bis-choline salt of tetrathiomolybdate or pharmaceutical compositions thereof. Bis-choline tetrathiomolybdate is also known as choline tetrathiomolybdate or ATN-224 or WTX101 or WTX-101 or DECUPRATE™/DECUPRATE™. "WV" stands for Wilson's disease.

[00109] "QOD" or "quaque altera die" means taking the drug every second day, for example, 15 mg QOD is understood in the art as taking a dose of 15 mg every second day. QD or "Quaque die" means taking the drug once a day, for example, 15 mg QD is understood in the art as taking a dose of 15 mg once a day. "SL" stands for standard treatment.

[00110] "Consistent study results" or "consistent study results that deviate from the norm" means the results of two or more determinations of the same indicator, conducted at two different time points. In certain embodiments of the invention, these determinations are carried out at intervals of one week. In some embodiments, embodiments of the invention, these determinations are carried out with an interval of two weeks.

[00111] "Non-ceruloplasmin bound copper" or "NCM" refers to the concentration of "free" copper in serum. Plasma copper is bound to ceruloplasmin or more labilely bound to other plasma proteins such as albumin or smaller circulating peptides. Labile bound copper that is not bound to ceruloplasmin (i.e., non-ceruloplasmin bound copper or NCM) is sometimes referred to as "free" copper. In a healthy individual (ie, a person not suffering from Wilson's disease), as a rule, more than 70% of all copper present in the blood plasma is associated with ceruloplasmin. In Wilson's disease, ceruloplasmin-bound copper concentrations are generally low and this may explain the low total plasma copper concentrations in patients with Wilson's disease. However, if "free" copper (i.e., not bound to ceruloplasmin) is calculated by subtracting ceruloplasmin bound copper from total serum copper, it is usually above the upper limit of normal (>15 mg/dl) . In untreated patients with Wilson's disease, the concentration of NCM, as a rule, exceeds 25 mcg / dl. To calculate the NCM score (in µg/dl), the amount of copper bound to cerudoplasmin (in mg/dl) is multiplied by 3; this value is then subtracted from the total serum copper concentration (in µg/dl).

[00112] "NCM _corrected " or "NCM _corr " means the concentration of NCM corrected for copper content in tetrathiomolybdate-copper-albumin complexes. Exemplary methods for determining NCM _corr are described by Weiss et al. Lancet Gastroenterol Hepatol. 2:869-876 (2017), which is incorporated herein in its entirety. The mechanisms of copper incorporation into ceruloplasmin are described by Hellman et al. J Bio. Chem. 48:46632-38 (2002).

[00113] "Model of the end stage of liver disease" or "MCSL" means a scoring system for assessing the severity of chronic liver disease. To predict a subject's survival, the ICFF takes into account the serum bilirubin concentration, the serum creatinine concentration, and the international normalization factor for prothrombin time (IMN). The calculation is carried out according to the following formula: MCCF=3.78 × ln[serum bilirubin concentration (mg/dL)] + 11.2 × ln[MCN] + 9.57 × ln[serum creatinine concentration (mg/dL) )] + 6.43

[00114] The "Modified Nasser Scale" is a scale for assessing the state of the liver and takes into account 5 laboratory parameters: aspartate aminotransferase concentration, international normalization coefficient, bilirubin concentration, albumin concentration, and white blood cell count. The score ranges from 0 to 20 points, with lower values indicating improvement.

[00115] "Fibrosis Index-4/Transient Elastography" or "FIB-4 Index" means a formula used to predict liver fibrosis based on standard biochemical parameters (ALT concentration, aspartate aminotransferase concentration, and platelet count) and age.

[00116] "Transient elastography" means a non-invasive imaging technique that assesses the degree of liver fibrosis or fatty deposits in the liver by determining the speed of propagation of sound waves in the liver based on a sonogram.

[00117] "Ceruloplasmin" means a ferroxidase encoded in the human body by the CP gene. Ceruloplasmin is the main copper-containing protein in the blood, also involved in iron metabolism.

[00118] "Total copper concentration and total molybdenum concentration" or "determination of total Cu concentration and total Mo concentration" means the determination of total copper concentration and total molybdenum (Mo) concentration in the patient's blood serum.

[00119] "Analysis of the mineral composition" means the determination of the concentrations of Mo, Cu and protein complex using size exclusion chromatography.

[00120] "Uniform Wilson's Disease Symptom Severity Rating Scale" or "UWDRS" means a clinical rating scale designed to assess the neurological manifestations of VWD, which can be broadly classified into 3 movement disorder syndromes: a. dystonic, b. atactic and s. parkinsonian syndrome. The UWDRS has three parts: UWDRS part I (consciousness, item 1), UWDRS part II (retrospective analysis of daily activity items [disability], items 2-11), and UWDRS part III (neurological examination, items 12-34). ). Typically, Part I and Part III of the UWDRS are performed by a neurologist. Part II of the UWDRS is typically completed by the subject or family. The UWDRS scale is described in Członkowska A et al. Neurol Neurochir Pol 41:1-12 (2007), which is incorporated herein in its entirety.

[00121] "Clinical Global Impression Scale - Disease Severity" or "CGI-S Scale" means a 7-point scale, according to which the physician must assess the severity of the subject's disease at the time of the examination based on their own clinical experience with subjects with a similar diagnosed disease. Based on clinical experience, the following assessment of the severity of the subject's disease at the time of examination is given: 1, normal, not sick; 2, borderline ill; 3, easily sick; 4, moderately ill; 5, severely ill; 6, seriously ill; or 7, very seriously ill.

[00122] "Clinical Global Impression Scale - Improvement" or "CGI-I scale" means a 7-point scale according to which the clinician must assess the degree of improvement or deterioration in the condition in comparison with the baseline condition at the beginning of treatment; the following score is given: 1, very significant improvement; 2, significant improvement; 3, minimal improvement; 4, no change; 5, minimal degradation; 6, significant deterioration or 7, very significant deterioration.

[00123] "Brief Psychiatric Rating Scale-24" or "BPRS-24" refers to a 24-item assessment tool that allows the investigator to assess the severity of psychiatric disorders. BPRS-24 evaluates 24 psychopathological symptoms. The presence and severity of psychopathological symptoms are assessed on a Likert scale in the range from 1 (absence) to 7 (extreme severity). The BPRS-24 can be assessed by a qualified physician.

[00124] "European Quality of Life Questionnaire - 5 Directions" or "EQ-5D" means an assessment tool consisting of the EQ-5D-5L descriptive system and the EQ visual analog scale. The descriptive system takes into account 5 areas (mobility, self-care, daily activities, pain/discomfort and anxiety/depression), each of which is divided into 5 levels depending on the severity (no problems/minor problems/moderate problems/severe problems/very serious problems) . When filling out the EQ-5D-5L questionnaire, the respondent is asked to indicate the state of his/her health by ticking (or putting a cross) in the box next to the most appropriate statement for each of the 5 areas. The result is a single-digit number indicating the level selected for this direction. The numbers for the 5 directions can be combined into a 5-digit number describing the health status of the respondent.

[00125] "Treatment Satisfaction Questionnaire" or "TSQM-9" means a tool for assessing the overall level of satisfaction or dissatisfaction with medications taken by subjects. This complex scale consists of 2 items of the TSQM-9 questionnaire: how satisfied are you that the positive effects of this drug outweigh the negative effects? All things considered, how satisfied or unhappy are you with this drug?

[00126] "The three symptoms that cause the most discomfort" means the three symptoms that cause the most discomfort to the subject. Each subject, or subject and caregiver, identifies the three symptoms that cause them the most discomfort, which are documented in writing, also documenting the impact of these symptoms on their daily activities. Where possible and appropriate, and with the consent of the subjects, the three symptoms that cause the most discomfort are recorded on video.

[00127] "Test walking 25 feet for time" means a tool to quantify the mobility and function of the legs, assessed by the time of walking a distance of 25 feet. The subject stands at one end of a clearly marked 25-foot stretch and is asked to walk the 25-foot distance as quickly as the subject is able to walk it with care. The timing starts at the request to start walking and stops when the subject reaches 25 feet. Once the specified distance has been covered, the subject is asked to walk the same distance again in the opposite direction. The score obtained by measuring the walking time for a distance of 25 feet is the average of two attempts. Subjects may use assistive devices when performing this task.

[00128] "Peg nine-hole test" or "9-HPT" means a short, standardized, quantitative test to assess upper limb function. Testing is done twice for both the dominant and non-dominant hand. The subject is seated at a table with a small shallow container with 9 pegs and a wooden or plastic tablet with 9 empty holes in front of the subject. After being asked to start the task and starting the stopwatch, the subject takes all nine pegs in turn, one peg at a time, and inserts them into the 9 holes as quickly as possible; once all holes are filled, the subject removes the pegs one at a time back into the shallow container as quickly as possible. After performing two consecutive tasks with the dominant hand, the subject immediately performs two consecutive tasks with the non-dominant hand. The score obtained from the 9-HPT is the average of 4 attempts.

[00129] The Stroop Non-Verbal Interference Test means an effective tool for assessing executive functioning, the ability to plan, apply knowledge, and make decisions. In psychology, the Stroop effect is a demonstration of interference in response time to a task. There is no verbal communication during the test. The test is conducted using non-verbal means, using gestures and demonstrations.

[00130] "Test of Number Strings" means a test evaluating forward and reverse playback (reverse) of sequences of numbers and a number string. Sequences of digits are presented starting from 2 digits, 2 tests are carried out with an increase in the length of the row. Testing is terminated if the subject cannot accurately reproduce a sequence of one length or when the maximum length of the sequence (9 digits, 8 replays backwards) is reached.

[00131] "Adverse event" means any adverse medical event in a subject of a clinical trial taking a medicinal product, which is not necessarily causally related to a given treatment. Therefore, an adverse event can be any adverse and/or unintended sign (including laboratory abnormalities), symptom or disease temporally associated with the use of an investigational medicinal product, whether or not associated with an investigational medicinal product. Clinically significant abnormalities in laboratory parameters or other studies, including neurologic examination results, are reported as adverse events. In deciding whether a deviation in laboratory values or other test results is clinically significant, the specialist will be guided by their medical opinion and scientific judgment. The result of any study that deviates from the norm and which is determined to be erroneous does not require reporting as an undesirable phenomenon.

[00132] The severity of all adverse events is assessed according to the Common terminological criteria for the evaluation of adverse events (CTCAE). These criteria can be found at http://ctep.cancer.gov/reporting/ctc.html. Adverse events not listed on the CTCAE are graded as follows: mild (CTCAE grade 1): transient symptoms, sign/symptom awareness that is easily tolerated and does not interfere with the subject's daily activities. Moderate (CTCAE Grade 2): Severe signs/symptoms that affect the daily activities of the subject, but are still acceptable. Severe (CTCAE Grade 3): Disabling signs/symptoms that significantly affect the subject's daily activities are unacceptable. Life-threatening (CTCAE grade 4): life-threatening or disabling adverse events. Death (CTCAE grade 5): death due to an adverse event.

[00133] "Adverse reaction (to a drug)" means all painful and unintended reactions to any dose of a drug; such reactions would be considered adverse drug reactions. "Reactions" to a drug means that a causal relationship between the drug and the adverse event is at least a reasonable possibility, i.e. a relationship cannot be ruled out.

[00134] "Unanticipated adverse drug reaction" means an adverse reaction whose nature or severity is inconsistent with applicable drug information.

[00135] "Pharmacological properties" means the absorption (absorption), distribution, metabolism and excretion of a drug.

[00136] "Adverse events of particular interest" means any new neurological symptom or clinically significant worsening of an existing neurological symptom after the start of investigational treatment; such an adverse event will be designated as an AEFI, regardless of whether it is serious or non-serious.

[00137] "Serious adverse events" means an adverse event or adverse reaction resulting in any of the following outcomes: death or life-threatening adverse event, need for hospitalization or prolongation of current hospitalization, permanent or significant disability/disability or significant impairment of the ability to conduct normal lifestyle, congenital anomaly/malformation, major medical event.

[00138] An adverse event or adverse reaction is considered "life-threatening" if, in the opinion of the investigator or sponsor, there is a risk of death of the subject if the event/reaction develops. This category does not include a phenomenon that, if it developed in a more severe form, could lead to death.

[00139] Any hospital stay of at least 1 night will be considered an admission to a hospital. A stay in the intensive care unit without an inpatient stay will not be recorded as an SAE according to the specified criteria, nor will hospitalization for an elective procedure, or for a procedure planned prior to signing informed consent. However, unanticipated complications and/or prolongation of hospital stay associated with elective surgery should be recorded as adverse events and assessed for severity. Inpatient stays due to social or situational conditions (i.e. no place to live, subject lives too far away to travel to the hospital) are not considered hospitalizations.

[00140] Significant medical events that may not result in death, are not life threatening, or do not require hospitalization may be considered a serious adverse event if, based on appropriate medical judgment, they may endanger the subject and may require medical or surgical intervention to prevent one of the above outcomes. Examples of such medical events include allergic bronchospasm requiring intensive care in the intensive care unit or at home, blood dyscrasia or seizures that do not result in hospitalization or drug dependence.

[00141] "History" means information about previous and concomitant drug therapy, previous and current diagnoses, conditions and operations that are considered significant; information about tobacco, alcohol and drug use.

[00142] "Clinical-instrumental assessment" or "Clinical-laboratory assessment" includes chemical analysis, hematological examination, coagulation assessment, and urinalysis (in combination with microscopy).

[00143] "Electrocardiogram parameters" means heart rate, RR interval, PR interval, QRS width, and QT interval.

[00144] "Basic vital signs" means heart rate, blood pressure, respiratory rate, temperature, and weight.

[00145] "Physical examination" means an assessment of the general appearance, determination of the state of the respiratory and cardiovascular system, examination of the abdomen, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid gland, as well as assessment of the state of the musculoskeletal system (including the spine and limbs). In the present study, the neurological examination was performed according to Part III of the Unified Wilson's Disease Symptom Severity Scale.

[00146] In the context of this document, the term "score" means the relative value, concentration, activity or numerical indicator obtained as a result of the study. It may be artificially set by one of skill in the art or generated using an algorithm, sometimes using samples with known analytes, optionally using samples of known concentrations or titers of known analytes. The score may be a number assigned manually by a person skilled in the art, or calculated from a formula or algorithm. The score can be a symbol, such as "-", "+" or "++". The score may be calculated by a formula or algorithm, or may be assigned based on visual inspection, measurement, or evaluation of an analysis result. When using samples of known concentrations or titers of known analytes, such samples can be analyzed diluted and undiluted, and a range of scores or a standard scoring curve can be obtained that can be used to assign or score unknown samples analyzed for similar analytes using the same analytical methods, in some embodiments of the invention.

EXAMPLES

Example 1: Bischoline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study.

Relevance

[00147] Wilson's disease is a genetic disorder in which copper accumulates in the liver, brain, and other tissues. Therapy was limited due to safety and efficacy concerns and multiple daily dosing. Bischoline tetrathiomolybdate (WTX101) is an orally administered first-in-class copper-binding molecule that targets copper within hepatocytes; WTX101 also reduces plasma concentrations of non-ceruloplasmin bound copper (NCM) by forming tripartite complexes with albumin and increasing biliary copper excretion. The efficacy and safety of WTX101 was evaluated at the start of treatment or early in the treatment of patients with Wilson's disease.

Methods

[00148] The phase 2 open-label study was conducted at 11 hospitals in the US and Europe. The study included patients aged at least 18 years who had not previously received treatment, or received treatment with chelators or zinc preparations for no more than 24 months, with Leipzig scores of 4 or more, in whom NCM concentrations were above the lower limit of the normal reference range ( ≥0.8 µmol/l). Depending on baseline NCM concentrations, patients who met the inclusion criteria received WTX101 monotherapy at an initial dose of 15-60 mg/day for the first 4-8 weeks, followed by an individualized dose depending on the response to treatment for the remainder of the time until until the 24th week. Researchers, other medical staff and patients were aware of the treatment being received. The primary endpoint was change at week 24 in tetrathiomolybdate-copper-albumin copper- _{adjusted NCM levels from baseline, with treatment success defined as reaching or maintaining a normalized NCM adjusted (} ≤2.3 µmol/L [upper limit of normal]), or achieving at least a 25% reduction in UCM _adjusted by week 24 from baseline. This study is registered with ClinicalTrials.gov, number NCT02273596.

results

[00149] The study included 28 patients who received WTX101; 22 (79%) patients completed the study before week 24. At week 24, 20 (71%, 95% CI 51.3-86.8; p < 0.0001) of 28 patients met the criteria for successful treatment: 16 (57%) patients treated with WTX101 either achieved or maintained normalized values NCM _corrected , in 4 (14%) patients there was at least a 25% decrease in the NCM _adjusted relative to baseline. The mean NCM value _adjusted by week 24 decreased by 72% from baseline (difference in mean limits was -2.4 µmol/L [SD 0.4], 95% CI: -3.2 to -1.6; p < 0.0001). Surprisingly, there were no cases of paradoxical aggravation of neurological symptoms associated with treatment. Liver function remained stable in all patients, although 11 (39%) of 28 patients treated with at least 30 mg/day of WTX101 showed reversible asymptomatic elevations in alanine or aspartate aminotransferase or γ-glutamyltransferase levels, with no increase in bilirubin levels. Seven patients (25%) reported 11 serious adverse events, including psychiatric disorders (6 events in 4 patients), gait disturbance (one event), elevated hepatic aminotransferases (two cases in two patients, 1 with agranulocytosis), and worsening of neurological functions (1 event likely related to the natural progression of the disease, although a causal relationship cannot be ruled out). For seven serious adverse events classified as psychiatric and gait disorders, a causal relationship to study drug was assessed as unlikely, although for the remaining 4 events it was assessed as possible or probable.

Interpretation

[00150] The results of the study suggest that WTX101 may be a promising new drug with a unique mechanism of action for the treatment of Wilson's disease. Given the once-daily dosing regimen and favorable safety profile, WTX101 may improve the management of patients suffering from this debilitating disease.

Introduction

[00151] Wilson's disease (WD) is an autosomal recessive disease characterized by impaired copper transport, resulting in accumulation of copper in the liver, brain, and other tissues. The disease is caused by mutations in the ATP7B gene, which codes for the copper-transporting ATPase. As a result of a decrease in ATP7B function, a decrease in copper incorporation into ceruloplasmin and a violation of copper excretion with bile are observed. Wilson's disease affects approximately one in 30,000 people, but the prevalence of the disease varies among populations and underdiagnosis can be significant. The clinical picture is very different and includes forms of liver disease, neurological and psychopathological symptoms, and the presence of a Kaiser-Fleischer ring on the cornea. Abnormal laboratory findings include elevated plasma concentrations of "free" non-ceruloplasmin-bound copper (NCM) and low circulating ceruloplasmin concentrations.

[00152] If Wilson's disease is not diagnosed and treated, it is unequivocally fatal. Oral medications approved to reduce copper decades ago include chelators (penicillamine and trientine) that increase urinary copper excretion, or zinc supplements that interfere with copper absorption (absorption) from the gastrointestinal tract.

[00153] These drugs have been studied in the course of a few prospective studies, the results indicate a significant degree of dissatisfaction with the need for efficacy, safety and ease of dosing regimens. In addition, patients with neurological manifestations starting treatment with penicillamine or trientine may experience a paradoxical early worsening of neurological disease with the rapid onset of new neurological signs or worsening of existing neurological signs, leading to severe disability. In clinical studies, the proportion of patients with neurological manifestations of Wilson's disease who developed early deterioration after initiation of chelator treatment ranged from 19% to 35%. Early aggravation of neurological symptoms may be irreversible and may be associated with the rapid mobilization of "free" copper.

[00154] Bischoline tetrathiomolybdate (WTX101) is an orally administered first-in-class copper-containing protein-binding molecule being investigated as a once-daily monotherapy for Wilson's disease. In clinical studies, the previous form of the drug, ammonium tetrathiomolybdate, quickly regulated the concentration of copper; however, it is too unstable for routine use. The bischoline moiety is a major advantage as it has improved stability and, unlike other available drugs, WTX101 appears to have direct intracellular activity in hepatocytes, in which WTX101 binds excess copper and increases biliary copper excretion. WTX101 also rapidly binds "free" copper in blood plasma to form a stable three-component complex of tetrathiomolybdate with copper and albumin.

Methods

[00155] An open-label Phase 2 study was conducted at 11 hospitals. Eligible patients were 18 years of age or older and diagnosed with Wilson's disease based on a Leipzig score of 4 or greater. At the time of enrollment in the study, patients had not previously received treatment, or received treatment with chelators or zinc preparations for no more than 24 months; NCM concentrations were above the lower limit of the normal reference range (≥0.8 µmol/L). Patients with decompensated liver cirrhosis, with an ICLR score greater than 11, or with a modified Nasser score (Revised King scale) greater than 6, were excluded from the study.

[00156] The protocol and all amendments have been approved by the organization's regional review boards and ethics committees. The study was overseen by an independent data and safety monitoring committee. All participants signed a written informed consent in accordance with the Declaration of Helsinki.

[00157] The investigators, other medical personnel, patients, and the study sponsor were aware of the treatment being received. Previously treated patients underwent a 48 hour washout period prior to initiation of WTX101 treatment. Given baseline concentrations of NCM in patients, the initial dose of WTX101 was 15-60 mg/day for the first 4-8 weeks, followed by an individualized dose depending on the response to treatment up to the 24th week. Although WTX101 was originally given twice daily, an early protocol amendment introduced WTX101 once daily (if deemed appropriate by the investigator).

[00158] In the case of a high concentration of alanine aminotransferase (ALT) in a patient receiving a dose of 120 mg/day, the regimen was adjusted with a decrease in the maximum dose from 300 mg/day to 60 mg/day.

[00159] Considering various factors, including biochemical and hematological parameters, clinical assessment, safety and NCM concentrations, and at the discretion of the principal investigator, the dose of WTX101 can be adjusted in predetermined "steps". Dose increases were stepped, each increase being limited to doubling the previous dose; dose escalation was not allowed if the concentration of NCM was within or below the normal range. The dose was temporarily reduced or stopped when two consecutive concentrations of ALT or aspartate aminotransferase (AST) were determined at least 2-5 times the normal range, with a decrease in hemoglobin concentration of 30% or more from the initial concentration, or with an increase in the score of neurological manifestations according to Part III Unified Wilson's Disease Rating Scale (UWDRS) (an accepted and validated system for quantifying neurological symptoms designed specifically for Wilson's disease) of 4 or more points.

[00160] Using total copper and ceruloplasmin plasma concentrations, the NCM score was calculated by subtracting the amount of ceruloplasmin-bound copper from the total copper concentration (determined by inductively coupled plasma mass spectrometry). The resulting NCM was then corrected by subtracting the amount of copper bound in the tetrathiomolybdate-copper-albumin complex after ingestion of WTX101, since the copper in this complex is not part of the pool of reactive toxic copper. The correction method used the average molar ratio of copper to molybdenum in a three-component complex, which was determined using the ratio between NCM and plasma molybdenum concentrations and confirmed by two independent methods. This method of adjusting the NCM index was validated by random selection of methods of analysis and validation samples.

[00161] The primary endpoint was the change at week 24 in NCM, measured as concentration of NCM adjusted for copper in tetrathiomolybdate-copper-albumin complexes (NCM _corrected ), from baseline. Treatment success was defined as achieving or maintaining a normalized UCM _adjusted (≤2.3 µmol/L [upper limit of normal]), or achieving at least a 25% reduction in UCM _adjusted by week 24 from baseline.

[00162] Secondary endpoints were safety and tolerability, change and time to normalization of NCM _{adjusted score} , clinical form of neurological disease, liver function, clinical symptoms, health-related quality of life (HRQOL), mental status and pharmacokinetics, and copper involved in metabolic processes, analysis of the mineral composition and the concentration of copper in the urine. Mental status, pharmacokinetic data, and copper concentrations were also assessed as endpoints. Neurological disease was defined as the degree of disability as assessed by the patient on the UWDRS scale (Part II), as well as neurological status assessed by a qualified specialist on the UWDRS scale (Part III). Synthetic liver function was assessed by monitoring international normalization coefficient (ICN) and albumin concentrations. In addition, changes in liver function were assessed using the modified Nasser scale (taking into account bilirubin concentration, MCI, AST concentration, albumin concentration, and leukocyte count) and in the course of a retrospective analysis using the ICLR scale (taking into account concentrations of bilirubin, creatinine, MCI, and the cause of liver disease). HRQOL was assessed using a visual analogue scale of the European Quality of Life Questionnaire - 5 directions (EQ VAS).

[00163] In the context of the relationship with the intake of the study drug (at the discretion of the investigator), the information on the adverse event (AE) contained information about the onset of the development of the AE, its duration, severity and severity.

[00164] The planned number of subjects to enroll in the study was 30 patients, with at least 15 patients expected to have received short (≤90 days) previous treatment with chelators or zinc preparations. Because the aim of the study was to provide mostly descriptive statistics, no formal power calculations were made. Changes in copper concentrations and scores were summarized over time using descriptive statistics. At-visit measures were assessed using a mixed-model analysis for repeated measures with a fixed effect; to model intersubject error, a generalized 1st order autoregressive covariance structure was used. The choice of the generalized covariance structure of the 1st order autoregression is due to the fact that it assumes a decrease in intersubject correlation with an increase in the time period between repeated measurements. SAS software (version 9.3) was used to calculate the limits of the means over time, as well as the corresponding 95% CI, SE, and two-tailed p-values.

[00165] The study included twenty-eight patients who received WTX101; 22 (79%) patients completed the study before week 24 ( FIG. 1 ). At baseline, 15 (54%) patients were female with a mean age of 34.1 years (SD 11.86) and ranged from 18-64 years. Nine (32%) patients were previously untreated for Wilson's disease. Nine (32%) patients were treated for less than 28 days, and ten (36%) patients were treated for 28 days to 2 years (mean 100 days [range 7-714]). At entry into the study, most patients had neurological signs of varying severity, most commonly dysarthria (19 [68%]), postural tremor (18 [64%]), alternating hand movement disorders (18 [64%]), and abnormal gait ( 17 [61%]), most often impaired gait in ataxia (12 [43%]). The mean UWDRS (Part III) score at baseline was 22.8 (SD 21.0; range 0-83), with only three (11%) patients having a score of 0 (no neurologic abnormalities). At the beginning of treatment, 13 (46%) patients had cirrhosis of the liver, established according to the medical history (seven patients) or diagnosed by assessing the index of the ratio of AST to platelets (six patients). Fourteen (50%) patients had 26 abnormal liver tests at study entry (12 for ALT, nine for AST, one for bilirubin, and four for MCI). Of these abnormal results, 24 exceeded the upper limit of the norm by 1-2 times, two results - by 3-5 times.

[00166] At week 24 or at the last dose for patients who completed treatment early, daily doses were 15 mg for six (21%) patients, 30 mg for 13 (46%) patients, and 60 mg (32%) for nine patients. More than 80% of the WTX101 doses in the study were taken once daily.

[00167] Treatment with WTX101 was accompanied by a rapid improvement in NCM _corrected , with mean NCM _adjusted values below the upper limit of normal by week 12 ( FIG. 2 ). At week 24, 20 (71%, 95% CI 51.3–86.8; p < 0.0001) of 28 patients were treated successfully: 16 (57%) achieved or maintained normalized NCM concentrations _adjusted and 4 (14%) found at least a 25% decrease in NCM _adjusted from baseline. Overall, up to week 24, mean NCM _adjusted was reduced by 72% from baseline (RMS difference was -2.4 µmol/L [SD 0.4], 95% CI -3.2 to -1, 6; p<0.0001; table 1, FIG. 2 ).

Table 1: Change at week 24 from baseline (primary and secondary endpoints)

Baseline 24th week Change From Baseline (SE, 95% CI)* p-value n Mean value (SD) n Average (SD)† NCM _corrected (µmol/l) 25 3.6 (2.1) 23 0.9 (1.0) -2.4
(0.4, -3.2 to -1.6) <0.0001 UWDRS score (Part II) 28 6.6 (10.0) 21 4.1 (8.2) -3.7
(0.9, -5.5 to 1.8) 0.0003 UWDRS score (part III) 28 22.8 (21.0) 21 16.6 (17.7) -8.7
(1.9, -12.5 to -5.0) <0.0001 Albumin (g/l) 28 39.2 (5.4) 23 40.9 (3.2) 2.3
(0.5, 1.26 to 3.42) <0.0001 MCS 27 1.11 (0.16) 22 1.06 (0.08) -0.05
(0.01, -0.08 to
-0.02) 0.0010 Bilirubin (mg/dl) 28 0.51 (0.29) 23 0.49 (0.27) 0.02
(0.03, -0.05 to 0.08) 0.6352 ALT (U/l) 28 42.6 (32.8) 23 36.8 (18.7) 48.4
(13.6, 21.38 to 75.48) 0.0006 AST (U/l) 28 36.6 (27.6) 23 28.2 (9.9) 3.8
(3.4, -2.89 to 10.59) 0.2590 GGT (U/l) 28 70.1 (64.0) 23 97.5 (77.7) 60.7
(19.1, 22.79 to 98.62) 0.0020 Platelets (1×10 ⁹ /l) 28 155.5 (72.5) 23 147.9 (63.2) 2.3
(3.4, -4.38 to 8.95) 0.4975 ICWP score ^‡ 27 7.7 (1.9) 21 7.2 (1.8) -0.5
(0.2, -0.86 to -0.08) 0.0180 Modified Nasser scale score 28 1.4 (1.0) 21 1.1 (0.6) -0.4
(0.2, -0.91 to 0.08) 0.0960 EQVAS 28 65.9 (23.0) 23 74.3 (16.9) 9.2
(2.9, 3.36 to 14.98) 0.0024

* Based on repeated measures mixed model analysis, all patient data collected at the start of treatment and at all follow-up visits up to and including week 24 are taken into account. †Absolute case-based means, excluding missing data or data from patients who discontinued treatment; one patient completed treatment at week 23, but at a time interval to include his measured plasma concentrations and EQVAS scores as values obtained at week 24. ‡Retrospective analysis.

The data presented in Table 1 are absolute mean values based on the observed case, not including missing data or data from patients who discontinued treatment. NCM _corrected means the concentration of non-cerruloplasmin-bound copper corrected for the copper content of tetrathiomolybdate-copper-albumin complexes. The UWDRS stands for Unified Wilson's Disease Symptom Severity Scale. MKN stands for International Normalization Factor. ALT stands for alanine aminotransferase. AST stands for aspertat aminotransferase. GGT means γ-glutamyltransferase. EQVAS stands for Visual Analogue Scale of the European Quality of Life Inventory.

[00168] The degree of disease-related disability was significantly reduced after treatment with WTX101 (Table 1, FIG. 3 ). Mean UWDRS scores (Part II) improved from 6.6 (SE 10.0) at baseline to 4.1 (8.2) at week 24 (Table 1, FIG. 3A ). UWDRS score (Part II) improved by at least 1 point in 12 (57%) patients and remained unchanged in nine (43%) patients; no patient reported worsening of the condition, except for a patient who stopped treatment at week 21 due to further worsening of the current neurological disease.

[00169] Mean UWDRS scores (Part III) improved significantly from 22.8 (21.0) at baseline to 16.6 (17.7) at week 24 (Table 1, FIG. 3B ). The UWDRS (Part III) score improved by 4 or more points in 14 (67%) patients and stabilized (within 3 points from baseline) in five (24%) patients at week 24. Two (10%) patients experienced a five-point deterioration: one patient had a score of 19 at baseline with fluctuations ranging from 16-27 over the course of the study, a second patient scored 3 at baseline and 8 at 18 and 24. th weeks; these patients had zero scores on the item "Disability". Surprisingly, no cases of paradoxical aggravation of neurological symptoms associated with the use of the study drug were reported within 12 weeks after the start of treatment.

[00170] While the improvements in MCI and albumin up to week 24 from baseline were statistically significant, they were quantitatively small, indicating stable liver function (Table 1). The state of the liver, assessed by the ICFP scale and the modified Nasser scale, was also almost unchanged throughout the study (table 1).

[00171] Clinical improvements were reflected in a significant increase in mean EQ VAS scores (Table 1).

[00172] Overall, WTX101 treatment was well tolerated and most adverse events were mild to moderate in intensity (summarized in Table 2). In the study of liver function, elevated concentrations of enzymes, primarily ALT, AST, or γ-glutamyltransferase, were recorded in 11 (39%) of 28 patients who received WTX101 at a dose of 30 mg / day or more, bilirubin concentrations did not increase. These increases in concentrations were generally observed after 4-10 weeks and were mostly mild to moderate, asymptomatic and normalized within 1-2 weeks after dose adjustment or discontinuation of treatment for up to 6 weeks. The median peak ALT concentration in these 11 patients was 197 U/L (range 101–1341), corresponding to a 7.2-fold increase from baseline. In three (11%) patients, the ALT concentration exceeded baseline values from 14.3 to 29.3 times, these patients discontinued treatment. The second highest concentration of ALT (615 U/l) was determined in one of the first included patients who received WTX101 at a dose of 120 mg/day. Subsequently, protocol changes were made to the WTX101 dosing regimen to reduce the maximum dose to 60 mg/day. The patient with the highest ALT concentration (1341 U/L) was treated with 30 mg/day WTX101 and this patient had previously had an increase in ALT concentration (peak 400 U/L) with previous treatment with penicillamine prior to enrollment in the study. In three patients with abnormal liver function tests, in whom the drug was discontinued due to an increase in ALT concentration, the changes in the indicators were reversible and were not associated with a significant increase in the concentration of bilirubin.

Table 2 Adverse events and serious adverse events reported during treatment

Number of patients (%) Patients reporting at least one adverse event that occurred after the start of treatment 17 (61%) Increase in ALT 8 (29%) Increasing GGT 8 (29%) AST increase 7 (25%) Elevation of liver enzymes 4 (14%) Increased blood alkaline phosphatase 3 (11%) Headache 2 (7%) Tremor 2 (7%) Nausea 2 (7%) Dry skin 2 (7%) Leukopenia 2 (7%) Patients reporting at least one serious adverse event that occurred after the start of treatment 7 (25%) Psychotic disorder fourteen%) Deviant behavior fourteen%) Violation of adaptation fourteen%) affective disorder fourteen%) Mania fourteen%) personality disorder fourteen%) Increase in ALT fourteen%) Elevation of liver enzymes (significant increase in ALT or AST) fourteen%) disturbed gait fourteen%) Agranulocytosis fourteen%) Deterioration of neurological functions fourteen%)

Post-treatment adverse events reported by the investigator in at least two patients and all serious adverse events occurring post-treatment are presented. The patient may have experienced more than one adverse event or serious adverse event. For seven serious adverse events classified as psychiatric and gait disturbances, a causal relationship to study drug was assessed as unlikely, although for the remaining 4 events it was assessed as possible or probable. Impairment of adjustment was reported in one patient, who later had an exacerbation of an acute situational disorder after 6 weeks (listed here as one serious adverse event). In another patient, two separate episodes of mania were reported over a 3-week period during the 24-week study (listed here as one serious adverse event). ALT stands for alanine aminotransferase. GGT means γ-glutamyltransferase. AST means aspartate aminotransferase.

[00173] Two (7%) patients had leukopenia, and one (4%) patient had a causal relationship between thrombocytopenia and study drug intake assessed as probable, possible, or certain; however, after dose adjustment in all patients, the indicators returned to normal. Several patients reported gastrointestinal or cutaneous adverse events associated with study medication (Table 2).

[00174] Eleven serious adverse events were reported in seven (25%) patients: psychiatric disorders (six events in four patients), elevated liver aminotransferases (two events in two patients, one patient associated with agranulocytosis), gait disturbance ( one event) and impaired neurological function (one event; Table 2). Serious adverse events from the central nervous system (psychiatric disorders) and disturbed gait were assessed as delayed serious adverse events or a causal relationship with the study drug and the development of these serious adverse events was assessed as unlikely due to already existing manifestations of neurological or psychiatric diseases; however, a causal relationship between the other 4 serious adverse events and study medication was assessed as possible or probable.

[00175] In a previously treated patient with pre-enrollment aggravation of neurological symptoms, there was a further deterioration in neurological function after the 12th week; the patient stopped treatment at 21 weeks; in this patient, the UWDRS (Part II) score was increased by 3 points, and the UWDRS (Part III) score was increased by 11 points from baseline. The deterioration in neurological status was assessed as likely related to the natural progression of the disease, although a causal relationship cannot be ruled out. The investigators discontinued treatment in two (7%) patients because psychiatric or behavioral symptoms made these patients unable to follow the protocol. In these patients, UWDRS scores (Part III) improved or remained unchanged.

Discussion

[00176] The results demonstrate that after approximately 3 months, WTX101 rapidly controlled copper concentrations, coupled with a significant decrease in corrected _NCM , which was accompanied by a significant early improvement in neurological symptoms and function in most patients. This study was the first multinational, prospective study in patients with Wilson's disease to evaluate treatment with the new oral drug WTX101, which has significant advantages in administration and dosing.

[00177] Previously available drugs may have been taken for several years before clinical improvement occurs in patients with Wilson's disease. With previous treatment regimens, most patients with liver disease or compensated cirrhosis of the liver could return to normal within 1–2 years, while improvement was slower in patients with neurological disease; in such patients, improvement in symptoms or resolution may not have occurred with the frequency observed in patients with impaired liver function. Without being bound by any particular theory, it is possible to suggest that the rapid improvement in biochemical and clinical parameters observed with WTX101 may be due to the novel, copper-specific and direct mechanism of action of WTX101 in hepatocytes, through which there is a decrease in the concentration of "free » toxic copper in blood plasma. The management of patients with neurological symptoms has been particularly challenging, as approximately half of patients with neurological disease still have residual signs even after several years of chelation therapy. In addition, an early paradoxical worsening of neurological symptoms can be observed in patients with neurological Wilson's disease even after the start of treatment with standard chelators, and neurological damage may be irreversible in half to a third of patients. In a study by Litwin et al., early worsening of neurological symptoms was observed in 12 (29%) of 42 patients with neurological Wilson's disease treated with penicillamine, with a median time from treatment initiation to worsening of neurological symptoms of 2.3 months. Litwin et al. Early neurological worsening in patients with Wilson's disease. J. Neurol Sci 355:162-67 (2015). Theoretically, the binding of WTX101 to copper to form an inert and large protein complex that is unable to redistribute into the CNS could explain the absence of a clear early worsening of neurological symptoms during the first 12 weeks of treatment. One possible explanation could be prior treatment with chelating agents for a long period of time, long enough that the aggravation of neurological symptoms with subsequent treatment with WTX101 did not occur; however, cases of early worsening of neurological symptoms have not been reported in previously untreated patients. One previously treated patient (less than 28 days of zinc supplementation) with pre-enrollment neurological worsening experienced further deterioration in neurological function despite dose increases associated with an inadequate clinical response to WTX101; and study treatment was discontinued at week 21. Although the deterioration in neurological function has been assessed as likely related to the natural progression of the disease, a causal relationship cannot be ruled out. In addition to the patient who discontinued treatment at week 21, two other participants discontinued WTX101 treatment due to neurological and psychopathological symptoms. Neurological, psychopathological symptoms, or a combination of neurological and psychopathological symptoms are common in patients with Wilson's disease, and these symptoms rendered these patients unable to perform examination procedures. Pre-existing psychiatric disorders also required several hospitalizations during the course of the study, which, by definition, were documented as serious adverse events. In fact, eight of the 11 reported serious adverse events in five patients were serious adverse events of a neurological or psychopathological nature.

[00178] Considering the MCI score and albumin concentration, synthetic liver function appears to have remained stable with WTX101 treatment during the 24-week study. This picture was observed in all patients, regardless of whether they had signs of cirrhosis. Of note, a reversible increase in liver function tests was observed in 39% of patients in our study, regardless of the stage of liver disease. The increase in rates was observed 4-10 weeks after the start of treatment at a dose of 30 mg / day or higher, and was mostly minor or moderate. Elevation in all of these patients was asymptomatic for liver disease. Liver function tests returned to normal within 1-2 weeks after dose adjustment or discontinuation of treatment. An increase in liver function tests in patients was not accompanied by a significant increase in the concentration of bilirubin, including patients who stopped taking the drug, indicating the absence of serious drug-induced liver damage. Similar dose-dependent early reversible increases in aminotransferase concentrations have been found in patients with Wilson's disease treated with ammonium tetrathiomolybdate; this phenomenon also responded to dose reduction or discontinuation of treatment. However, similar abnormalities in liver function tests have not been reported with the use of tetrathiomolybdate in patients without liver disease or primary biliary cirrhosis; this fact suggests that the observed effects are specific to Wilson's disease. One mechanism for the increase in liver enzymes in response to WTX101 treatment may be mediated by WTX101's ability to reduce copper concentration, which is the removal of copper from pools in the liver, including metallothionein, which leads to a subsequent transient increase in hepatic aminotransferases. However, the exact mechanism remains to be elucidated.

[00179] The use of previously available drugs for the treatment of Wilson's disease has been associated with other potentially serious adverse events, which have often been the reason for stopping treatment and changing treatment. In a retrospective study, 32% of patients treated with chelators and 11% of patients treated with zinc preparations discontinued treatment due to adverse events. An association has been demonstrated between penicillamine use and early allergic reactions such as fever and rash, as well as various skin reactions and late reactions, including lupus-like syndrome and nephrotoxicity. Adverse events from the gastrointestinal tract are often reported during treatment with zinc preparations; 40% of children in the Polish cohort treated with zinc preparations developed gastrointestinal adverse events. Wiernicka et al., Gastrointestinal side effects in children with Wilson's disease treated with zinc sulphate. World J Gastroenterol 19:4356-62 (2013). In our study, two patients reported nausea or dry skin thought to be related to the study treatment, but these events were generally mild to moderate in intensity and patients did not discontinue treatment. Six patients discontinued study treatment. These treatment discontinuations reflect the chronic, life-limiting nature of Wilson's disease in patients with symptomatic disease, with the majority of included patients showing varying degrees of severity of neurological or psychiatric manifestations, as well as an exploratory approach in which the original dosage regimen needed to be changed.

[00180] Previously available drugs for the treatment of Wilson's disease were provided in the form of several daily doses, the frequency of administration was up to four times a day, the drugs had to be taken on an empty stomach. Studies show that up to 45% of patients receiving modern treatment demonstrate low or questionable long-term adherence to treatment. Failure to comply with lifelong treatment may result in relapse of symptoms and progression of liver disease, or neurological or psychiatric symptoms, although there is individual variability over time. WTX101 can be taken orally once a day, which may improve adherence to treatment and improve patient outcomes.

[00181] While the sample size is sufficient to study an orphan drug in a phase 2 trial, this sample size is relatively small for evaluating outcomes in clinically heterogeneous disease. However, all results were consistent regardless of the scoring parameter used, confirming the overall beneficial effect of WTX101 in the study population. Patients with decompensated liver disease with elevated ICLS scores were excluded from the study. The need for a mixed population of previously untreated and treated patients is due to registration difficulties encountered in rare disease research and because patients with Wilson's disease often begin treatment shortly after diagnosis. The inclusion of this population in our study also allowed us to evaluate the effects of WTX101 in patients who had previously received chelation or zinc therapy. The study was uncontrolled and open. While internal controls are desirable, they are not always possible in the early stages of drug development for orphan diseases. However, non-biased improvements were achieved, particularly in copper control and liver function. Although the study was relatively short, extensive research is ongoing to further investigate the long-term safety and efficacy of WTX101.

[00182] In conclusion, treatment with WTX101 rapidly reduced "free" copper concentrations in patients with Wilson's disease, and control of copper concentration was accompanied by a decrease in the degree of disability, improvement in neurological status and stable liver function for 24 weeks. When dose adjusted, WTX101 showed a favorable safety profile in combination with a simple once-daily oral regimen and no effect of food on drug absorption (absorption). Thus, WTX101 is able to meet several unmet clinical needs.

Example 2: Long-term efficacy and safety of WTX101 in Wilson's disease: Evidence from an ongoing phase 2 extension study.

[00183] In Example 1, WTX101 monotherapy (oral, once daily) was accompanied by a rapid reduction and control of NCM levels, a decrease in the degree of disability, and an improvement in neurological status without early exacerbation of treatment-related neurological symptoms, in combination with stabilization of liver function in patients with BV at 24 weeks. Efficacy and safety data from the 72-week extension period of the ongoing phase 2 study is the first prospective report on the long-term control of WTX101 Wilson's disease.

[00184] Example 1 is an open-label, multicentre, non-comparative, phase 2 study in 28 adult patients diagnosed with BV based on a Leipzig score of 4 or greater. To include patients in the study, NCM concentrations had to exceed the lower limit of the normal reference range (≥0.8 µmol). Participants were naive for BV (n=9), or received chelation or zinc therapy for ≤24 months (<28 days, n=9; 8 days to 2 years, n=10). Depending on the response to treatment, participants received individualized doses of WTX101 in the range of 15-120 mg/day for 24 weeks, taking into account the concentration of NCM, clinical assessment and safety criteria.

[00185] Below are the data obtained during the first 72 weeks of the additional period for the following indicators: (a) NCM concentrations corrected for the content of bound copper in tetrathiomolybdate-copper-albumin complexes (NCM _corrected ); (b) Liver status assessed using standard laboratory tests and based on the End-Stage Liver Disease Model (EISL) score (taking into account bilirubin, creatinine concentrations, and International Normalization Factor [IMN]); (c) disability as assessed by the patient using the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS, Part II), and neurological status as assessed according to the UWDRS (Part III); and (d) safety.

[00186] At the beginning of the main study, 46% of patients had cirrhosis of the liver, established according to the medical history (n=7) or diagnosed by assessing the index of the ratio of AST to platelets (n=6). At week 24 or at the last dose in patients who completed treatment early, daily doses were 15 mg for six patients, 30 mg for 13 patients, and 60 mg for nine patients. All 22 patients who completed the main 24-week study participated in the extension period described in this Example.

[00187] Twenty patients completed treatment by week 72. One patient stopped treatment because she wanted to become pregnant. One patient was unable to perform the study procedures due to the progressive course of the disease despite ongoing treatment.

Table 3. Demographics and characteristics of participants at the beginning of the main and additional periods

Characteristics Start of the main period (week 0)
N=28 Start of extra period (24th week)
N=22 Average age (range), years 34.1 (18-64) 36.5 (18-64) Female, n (%) 15 (54) 12 (55) NCM _corrected , µmol 3.6±0.4 0.9±0.2 UWDRS score (Part II) 6.6 ± 1.9 4.1 ± 1.8 UWDRS score (part III) 22.8 ± 4.0 16.6 ± 3.9 ICWP score 7.7±0.4 7.2±0.4 ALT, U/l 42.6 ± 6.2 36.8 ± 3.9 Albumin, g/l 39.2 ± 1.0 40.9±0.7 MKN 1 .11 ± 0.0 1.06±0.0

[00188] Mean ± standard error if specified

Concentrations of "free" copper in blood plasma

[00189] Baseline Elevated Mean (MAV) of NCM _corrected (3.6 [0.4] µmol) decreased and was controlled at week 24 (0.9 [0.2] µmol) and remained controlled at week 72 week (0.5 [0.2] µmol) ( FIG. 4).

liver function

[00190] The mean values of MCI, albumin concentration, ALT concentration and ICSL score improved or remained unchanged between the 24th and 72nd weeks, indicating the stability of liver function ( FIG. 5 ).

[00191] Reversible increases in ALT concentration requiring dose adjustment, observed in 39% of patients (at a dose of 30 mg / day or more) up to the 24th week (Example 1), were not observed during an additional period.

[00192] Patients showed continuous improvement in mean UWDRS disability score and neurological sign score from weeks 24 to 72 ( FIG. 6 ).

[00193] In most cases, WTX101 was well tolerated during the 72nd week of treatment. Overall, reported adverse events (AEs) and serious adverse events (SAEs) decreased by approximately 50% from weeks 1-24 to weeks 25-72 ( FIG. 7 , Table 4). Between weeks 24 and 72, 89% of AEs were mild or moderate in intensity, 89% of adverse events were considered unrelated to treatment, or a causal relationship between adverse events and treatment was assessed as unlikely.

[00194] Low platelets (56%) and neutrophils (32%) were observed at baseline, and a similar pattern was observed throughout the follow-up period. Most cases were not accompanied by low concentrations of NCM and are unlikely to reflect copper deficiency. During the follow-up period, low hemoglobin concentration was rarely determined: 5.2% of the values were below the normal range, 7 patients had a low hemoglobin concentration at some point, but this indicator did not fall below 100 g / l. Two subjects had neutropenia associated with mild anemia and low NCM concentrations, theoretically consistent with copper deficiency at 36 and 72 weeks, respectively; both indicators quickly responded to dose reduction.

Table 4. SAEs reported during the main and extension periods

Number of patients in whom the investigator reported ≥1 SAE according to preferred terms WTX101 Causal relationship with study drug according to the investigator The period from the start of treatment to the 24th week 11 events
7 patients Psychotic disorder 1 No connection Deviant behavior 1 No connection Violation of adaptation 1 No connection affective disorder 1 No connection Mania 1 Communication is unlikely personality disorder 1 Communication is unlikely Increase in ALT 1 Possible connection Elevation of liver enzymes (significant increase in ALT/AST) 1 Probable connection disturbed gait 1 Communication is unlikely Agranulocytosis 1 Probable connection Deterioration of neurological functions 1 Possible connection
(most likely due to disease progression) After 24 weeks 6 events in 5 patients Mania (38th week) 1 Communication is unlikely Sharp pain in the lower back (37 weeks) 1 No connection BV exacerbation* (46th week) 1 Possible connection
(most likely due to disease progression) Neutropenia† (36 weeks) 1 Possible connection Vertigo‡ (113 weeks) 1 Possible connection Loss of consciousness ^‡ (113 weeks) 1 Possible connection

* In one patient with a progressive course of the disease, a neuropsychiatric exacerbation was noted, despite ongoing treatment. Although the development of SAEs is likely related to the progression of BV, a causal relationship cannot be ruled out and, in the investigator's opinion, there is a possible association between SAEs and study medication; the dose of the drug for this patient was not adjusted.

† Grade 1 neutropenia resolved after dose reduction.

‡ One patient reported severe weakness, dizziness, then lost consciousness and was hospitalized overnight (cause unknown).

[00195] Primary improvements in free copper levels, liver health, and neurological status were maintained or further improved with WTX101 treatment between weeks 24 and 72; this picture demonstrates the long-term control of BV when taking WTX101 once a day. WTX101 is well tolerated by patients with VWD after 24 weeks of treatment. These results, combined with a simple dosing regimen, indicate that WTX101 addresses several unmet needs in the treatment of VWD.

Example 3: Phase 3 Randomized, Masked, Multicentre, Efficacy and Safety Study of WTX101 Taken for 48 Weeks Compared to Standard Treatment in Wilson's Disease Patients 18 Years of Age and Older with an Additional Stage of Up to 60 Months.

Study Design Summary

[00196] A randomized, blinded, multicenter trial to investigate the efficacy and safety of an individualized WTX101 regimen for 48 weeks versus SL will be conducted in patients with VWD 18 years of age or older.

[00197] The study will include approximately 102 subjects at approximately 5-10 research centers in North America and approximately 15-25 research centers in other regions of the world.

[00198] Eligible subjects with BV who received standard of care (ST) (i.e., penicillamine or trientine chelation therapy, zinc treatment, or a combination of chelation therapy with zinc) for more than 28 days (Cohort 1), or subjects previously naive or receiving standard treatment (i.e. penicillamine or trientine chelation, zinc treatment, or combination of chelation with zinc) for up to 28 days (Cohort 2) will be randomized in a 2:1 ratio to the WTX101 or standard treatment group (either as continuation treatment in Cohort 1 or as continuation or primary treatment in Cohort 2). Randomization will be stratified by previously received standard treatment.

[00199] Subjects meeting all inclusion criteria and not meeting the exclusion criteria will be included in the study as outpatients. Previously treated subjects randomized to receive WTX101 immediately prior to initiation of WTX101 treatment will be required to undergo a washout period from received standard treatment of at least 48 hours. Subjects who meet the inclusion criteria and are randomized to receive WTX101 will receive WTX101 orally in the form of delayed release tablets at doses ranging from 15 mg every other day (QOD) to 60 mg QD. A maximum dose up to 90mg QD will only be discussed and agreed upon with the medical monitor if the following criteria are met: NCC _adjusted above upper limit of normal (ULN); alanine aminotransferase (ALT) concentration is less than 2 x ULN; hematological parameters (hemoglobin, platelets and neutrophils) exceed the thresholds requiring dose adjustment in accordance with Table 1. Efficacy and safety will be evaluated during scheduled visits; adverse events and concomitant therapy will be continuously monitored throughout the study.

[00200] The visit plan will include a screening visit, inclusion visit, study visit, and last study visit (EOS) (or early study termination [ET] visit). The visit schedule is shown below.

[00201] The screening visit will take place no later than 28 days prior to the inclusion visit (Day 1). After the Day 1 visit, assessment will be conducted by telephone at Week 1, Week 2, Week 30 and Week 42 (Day 8, Day 15, Day 211 and 295- day, respectively) followed by study visits at week 4, week 6, week 8, week 12, week 18, week 24, week 36, and week 48 week (29th day, 43rd day, 57th day, 85th day, 127th day, 169th day, 253rd day and 337th day, respectively).

[00202] Subjects who complete the 48-week treatment period will be offered the opportunity to participate in an additional phase of the study to evaluate the long-term safety and duration of the therapeutic effect of WTX101. If the subject decides not to participate in this additional step, he/she will be assisted in the transition to standard treatment for BV under the supervision of the attending physician.

[00203] The last study visit at week 52 (day 365) will be attended only by those subjects who will not participate in the extra step. For each subject who will not participate in the extension phase, the main phase of the study will end approximately 52 weeks (~365 days) after the start of treatment on day 1 (48 weeks of treatment with the last study visit 4 weeks after the date of enrollment last dose). For each subject who participates in the extension phase, the main phase of the study will end approximately 48 weeks (day 337) after the start of treatment on day 1.

Dose modification for individual study participants

[00204] The specific criteria under which it is necessary to temporarily stop taking or limit the increase in the dose of WTX101 are detailed in table 5.

Table 5. Individualized dose modification

Indicator/parameter Result Terms Cancel or change the WTX101 reception pattern Making changes to security monitoring ^a Re-administration of the drug ^{b, c} ALT >5-fold increase from baseline Initial ALT concentration exceeds the normal range Temporarily stop Contact subject within 48 hours to arrange for retesting
Weekly monitoring in dynamics Dose of 15 mg QD with more than 2-fold increase in ALT concentration from baseline >5 times ULN The initial concentration of ALT is within the normal range Temporarily stop Contact subject within 48 hours to arrange for retesting
Weekly monitoring in dynamics Dose of 15 mg QD in case of more than 2 times ALT ULN >2-fold increase from baseline Initial ALT concentration exceeds the normal range Reduce dose to previous dose in case of dose increase, or reduce dose to 15 mg QOD if patient received 15 mg QD. It is forbidden to further increase the dose until the normalization of the indicator that deviates from the norm. Weekly monitoring in dynamics Not provided >2x ULN Initial ALT concentration exceeds the normal range Reduce dose to previous dose in case of dose increase, or reduce dose to 15 mg QOD if patient received 15 mg QD. It is forbidden to further increase the dose until the normalization of the indicator that deviates from the norm. Weekly monitoring in dynamics Not provided Hemoglobin <8 g/dl in the absence of bleeding Missing Temporarily stop Weekly monitoring in dynamics Dose of 15 mg QD if Hgb and other heme parameters (neutrophils and platelets) match baseline More than 30% reduction from baseline Missing Reduce dose to previous dose in case of dose increase, or reduce dose to 15 mg QOD if patient received 15 mg QD. It is forbidden to further increase the dose until the normalization of the indicator that deviates from the norm. Weekly monitoring in dynamics Not provided platelets <30000 µl Missing Temporarily stop Weekly monitoring in dynamics Dose of 15 mg QD if Hgb and other heme parameters (neutrophils and platelets) match baseline More than 30% reduction from baseline Baseline platelet count is below the normal range Reduce dose to previous dose in case of dose increase, or reduce dose to 15 mg QOD if patient received 15 mg QD. It is forbidden to further increase the dose until the normalization of the indicator that deviates from the norm. Weekly monitoring in dynamics Not provided Neutrophils less than 1.0×10 ³ /µl Missing Temporarily stop Weekly monitoring in dynamics Dose of 15 mg QD if Hgb and other heme parameters (neutrophils and platelets) match baseline More than 30% reduction from baseline Baseline neutrophil count is below normal range Reduce dose to previous dose in case of dose increase, or reduce dose to 15 mg QOD if patient received 15 mg QD. It is forbidden to further increase the dose until the normalization of the indicator that deviates from the norm. Weekly monitoring in dynamics Not provided Bilirubin >2x ULN and more than 3x ULN ALT Missing Temporarily stop Weekly monitoring in dynamics Dose of 15 mg QD if bilirubin concentration is below ULN Neurological examination with UWDRS score (Part III) An increase in score of ≥4 points from baseline of ≥20 points.
A score increase of ≥6 points from baseline of ≥20 points,
OR clinically significant signs of exacerbation of neurological symptoms 2 or more time points, OR a clear pattern of neurological deterioration Temporarily stop Weekly assessment according to the UWDRS scale in dynamics A dose that is 50% of the previous dose, subject to stabilization of the score on the UWDRS scale; defined as the absence of an increase in score during two consecutive examinations, and after discussion with a medical monitor. a. In the event of changes in safety monitoring, weekly monitoring of laboratory parameters in dynamics can be completed by the family nurse, if a routine study visit is not scheduled during the specified period.
b. No more than 3 repeat prescriptions will be allowed
c. Patients who received a dose of 15 mg QOD will receive a dose of 15 mg QOD in case of re-administration of the drug.
ALT=alania aminotransferase; Heme=hematological; Hgb=hemoglobin; QD=once a day; QOD=every second day; ULN=upper limit of normal; UWDRS=Uniform Wilson's Disease Symptom Severity Rating Scale

[00205] Dose change criteria apply when there are two consecutive results (i.e., obtained during two consecutive visits) of predetermined indicators of toxicity or deterioration of certain laboratory parameters or UWDRS scores (Part III). Weekly monitoring in dynamics will be carried out until the results are obtained, corresponding to the baseline or within the normal range. Then the study will be repeated after 2 weeks. If the results are consistent with baseline or within the normal range, the schedule for taking the drug according to the protocol will be resumed.

Study duration

[00206] For each subject, the main phase of the study will end approximately 52 weeks (~365 days) after the start of treatment on study day 1 (48 weeks of treatment with the last study visit 4 weeks after the last dose date if the subject does not will take part in the extra period). Subjects who complete the 48-week treatment period will be offered the opportunity to participate in an additional phase of the study to assess the long-term safety and duration of treatment effect of WTX101. If the subject decides not to participate in the extra step, he/she will be assisted in the transition to the standard treatment for BV under the supervision of the attending physician.

[00207] Unscheduled visits are possible if, at the discretion of the investigator, there is a need for additional clinical evaluation, or if the subject's performance meets the criteria for dose changes. In addition, if there is a clear worsening of neurological symptoms, as evidenced by relevant signs or symptoms, additional neurological examinations will be performed at the discretion of the investigator.

[00208] All subjects who complete the 48-week randomized treatment period in the WTX101-301 study will be offered the opportunity to participate in an open extension phase of up to 60 months during which they will receive WTX101 treatment. The purpose of the additional step is to evaluate the duration of effect, as well as the long-term safety and efficacy of WTX101. Subjects will be eligible to participate in the additional phase until WTX101 becomes commercially available in their countries.

Treatment groups

[00209] Subjects will receive WTX101 at doses ranging from 15 mg QOD to 60 mg QD or receive standard treatment. Subjects will be randomized into 1 of 2 cohorts: Cohort 1 - subjects who received chelation therapy or treatment with zinc preparations for more than 28 days, or a combination of chelation therapy with zinc preparations, or Cohort 2 - subjects who previously received no treatment or previously received chelation therapy. therapy or treatment with zinc preparations, or a combination of chelation therapy with zinc preparations for no more than 28 days.

Dose rationale

[00210] If necessary, dose adjustment of WTX101 will be performed in individual subjects according to protocol instructions. Detailed instructions for use when changing the dose of WTX101 are given in Table 5.

[00211] In all subjects, the initial dose of WTX101 is 15 mg QD. After 4 weeks, subsequent WTX101 intake will be individualized. Instructions for use take into account many factors, including biochemical and hematological parameters, clinical assessment, safety and NCM _adjusted value.

[00212] Dose escalation is at the discretion of the Principal Investigator in "steps" of 15 mg at least 4 weeks apart if the disease is not adequately controlled, taking into account the clinical condition of the subject and the concentration of "free" copper in the blood, measured as NCM /NCM _adjusted , and if none of the dose change criteria apply. After increasing the dose for the subject every 2 weeks for a 4-week period, adverse events and laboratory results will be monitored. If a routine study visit is not scheduled during the specified period, monitoring of these indicators can be completed by the family nurse.

[00213] If the concentration of NCM _adjusted has decreased to within the normal range (<2.3 µmol/L) and the subject's clinical condition is stable or improving on the results of 2 consecutive examinations, the dose of WTX101 may be maintained or reduced at the discretion of the principal investigator. To avoid overdose, the dose may be reduced at any time at the discretion of the Principal Investigator, based on the following criteria: if the subject's clinical condition indicates a possible overdose and/or NCM/NCM values _adjusted below the normal range. However, the use of the NCM _adjusted score as a criterion for dose adjustment is optional, reflecting differing treatment practices in the study centers participating in the global study. The dose should be reduced or treatment should be discontinued if any of the criteria for dose change apply.

Taking an investigational drug

[00214] WTX101 will be provided in the form of oral tablets containing 15 mg of bischoline tetrathiomolybdate. WTX101 will be given in doses ranging from 15mg QOD to 60mg QD. The intake of a maximum dose of up to 90 mg QD must be discussed and agreed with a medical monitor, and only if the indicators meet the following criteria: NCM _adjusted over ULN; less than 2-fold excess of ALT VGN; hematological parameters (hemoglobin, platelets and neutrophils) exceed the threshold values requiring a dose change in accordance with table 1.

[00215] WTX101 will be taken for a 48 week QD or QOD (taken in the morning) treatment period on an empty stomach (1 hour before or 2 hours after a meal). The reception of the WTX101 is described in more detail below.

[00216] Individualized intake of WTX101 will be implemented throughout the study, taking into account the following indicators: clinical criteria: dose selection taking into account the state of the liver and neurological status; NCM _Adjusted : Dose adjustment based on NCM concentrations adjusted for the amount of Cu bound to WTX101 in the ternary complex and safety monitoring results: Dose modification criteria take into account the results of planned studies evaluating the generally recognized hematological effects observed with a decrease in copper concentration, liver test results and neurological examination.

[00217] The dose of WTX101 can also be reduced in the event of an adverse event requiring dose reduction. Instructions for use to guide the development of certain events are presented in the Dose Modification Criteria (Table 5); dose reduction in the event of other events will be carried out by the principal investigator of the research center (or co-investigator, if necessary) on an individual basis in cooperation with the medical monitor.

[00218] All subjects on study day 1 will receive an initial dose of WTX101 of 15 mg QD and remain unchanged for 4 weeks; after 4 weeks, dose escalation to 30 mg QD is at the discretion of the principal investigator if the disease is not adequately controlled, taking into account the clinical condition of the subject and the concentration of “free” copper in the blood, measured as NCM / NCM _corrected , and if none of the criteria for change is applicable doses. Taking into account the above criteria, a further increase in the dose is possible at the discretion of the principal investigator in “steps” of 15 mg with an interval of at least 4 weeks.

[00219] If the concentration of NCM _adjusted has fallen within the normal range (<2.3 µmol/L) and the subject's clinical condition is stable or improving on the results of 2 consecutive examinations, the dose of WTX101 may be maintained or reduced at the discretion of the principal investigator. To avoid overdose, the dose may be reduced at any time at the discretion of the Principal Investigator, based on the following criteria: if the subject's clinical condition indicates a possible overdose and/or NCM/NCM values _adjusted below the normal range. However, the use of the NCM _adjusted score as a criterion for dose adjustment is optional, reflecting differing treatment practices in the study centers participating in the global study. The dose should be reduced or treatment should be discontinued if any of the criteria for dose change apply.

[00220] The expected maximum dose is 60 mg QD, but higher doses may be considered on an individual basis in cooperation with a medical monitor. The intake of a maximum dose of up to 90 mg QD must be discussed and agreed with the medical monitor, and only if the indicators meet the following criteria: NCM _adjusted over ULN; less than 2-fold excess of ALT VGN; hematological parameters (hemoglobin, platelets and neutrophils) exceed the threshold values requiring a dose change in accordance with table 5.

[00221] In order to ensure measurement accuracy, the following data is taken into account. Estrogens are able to disrupt the excretion of Cu with bile. Vitamin E has been used as adjuvant therapy in BV treatment regimens. Subjects should not take vitamins and/or mineral complexes containing Cu, Zn, or Mo. Contrast agents containing gadolinium and iodine are known to interfere with Mo test results. Contrast agents containing gadolinium and iodine are not recommended for use within 96 hours prior to Mo tests. Barium-containing contrast agents are known to interfere with Cu test results. Barium contrast agents are not recommended for use within 96 hours prior to performing Cu tests. Subjects should avoid high Cu foods and drinks throughout the study period.

[00222] After randomization and washout (if necessary), subjects come for visits and procedures: visits 1 to 30 weeks and visit 42 weeks will occur within ± 3 days of the scheduled visit date; week 36 and week 48 visits will occur within ± 7 days of the scheduled visit date.

Efficiency mark

[00223] The primary evaluation of efficacy is to control the concentration of "free" Cu, defined as the percentage change in the concentration of NCM by week 48 from baseline (day 1). In subjects treated with WTX101, NCM concentrations will be adjusted for the amount of Cu bound by WTX101 in the ternary complex (TCC).

[00224] The secondary evaluation of effectiveness includes an assessment of: the state of the liver according to the ICSL scale; the degree of disability on the UWDRS scale (part II); neurological status according to the UWDRS scale (part III); clinical condition on the Overall Clinical Impression Scale (points 1 and 2 of the scale); and also includes the response rate of the NCM score to treatment.

[00225] The tertiary efficacy evaluation includes: an individual assessment of each of the three symptoms that cause the greatest discomfort to the subject; assessment of the degree of liver fibrosis using the FIB-4 index and transient elastography; assessment of the state of the liver according to the modified Naser scale; assessment of psychopathological symptoms on the BPRS-24 scale; and assessment at the endpoint of patients' quality of life according to the data they provided when filling out the EQ-5D and TSQM-9 questionnaires.

Search indicators in evaluating effectiveness include:

[00226] Assessing Cu control using exploratory measurements of total Cu, "free" Cu, PUF-Cu, and plasma Cu; plasma Mo concentrations; 24-hour urinary excretion of Cu and Mo; evaluating the results of measuring the walking time for 25 feet; evaluating the results of the 9-HPT test; evaluating the results of the non-verbal Stroop interference test; and evaluating the results of the digital series test.

Statistics

[00227] All statistical analyzes will be performed in accordance with generally recognized techniques in the art. A general description of the statistical methods that will be used to analyze efficacy and safety data is provided below. Statistical analyzes will be performed using ^SAS® software, version 9.3 or later, SAS Institute, Cary, NC, USA.

[00228] The primary endpoint is control of “free” Cu concentration, defined as the percentage change in NCM concentration by week 48 from baseline; in subjects treated with WTX101, NCM concentrations will be adjusted for the amount of Cu bound by WTX101 in the ternary complex (TCC).

[00229] The percentage change in NCM concentration from baseline will be estimated using repeated measures mixed model (MMRM) analysis stratified by cohort and prior SL. Changes from baseline at week 4, week 8, week 12, week 24, week 36 and week 48 will be taken into account. The evaluation will be carried out using the maximum likelihood method. The model will be stratified by cohort and prior SL. For better normalization of the data, it is possible to carry out a logarithmic transformation of the NCM indicator before analysis. A fixed effects model will be used for randomized treatment (WTX101 or SL) to assess the relationship between therapeutic effect of randomized treatment and visit, with baseline NCM concentration used as a covariate. The relationship between the visit and the therapeutic effect will remain in the model regardless of the significance. An unstructured covariance matrix will be used to model the intersubject error, and the Kenward-Roger approximation will be used to estimate the degrees of freedom. If the unstructured covariance matrix does not converge, the following covariance structures will be used in order until convergence is achieved: Toeplitz with Heterogeneity, Autoregression with Heterogeneity, Toeplitz and Autoregression. Of primary interest is the difference at week 48 between subjects receiving WTX101 and subjects receiving SL. The following model data will be provided: difference between randomized treatments as mean percent change in NCM concentration at week 48, two-sided 95% confidence interval (CI), and p-value. If the lower limit of the two-tailed 95% CI rules out a difference of -15%, it will be concluded that WTX101 is not superior to SL in the general patient population; if the lower limit of the two-tailed 95% CI rules out a difference of 0%, it will be concluded that WTX101 is superior to SL in the general patient population. Separately, as graphs, changes in the limits of the means (TS) from baseline and the corresponding standard errors (SE) for earlier time points (i.e., 4th week, 8th week, 12th week, 24- I week and 36th week) over time in the treatment group.

[00230] An additional analysis of the primary endpoint in cohort 1 will be similar to the analysis of the general population, except that the analysis will not be stratified by cohort.

[00231] A descriptive analysis of the percentage change in NCM concentration from baseline will be performed using MMRM; no formal statistical comparison will be made between randomized treatment groups. Percentage change at week 4, week 8, week 12, week 24, week 36 and week 48 from baseline will be analyzed using the model parameters used to analyze data from subjects in cohort 1 . Of primary interest are intergroup differences within the mean (PS), SE, and p-values for the percentage change in NCM concentration at week 48 from baseline. Separately, in the form of graphs, the between-group differences in changes in the limits of the mean (TS) from baseline and the corresponding standard errors (SE) for earlier time points (i.e., 4th week, 8th week, 12th week, 24th week and 36th week) in dynamics.

[00232] Secondary efficacy endpoints: Change in liver status at week 48 from baseline, as measured by ICFP score; change in UWDRS score (part II) by week 48 from baseline; change in UWDRS score (part III) by week 48 from baseline; change in scores on the CGI-I and CGI-S scales by week 48 relative to baseline, and the response rate of the NCM indicator to NCM treatment at week 48.

[00233] Secondary endpoints will be analyzed similarly to the primary endpoint, MMRM analysis stratified by cohort will be used, of primary interest will be the difference at week 48 between subjects receiving SL and subjects receiving WTX101. An additional comparative analysis of data from subjects of cohort 1 and an additional descriptive intergroup analysis of data from subjects of cohort 2 will be carried out. The total scores for endpoints b, c and d will be analyzed.

[00234] NCM score response to treatment is defined as the proportion of subjects who achieve or maintain normalized NCM or NCM _corrected concentrations (0.8-2.3 µmol) or achieve at week 48 at least a 25% reduction in NCM or NCM _adjusted . In subjects treated with WTX101, NCM concentrations will be adjusted for the amount of Cu bound by WTX101 in the TCC.

[00235] Subjects for which no data is available at week 48 will be considered as non-reactive. These data will be analyzed by cohort-stratified logistic regression, taking into account randomized treatment and baseline NCM concentration. In this case, an additional comparative analysis of the data of the subjects of the 1st cohort and an additional descriptive intergroup analysis of the data of the subjects of the 2nd cohort were also carried out.

Example 4: Absorption (absorption) of bischoline tetrathiomolybdate after taking a single dose of an enteric-coated formulation after meals and on an empty stomach and in an uncoated formulation taken on an empty stomach in combination with a proton pump inhibitor.

[00236] An open-label, single-center, randomized, three-period, six-sequence, three-component, cross-over study was conducted to assess the PK (pharmacokinetics) of single doses of bischoline tetrathiomolybdate in healthy subjects based on the measurement of total plasma Mo concentration. Eighteen (18) healthy non-smoking male and female adult subjects received treatment A, B, or C for three periods according to the study design shown in FIGURES 8A and 8B . Subjects received each treatment once. Subjects were randomized to receive treatment according to one of the following six sequences: ABC, ACB, BAC, BCA, CAB, and CBA. All study drugs were taken orally with approximately 240 ml of water. Subjects were informed that the study drug should not be crushed, divided, or chewed.

Treatment A: 60 mg of bis-choline tetrathiomolybdate (2 bis-choline tetrathiomolybdate enteric-coated (KO) tablets, 30 mg) at hour 0 on day 1 after an overnight fasting period.

Treatment B: 60 mg of bis-choline tetrathiomolybdate (2 tablets of bis-choline tetrathiomolybdate (KO), 30 mg, see Table 6) at hour 0 on day 1 30 minutes after starting a high-fat breakfast with the preceding overnight fasting.

Treatment C: omeprazole 20 mg (1 PPI (proton pump inhibitor) delayed-release capsule), 20 mg, QD in the morning on days -5 to -1 after an overnight fasting period, omeprazole 20 mg (delayed-release capsule) at -1 hour on day 1 after an overnight fasting period and 60 mg of bis-choline tetrathiomolybdate (2 capsules of bis-choline tetrathiomolybdate uncoated (BO), 30 mg. see Table 7) at hour 0 at 1 th day.

Table 6

Ingredient quality standard Function Composition (per dosage per tablet) 10 mg 30 mg WTX101 intracompany Active substance 10 mg 30 mg Tribasic calcium phosphate NF Diluent 81 mg 79.2 mg Sodium carbonate anhydrous NF buffer agent 5.0 mg 6.0 mg sodium starch glycolate NF Baking powder 2.0 mg 2.4 mg Magnesium stearate NF Lubricant 2.0 mg 2.4 mg Complete system for transparent film coating OPADRY ^® / OPADRY ^® 03K19229 intracompany "Preshell" 6.0 mg 7.2 mg Acryl-FROM White/Acryl-EZE White intracompany Enteric coating 7.7 mg 8.9 mg

Table 7

Ingredient quality standard Function Composition (per capsule) WTX101 intracompany Active substance 30 mg Calcium phosphate dibasic anhydrous USP Diluent 475 mg Sodium carbonate anhydrous NF buffer agent 25 mg Hydroxypropyl methylcellulose capsules (size 1) intracompany Capsule 1 capsule

[00237] All 18 subjects included in and completed the study were included in the safety and PK analysis. However, data from one subject were excluded from the PK analysis by descriptive statistics and treatment B statistical analysis due to a measurable total plasma Mo concentration of more than 40% of the corresponding C _max (maximum measured plasma concentration) prior to receiving the drug. Thus, the PK analysis population included 18 patients who received the KO tablet (Treatment A) and BO+PPI on an empty stomach (Treatment C), and 17 patients who received the KO tablet (Treatment B) after a meal.

Pharmacokinetic data

[00238] The following pharmacokinetic indicators of the total concentration of Mo in blood plasma were calculated:

AUC0-t: area under the concentration-time curve from time 0 to the time the last measurable concentration was determined, calculated using the linear trapezoidal method.

AUC0-inf: area under the concentration-time curve from 0 to infinity. AUC0-inf is calculated as the sum of AUC0-t and the ratio of the last measurable plasma concentration to the elimination rate constant.

Cmax: maximum measured plasma concentration in the specified time period.

tmax: time to reach maximum plasma concentration. If the maximum value was determined at more than one time point, tmax was determined as the first time point with that value.

λz: First order constant of the apparent rate of terminal elimination calculated from the concentration-time curve in semi-logarithmic coordinates. The parameter was calculated using a least squares linear regression analysis using the maximum number of points in the terminal logarithmic phase (for example, 3 or more non-zero plasma concentrations), starting from the last non-zero concentration.

t½: first order apparent half-life calculated as 0.693/λz.

Tlag suction delay time (absorption)

CL/F: apparent clearance after oral administration of the drug

Vz/F: apparent volume of distribution after oral administration of the drug

[00239] As shown in FIGURES 8A and 8B , the mean ± standard error of total plasma Mo concentrations were slightly lower after fasting KO tablet (Treatment A) compared with fasting uncoated capsules (BO) + PPIs (Treatment A). C). However, there was variability among subjects: 3 out of 18 found much lower concentrations when taking the KO tablet, 5 showed a similar pattern of mean values, and 10 found more comparable or similar concentrations when receiving both treatments.

[00240] The lower arithmetic mean (Table 8) and geometric mean (Table 7) values of C _max , AUC _0-t and AUC _inf of KO tablets taken on an empty stomach (Treatment A) are consistent with the mean plasma concentrations compared to unshelled capsule (BO) + PPI taken on an empty stomach (treatment C). The ratio of geometric mean values ranged from 75.81% to 87.16%, with the lower limits of the respective 90% CIs being less than 80.00% (Table 9), indicating a decrease in exposure on average. The median T _max was comparable for both treatments, 4.54 and 4.50 hours, respectively, with comparable ranges (Table 8).

[00241] Four (4) out of 18 subjects had an absorption delay (absorption) time after taking the KO tablet on an empty stomach, the median (range) was 2.00 hours (2.00 to 3.00 hours) (Table 8).

[00242] Taking the KO tablet after a meal (treatment B) was characterized by a significant decrease in mean plasma Mo concentrations (Figure 5). This phenomenon was also observed in all but 2 of the 17 subjects whose data were taken into account in the analysis of this treatment. C _max , AUC _0-t and AUC _inf were lower after taking the KO tablet after a meal (tables 4 and 5), the ratio of the geometric mean values was in the range from 25.20% to 40.49%, indicating a significant decrease in absorption (absorption). The median T _max was comparable for drug administration after a meal and on an empty stomach, 4.55 and 4.54 hours, respectively, with comparable ranges (Table 8). Compared to fasting KO tablet (Treatment A), more subjects (6 subjects) found an absorption delay time and a median increase (range) of up to 3.00 hours (range 2.00 to 5.00 hours) ( table 8).

[00243] The mean t½ was virtually the same for all 3 treatments (Table 8) with an overall mean of ~48 hours or 2 days. CL/F and Vz/F values were also comparable for the 2 treatments when taken on an empty stomach, however, due to the lower bioavailability observed after taking the KO tablet after a meal, these values were higher for this treatment.

[00244] The lowest intersubject coefficients of variability (MCV) for C _max , AUC _0-t and AUC _inf were observed with fasted BO+PPI capsules (treatment C), values ranging from 15.8% to 19.1% ( table 8). Fasting KO tablet (Treatment A) is characterized by an increase in MCV (from 26.1% to 35.2%; Table 8). MCVs were much higher, especially AUC _0-t and AUC _inf, 81.5% and 72.6%, respectively, (Table 8) when taking the KO tablet after a high-calorie/high-fat meal. Compared with fasting KO tablets, MCV AUC values were approximately 2.2-fold higher when KO tablets were taken after a meal.

[00245] As shown in FIGURES 8A and 8B , there was a slight decrease in the mean ± standard error parameter of plasma Mo concentration after fasting KO tablet (Treatment A) compared to fasting BO+PPI (Treatment C). Similar trends were observed for C _max , AUC _(0-t) and AUC _(inf) (tables 6 and 7). However, analysis of individual subject data indicates that while some subjects showed a similar pattern, most subjects showed an overall Mo-time profile comparable to that of bis-choline tetrathiomolybdate tablets with KO and bis-choline tetrathiomolybdate dosage form. BO + PPI on an empty stomach. However, taking bischoline tetrathiomolybdate tablets with KO (treatment B) after a meal is characterized by a decrease in absorption (absorption) of 60-75%, which was systemic in most subjects.

Table 8. Summary table of PK values derived from measurements of total Mo after single dose (60 mg, 2 x 30 mg) WTX101 tablets with fasted KO (Treatment A) and after meals (Treatment B) and BO+PPI on an empty stomach (treatment C)

Index* Treatment KO tablet, taken on an empty stomach KO tablet after meals BO + PPI, fasting _Tlag (h) 2.00 (4)
[2.00-3.00] 3.00 (6)
[2.00-5.00] -† _Cmax (ng/ml) 376 ± 98.0 (18) 187 ± 118 (17) 442 ± 69.6 (18) T _max (h) 4.54 (18)
[3.00-9.53] 4.55 (17)
[3.52-9.51] 4.50 (18)
[2.99-10.0] AUC _(0-t) (h×ng/ml) 16.026 ± 5.635 (18) 5.740 ± 4.681 (17) 19.809 ± 3.509 (18) AUC _(inf) (h×ng/ml) 17.258 ± 5.955 (18) 6.973 ± 5.065 (15) 21.047 ± 4.022 (17) λz (1/h) 0.0140 ± 0.0023 (18) 0.0258 ± 0.0303 (15) 0.0145 ± 0.0014 (17) t½ (h) 51.0 ± 8.87 (18) 43.5 ± 20.9 (15) 48.2 ± 4.86 (17) CL/F (l/h) 0.92 ± 0.51 (18) 6.34 ± 11.9 (15) 0.66 ± 0.13 (17) Vz/F (l) 66.6 ± 34.0 (18) 175 ± 98.1 (15) 45.2 ± 8.31 (17)

*Arithmetic mean ± standard deviation (N) excluding T _max for which median (N) is given [range]

† The rate cannot be estimated for subjects who received this treatment.

Table 9. Statistical analysis of PK values derived from total Mo concentration after single dose (60 mg, 2 x 30 mg) WTX101 tablets with fasted KO (Treatment A) and after meals (Treatment B) and BO+PPI on an empty stomach (treatment C)

Index Limit of geometric mean values Ratio of geometric mean values (%)* Intersubject CV (%) Analysis Reference value Calculated value 90% confidence interval KO tablet, fasting versus BO+PPI, fasting Cmax 360.88 436.61 82.65 63.91 → 106.90 47.98 AUC(0-t) 14,790.84 19,511.14 75.81 52.23 → 110.02 73.76 AUC(inf) 15,997.76 18,353.45 87.16 64.59 → 117.63 55.30 KO tablet, taken after meals vs. KO tablets, taken on an empty stomach Cmax 146.11 360.88 40.49 31.12 → 52.68 47.98 AUC(0-t) 3,726.71 14,790.84 25.20 17.21 → 36.89 73.76 AUC(inf) 5,071.14 15,997.76 31.70 23.12 → 43.47 55.30

*Based on the results of the analysis of natural logarithms of indicators

Table 10. Summary table of intersubject coefficients of variability of indicators C _max .AUC _{0- t} , and AUC _inf derived from measurements of total Mo concentration after a single dose (60 mg, 2 x 30 mg) of WTX101 tablets with fasted KO (Treatment A) and after meals (Treatment B) and fasted BO+PPI (Treatment C)

Index* Treatment KO tablet, taken on an empty stomach KO tablet, taken at mealtimes BO + PPI, fasting Cmax(ng/ml) 26.1 39.9 15.8 AUC(0-t) (h×ng/ml) 35.2 81.5 17.7 AUC(inf) (h×ng/ml) 34.5 72.6 19.1

*Intersubject Coefficient of Variation (%).

Example 5: Improvement in neurological status of patients with Wilson's disease treated with WTX101 in an open-label, multicenter Phase 2 study

[00246] Data from the Phase 2 study described in Example 1 was further analyzed to assess specific neurological changes after 24 weeks of treatment with WTX101.

Methods

[00247] Adult patients with BV (previously untreated or treated with chelation therapy or zinc supplementation for up to 2 years) received an individualized dose of WTX101 (15-120 mg once daily) for 24 days depending on response to treatment. -x weeks. Changes in neurological status were assessed using the Unified Wilson's Disease Symptom Severity Scale (UWDRS).

results

[00248] Of the 28 patients included in the study, 25 patients had neurological manifestations. Baseline mean UWDRS (Part II, disability) and UWDRS (Part III, neurological status) scores were 6.6 (SD 10.0; range 0-35) and 22.8 (SD 21.0; range 0-83), respectively. By week 24, both the mean [SD] score on the UWDRS (Part II) (4.1 [8.2]; p < 0.001) and the mean UWDRS (Part III) score (16.6 [ 17.7], p<0.0001). Between the total scores obtained for parts II and III in dynamics, there was a significant prognostic relationship (p<0.0001). At the beginning of treatment, the most common disorders according to the UWDRS scale (part III) were postural hand tremor (71%), dysarthria (68%), gait disorders (61%), according to the item "Mobility and coordination of limbs": alternating hand movements (71% ), tapping fingers (57%), changes in handwriting (54%) and leg movement (54%). The most significant changes were noted for the items "Handwriting" and "Dysarthria" (mean score [SD] 2.0 [0.8] and 1.8 [0.9], respectively). At 24 weeks, the most significant improvements in mean score (% change) were observed for handwriting (51.4%), leg mobility (40.8%), postural hand tremor (39.5%), and alternating hand movements (35.0% ). Grouping items for general tremor or mobility and limb coordination showed similar improvements (34.2% and 29.2%, respectively). Overall, WTX101 was well tolerated and no drug-related early worsening of neurological symptoms was observed.

findings

[00249] In this cohort of patients with BV, neurological manifestations were common. In a prospective 24-week phase 2 study in patients with VWD, treatment with WTX101 resulted in a rapid reduction in disability and improvement in neurological status. Improvement in neurological status after treatment with WTX101 correlated with a reduction in patient-reported disability.

Example 6: Improvement in neurological status of patients with Wilson's disease treated with WTX101 in an open-label, multicenter Phase 2 study

[00250] The data from the phase 2 study described in Example 1 was further analyzed to assess the features of neurological manifestations in patients with Wilson's disease (WD) and specific neurological changes after 24 weeks of treatment with WTX101. The analysis of the obtained data was generally carried out as described in Example 5.

[00251] Despite the fact that neurological manifestations can very quickly lead to disability, previously available drugs did not always relieve symptoms, in some cases they caused the development of a known paradoxical early worsening of neurological disease and / or were poorly tolerated by patients. Bischoline tetrathiomolybdate (WTX101) in a 24-week phase 2 study (NCT02273596; EudraCT 2014-001703-41) demonstrated rapid control of non-ceruloplasmin bound copper (NCM) concentrations and a favorable safety profile, mean NCM concentrations fell below the upper limit of normal by week 12.

[00252] Analysis of neurological manifestations according to the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS) showed a reduction in symptom severity without paradoxical early worsening. Changes in neurological manifestations in the study were studied in detail using data obtained from the assessment according to the UWDRS scale (part III, neurological status). In addition, the present Example examined the quantitative relationship between reported patients (Part II) and assessed by specialists (Part III) for the neurological manifestations of Wilson's disease.

Methods

[00253] Adult patients (over 18 years of age) diagnosed with Wilson's disease (Leipzig score of 4 or more) were included in the study if they had not previously received treatment for Wilson's disease, or received treatment with chelators or zinc preparations within no more than 24 months; if NCM concentrations in patients were above the lower limit of the normal reference range (i.e., not less than 0.8 µmol / l). From the study, there were patients with decompensated cirrhosis of the liver, with an ICSL score of more than 11, or with a modified Nasser score (Revised King scale) of more than 6.

[00254] A 24-week phase 2 open label study was conducted in the US and Europe. During the first 4-8 weeks, patients received WTX101 at a dose of 15-60 mg/day, depending on the initial concentrations of NCM, adjusted for the concentration of molybdenum in plasma (excluding baseline concentrations). Subsequently, the dose was adjusted based on laboratory results (in particular, NCM concentrations adjusted for plasma molybdenum concentrations) and clinical assessments (the maximum daily dose taken was 120 mg).

[00255] The degree of disability and neurological status were assessed according to parts II and III, respectively, of the UWDRS at the beginning of treatment and at 4, 8, 12, 18, and 24 weeks. Disability (Part II): 10-item questionnaire completed by patients (range of total scores: 0-40; higher scores indicate more severe disability). Neurological Status (Part III): The 23-item portion of the UWDRS is performed by the clinician (range of total scores: 0-143; higher scores indicate more severe neurological status). Data (total scores for Parts II and III of the UWDRS and AEs) are briefly summarized in the context of the Outcomes section.

[00256] The relationship between total disability scores and neurological status was studied in order to better understand and quantify the effect of treatment on neurological manifestations in order to develop optimal treatment regimens while minimizing AEs. Baseline UWDRS neurological status scores at week 24 and change from baseline to week 24 were calculated for: any single neurological manifestation, according to UWDRS items, present in at least 50% of patients; and for groups of items (that is, a number of individual items that can be considered as representing specific patient phenotypes [ Table 11 ]).

Table 11. The structure of groups of items of neurological manifestations according to the UWDRS scale

Item group Individual neurological status items included in the group (item number according to the UWDRS scale) Total score range ^b General tremor Resting tremor (15); head tremor (16); hands - postural tremor (21A) and bird flapping tremor (21B); postural tremor - legs (24); jaw tremor (31) 0-45 General gait Getting up from a chair (27); body position - torsion dystonia (28A ^a ), postural ataxia (28B), and parkinsonism (28C); gait - leg dystonia (29A ^a ), ataxia (29B), and parkinsonism (29C) 0-32 Dystonia Oromandibular dystonia (13A); cervical dystonia (25); dystonia of the arm and hand (26); torsion dystonia (28A ^a ); gait - dystonia of the legs (29A ^a ) 0-28 Mobility and coordination of limbs Finger tapping (18); quick alternating hand movements (19); handwriting (20); finger-nose test (22); leg mobility (23) 0-36 Rigidity Neurological manifestations of the arms, legs and neck (17) 0-20

^a An individual subclause is not unique to one group; ^b the scores of the individual items are summed to obtain the total score of the group of items

[00257] Limits of means (standard error [SE], 95% confidence intervals [CI]) were calculated for changes in UWDRS total scores from baseline using mixed model analysis for repeated measures; significance was assessed using two-tailed p-values. To study and quantify the relationship between total scores on the UWDRS scale (Parts II and III), random coefficients were analyzed using each patient's scores obtained at all visits in the study. Summary statistics of other outcomes were calculated.

results

[00258] A total of 28 patients received WTX101 ( Table 12 ). Six patients discontinued treatment. Three patients developed AEs of a non-neurological nature, two patients had mental disorders and these patients could not follow the protocol, one patient had an aggravation of neurological symptoms due to the progression of the disease.

Table 12 Baseline characteristics of patients

Patients (N=28) Women, n (%) 15 (54) Age, years, mean (SD) [range] 34.1 (11.86) [18-64] UWDRS Total Scores, Mean (SD) Part II (disability) 6.6 (10.0) Part III (neurological status) 22.8 (21.0) Neurological disordersa, n (%) 25 (89) Previously received treatment for Wilson's disease, n (%) The patient did not receive treatment 9 (32) Less than 28 days 9 (32) From 28 days to 2 years 10 (36)

^a Patients whose baseline UWDRS (Part III) score was ≥ 1.

Degree of disability and neurological status according to the UWDRS scale: total scores

[00259] Mean overall scores (SD) improved at week 24: 4.1 (8.2) for disability and 16.6 (17.7) for neurological status. Improvements were significant in both cases (change in cut-off mean [SE, 95% CI] from baseline): -3.7 (0.9; -5.5 to -1.8; p=0.0003) for disability and -8.7 (1.9; -12.5 to -5.0; p<0.0001) for neurological status. There was a significant positive linear relationship between UWDRS (Part II) and UWDRS (Part III) total scores (p<0.0001).

Neurological status according to the UWDRS scale: individual items and groups of items

Baseline

[00260] Individual Items: Of the six neurological manifestations on the UWDRS scale present in at least 50% of patients, the most common were postural hand tremor, rapid alternating hand movements, and dysarthria (speech) ( FIG. 9 ). Given differences in maximum possible scores between items (ie, 4 or 8), handwriting and speech impairments were the most significant ( FIGURES 10A and 10B ).

[00261] Item Groups: Tremor was reported in the largest proportion of patients (23 patients, 82%), followed by gait disturbances (17.61%), dystonia (15.54%), limb mobility and coordination disorders (15 , 54%) and rigidity (12, 43%). Considering differences in maximum possible scores between item groups ( Table 11 ), stiffness was most pronounced (mean [SD]: 3.5 [2.9]), followed by tremor (7.4 [7.0] ), dystonia (3.9 [4.4]), gait disturbances (4.4 [4.1]), mobility disorders and limb coordination (1.3 [0.5]).

Changes at week 24 from baseline

[00262] Selected points: The results of descriptive statistics show that the largest mean percentage improvement was observed for handwriting and leg mobility ( FIGURES 11A and 11B ), with only a few patients experiencing any deterioration in scores ( FIG. 12 ). Two patients had a 2-point deterioration (finger tapping); other deterioration amounted to 1 point.

[00263] Item Groups: Improvements in tremor scores (mean [SD], 34.2% [61.7]) and limb mobility and coordination (29.2% [72.2]) were broadly similar to those for individual items . Of the 22 patients included in the analysis, four and three, respectively, had any deterioration in scores (deterioration of 1 point in five cases, 3 points in one case [tremor] and 4 points in one case [motility]. and limb coordination]). Worsening of total stiffness (26.9% [169.6]), dystonia (15.0% [135.2]) and gait (4.2% [77.8]) scores were noted in four, three and six subjects. , respectively (deterioration of 1-8 points for rigidity, 2-4 points for dystonia, and 1-6 points for general gait).

findings

[00264] A phase 2 study demonstrated that treatment with WTX101 can meet important unmet needs in Wilson's disease. Improvement in neurological status after treatment with WTX101 correlated with a reduction in patient-reported disability. When taking WTX101, there was a decrease in the degree of disability and an improvement in neurological status; WTX101 was well tolerated.

Example 7 Analysis of data from patients with cirrhosis and patients without cirrhosis

[00265] Mortality in Wilson's disease is usually due to decompensated liver cirrhosis and liver failure; thus, liver function is an important factor in determining appropriate treatment regimens. The outcomes of patients with cirrhosis and patients without cirrhosis in the patient pool of Example 1 were analyzed, supplemented by data obtained during the 48 weeks of the 3-year additional period of the main study. Example 1 is an open uncontrolled study with a treatment duration of 24 weeks with WTX101; the initial dose of WTX101 was 15-60 mg/day, followed by an individualized dose depending on the response to treatment (the maximum dose was 120 mg/day). An additional step is a 3-year, open-label, uncontrolled study in which patients will continue to receive an individualized dose of WTX101 once a day, depending on the response to treatment.

[00266] In the analysis presented in this Example, patients were characterized as having cirrhosis of the liver according to the medical history (biopsy or imaging) or according to the results of the AST to platelet ratio index (APRI index) (AST means aspartate aminotransferase). Summary statistics of baseline demographic data, NCM correct concentrations, ALT concentrations, scores on the ICFP scale and on the modified Nasser scale, albumin concentration, international normalization coefficient ( _MKN ), degree of disability and neurological status according to the Unified Wilson's disease symptom severity scale, and undesirable phenomena (AE). Of the 15 patients with cirrhosis, 13 completed the main study, and all of these patients are participating in the extension study. Of the 13 patients without cirrhosis, nine completed the main study, and all of these patients are participating in the extension study. The scheme of distribution of patients in the expanded study is presented in FIG. 12 .

[ ₀₀₂₆₇ ] The baseline NCM correct for patients with cirrhosis was 3.6 µmol/L; the indicator of NCM _{is correct for} patients without cirrhosis - 3.7 µmol/l. _WTX101 was associated with a similar decrease in NCM correct concentrations at week 24 from baseline in patients with cirrhosis and in patients without cirrhosis; the improvements observed at week 24 were maintained until week 48. The NCM _correct concentrations are shown in FIG. 13.

[00268] During the main study, an increase in ALT concentrations requiring dose adjustment was observed in five patients with cirrhosis and in seven patients without cirrhosis. The increase in ALT concentrations led to the exclusion of three patients without cirrhosis from the study. The increase in ALT concentrations during the main study was not accompanied by an increase in bilirubin concentrations. From weeks 24 to 48, there was no increase in ALT concentrations requiring dose adjustment, and ALT concentrations were stable regardless of the presence of cirrhosis. ALT concentrations in patients with cirrhosis and in patients without cirrhosis are shown in FIG. 14 . Baseline scores on the ICLS scale (severity of liver disease; score range 6-40) ( FIG. 15 ) and modified Nasser scale (prognostic index; score range 0-20) ( FIG. 16 ) were low and remained stable during the main study and up to the 48th week.

[00269] Mean values of albumin concentration ( FIG. 17A ) and international normalization coefficient (IMN) ( FIG. 17B ) of patients with cirrhosis and patients without cirrhosis were stable during the main study and until the 48th week. Baseline mean albumin concentration ( FIG. 17A ) and clotting time ( FIG. 18 ) were within normal ranges. These parameters remained stable during the main study and up to week 48 in patients with cirrhosis and in patients without cirrhosis. The UWDRS scale was used to assess the degree of disability reported by patients and the neurological status assessed by the physician. Improvements were observed during the main study and up to week 48 in all patients, regardless of the presence of cirrhosis ( FIGURES 19A and 19B ). The tolerability profile of WTX101 was favorable and similar in patients with cirrhosis and in patients without cirrhosis. During the main study, adverse events (AEs) occurred in 10 patients with cirrhosis and 12 patients without cirrhosis. The most common AEs were elevated ALT and GGT (each of these AEs occurred in three patients with cirrhosis and five patients without cirrhosis), elevated AST concentrations (in four patients in each group) and tremor (in four patients without cirrhosis) . During the extension period, AEs developed in fewer patients compared with the main study period (nine patients with cirrhosis and six patients without cirrhosis). The most common AE was urinary tract infection (four patients with cirrhosis). Serious adverse events (SAEs) occurred in four patients with cirrhosis and six patients without cirrhosis within 0-48 weeks. During an additional period, two patients with cirrhosis experienced SAEs possibly related to WTX101. One patient developed neutropenia, one patient had hepatolenticular degeneration.

[00270] In the present analysis, improvement in copper concentration control with WTX101 treatment relative to baseline was maintained from week 24 to week 48 of WTX101 treatment in both patient groups. With WTX101 treatment, liver function was stable up to 48 weeks in patients with cirrhosis and in patients without cirrhosis. The tolerability profile of WTX101 was favorable and did not depend on the presence of cirrhosis. Thus, WTX101 treatment continues to be effective and well tolerated, whether or not WTX101-treated patients had cirrhosis prior to treatment.

[00271] A person skilled in the art will understand that the specific threshold values disclosed in this application may vary somewhat depending on the specific conditions of the research and the methods of analysis used. In addition, one skilled in the art will appreciate that thresholds characterized as "greater than/greater than" or "less than" in some embodiments of the invention may mean "amounts to or exceeds/above" or "amounts to or less", respectively. . Likewise, one of skill in the art will appreciate that thresholds characterized as "is or exceeds/greater" or "is or is less" in some embodiments of the present invention may mean "greater than/greater" or "less than", respectively.

[00272] The above detailed description of the invention is given for clarity of understanding only and is not intended to be limiting as modifications will be apparent to those skilled in the art.

[00273] Although the present invention has been described in conjunction with specific embodiments, it should be understood that further modifications thereof are possible, and this application is intended to cover any variations, uses, or adaptations of the invention consistent with the general principles of the disclosure, including such departures from the present disclosure, which are within known or customary practice in the technical field to which the invention pertains, and which may apply to the essential features set forth above in this application and in accordance with the scope of the appended claims.

[00274] All references, articles, publications, patents, patent publications, and patent applications cited in this application are incorporated by reference in their entirety for all purposes. However, the mention of any reference, article, publication, patent, patent publication and patent application cited in this application is not and should not be construed as an endorsement or any form of suggestion that they are part of the prior art, which includes knowledge in any country of the world.

Claims (212)

1. A method of treating Wilson's disease in a patient in need thereof, comprising taking 15 mg of bischoline tetrathiomolybdate once a day, while taking bischoline tetrathiomolybdate on an empty stomach. 2. A method for treating Wilson's disease in a patient in need thereof, comprising taking 15 mg of bischoline tetrathiomolybdate once every other day, while taking bischoline tetrathiomolybdate on an empty stomach. 3. A method for treating Wilson's disease in a patient in need thereof, comprising taking 15 mg of bis-choline tetrathiomolybdate once every second day, while taking bis-choline tetrathiomolybdate on an empty stomach. 4. The method according to any one of paragraphs. 1-3, characterized in that 15 mg of tetrathiomolybdate bischoline is taken in a delayed release dosage form. 5. The method according to p. 4, characterized in that the dosage form is a tablet or capsule. 6. The method according to p. 5, characterized in that the dosage form is a tablet. 7. The method according to any one of paragraphs. 1-6, characterized in that the patient has a decrease in the NCM _corrected , measured after 24 weeks of admission, in comparison with the patient's NCM _adjusted , measured before admission. 8. The method of claim. 7, characterized in that the patient has a decrease in the NCM _corrected by at least 20% when measured after 24 weeks of admission in comparison with the patient's NCM _corrected , measured before admission. 9. The method of claim. 7, characterized in that the patient has a decrease in the NCM _corrected by at least 35% when measured after 24 weeks of admission in comparison with the patient's NCM _corrected , measured before admission. 10. The method of claim. 7, characterized in that the patient has a decrease in the NCM _corrected by at least 50% when measured after 24 weeks of admission in comparison with the patient's NCM _corrected , measured before admission. 11. The method of claim. 7, characterized in that the patient has a decrease in the NCM _corrected by at least 75% when measured after 24 weeks of admission in comparison with the patient's NCM _corrected , measured before admission. 12. The method according to any one of paragraphs. 1-6, characterized in that the patient has a decrease in the NCM _corrected , measured after 48 weeks of admission, in comparison with the patient's NCM _adjusted , measured before admission. 13. The method of claim. 12, wherein the patient has a decrease in the NCM _corrected by at least 20% when measured after 48 weeks of admission compared to the patient's NCM _adjusted before admission. 14. The method of claim. 12, wherein the patient has a decrease in the NCM _corrected by at least 35% when measured after 48 weeks of admission compared to the patient's NCM _adjusted before admission. 15. The method according to claim 12, wherein the patient has a decrease in the NCM _corrected by at least 50% when measured after 48 weeks of admission compared to the patient's NCM _adjusted before admission. 16. The method of claim. 12, wherein the patient has a decrease in the NCM _corrected by at least 75% when measured after 48 weeks of admission compared to the patient's NCM _adjusted before admission. 17. A method of treating Wilson's disease in a patient in need thereof, comprising daily intake of 30 to 90 mg of bis-choline tetrathiomolybdate, where bis-choline tetrathiomolybdate is taken on an empty stomach and one or more of the following is determined in the patient: a) the NCM _corrected value is greater than 2.3 µmol/L; b) concentration of alanine aminotransferase (ALT) - less than 80 IU/ml; c) hemoglobin concentration exceeds 8 g/dl; d) the number of platelets exceeds 30,000/µl; and e) the number of neutrophils exceeds 10 ³ /µl. 18. The method according to p. 17, characterized in that it includes daily intake of 30 mg of bis-choline tetrathiomolybdate. 19. The method according to claim 17, characterized in that it includes daily intake of 45 mg of bis-choline tetrathiomolybdate. 20. The method according to claim 17, characterized in that it includes daily intake of 60 mg of bis-choline tetrathiomolybdate. 21. The method according to claim 17, characterized in that it includes daily intake of 75 mg of bis-choline tetrathiomolybdate. 22. The method according to claim 17, characterized in that it includes daily intake of 90 mg of bis-choline tetrathiomolybdate. 23. A method for modifying a bischoline tetrathiomolybdate dosing schedule for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, wherein said patient has a measured alanine aminotransferase (ALT) concentration of at least two times the ALT concentration measured in the patient at the start of treatment bis-choline tetrathiomolybdate, including reduction in the dose of bis-choline tetrathiomolybdate, while: for a patient receiving a dose of 15 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate every second day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; or for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day. 24. A method for modifying a bischoline tetrathiomolybdate dosing regimen for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, wherein said patient has a measured alanine aminotransferase (ALT) concentration of at least two times the upper limit of normal (ULN), comprising reduction in the dose of bis-choline tetrathiomolybdate, while: for a patient receiving a dose of 15 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate every second day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; or for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day. 25. The method according to p. 24, characterized in that the ULN is 30-45 IU / ml. 26. The method according to p. 24, characterized in that the ULN is 34 IU / ml. 27. The method according to p. 24, characterized in that the ULN is 40 IU / ml. 28. A method for modifying a bischoline tetrathiomolybdate dosing regimen for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, wherein said patient has a measured hemoglobin concentration of 70% or less of the hemoglobin concentration measured in the patient at the start of bischoline tetrathiomolybdate treatment , including reduction in the dose of bis-choline tetrathiomolybdate, while: for a patient receiving a dose of 15 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate every second day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; or for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day. 29. A method for modifying a bischoline tetrathiomolybdate dosing regimen for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, said patient having a platelet count of 70% or less of the platelet count determined in the patient at the start of bischoline treatment tetrathiomolybdate, including reduction in the dose of bis-choline tetrathiomolybdate, while: for a patient receiving a dose of 15 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate every second day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; or for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day. 30. A method for modifying a bischoline tetrathiomolybdate dosing regimen for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, said patient having a neutrophil count of 70% or less of the neutrophil count determined in the patient at the start of bischoline treatment tetrathiomolybdate, including reduction in the dose of bis-choline tetrathiomolybdate, while: for a patient receiving a dose of 15 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate every other day; for a patient receiving a dose of 30 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 45 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 60 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; for a patient receiving a dose of 75 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; or for a patient receiving a dose of 90 mg of bischoline tetrathiomolybdate once a day, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once a day. 31. A method for modifying a bischoline tetrathiomolybdate dosing schedule for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, wherein said patient has a measured alanine aminotransferase (ALT) concentration that is more than five times the ALT concentration measured in the patient at the start of bischoline treatment. -choline tetrathiomolybdate, including: a) withdrawal of bis-choline tetrathiomolybdate; b) reception 15 mg of bischoline tetrathiomolybdate every second day in a patient who received a dose of 15 mg of bischoline tetrathiomolybdate every second day before discontinuation of bischoline tetrathiomolybdate, or 15 mg/day of bischoline tetrathiomolybdate in a patient who received a dose of 15-90 mg once a day before discontinuation of bischoline tetrathiomolybdate, as soon as in said patient the measured ALT concentration is half the concentration measured in the patient at the start of treatment with bischoline with tetrathiomolybdate. 32. A method for modifying the bischoline tetrathiomolybdate regimen for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, wherein the measured alanine aminotransferase (ALT) concentration in said patient exceeds 200 IU/mL, comprising: a) withdrawal of bis-choline tetrathiomolybdate; b) reception 15 mg of bischoline tetrathiomolybdate every second day in a patient who received a dose of 15 mg of bischoline tetrathiomolybdate every second day before discontinuation of bischoline tetrathiomolybdate, or 15 mg/day of bischoline tetrathiomolybdate in a patient who received a dose of 15-90 mg once a day before discontinuation of bischoline tetrathiomolybdate, as soon as the specified patient's measured ALT concentration is half the concentration measured in the patient at the beginning of treatment with bischoline tetrathiomolybdate. 33. A method for modifying a bischoline tetrathiomolybdate dosing regimen for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, wherein said patient has a measured hemoglobin concentration of less than 8 g/dl in the absence of bleeding, comprising: a) withdrawal of bis-choline tetrathiomolybdate; b) reception 15 mg of bischoline tetrathiomolybdate every second day in a patient who received a dose of 15 mg of bischoline tetrathiomolybdate every second day before discontinuation of bischoline tetrathiomolybdate, or 15 mg/day of bischoline tetrathiomolybdate in a patient who received a dose of 15-90 mg once a day before discontinuation of bischoline tetrathiomolybdate, once said patient has a measured hemoglobin concentration equivalent to the hemoglobin concentration measured in the patient at the start of bischoline tetrathiomolybdate treatment. 34. A method for modifying a bischoline tetrathiomolybdate dosing regimen for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, wherein said patient has a platelet count of less than 30,000/µl, comprising: a) withdrawal of bis-choline tetrathiomolybdate; b) reception 15 mg of bischoline tetrathiomolybdate every second day in a patient who received a dose of 15 mg of bischoline tetrathiomolybdate every second day before discontinuation of bischoline tetrathiomolybdate, or 15 mg/day of bischoline tetrathiomolybdate in a patient who received a dose of 15-90 mg once a day before discontinuation of bischoline tetrathiomolybdate, as soon as the specified patient's platelet count is equivalent to the platelet count determined in the patient at the beginning of treatment with bischoline tetrathiomolybdate. 35. A method for changing the regimen for taking bis-choline tetrathiomolybdate for a patient with Wilson's disease receiving treatment with bis-choline tetrathiomolybdate, wherein said patient has a neutrophil count of less than 1.0×10 ³ /μl, including: a) withdrawal of bis-choline tetrathiomolybdate; b) reception 15 mg of bischoline tetrathiomolybdate every second day in a patient who received a dose of 15 mg of bischoline tetrathiomolybdate every second day before discontinuation of bischoline tetrathiomolybdate, or 15 mg/day of bischoline tetrathiomolybdate in a patient who received a dose of 15-90 mg once a day before discontinuation of bischoline tetrathiomolybdate, as soon as the specified patient has a neutrophil count equivalent to the neutrophil count determined in the patient at the start of treatment with bischoline with tetrathiomolybdate. 36. A method for modifying a bischoline tetrathiomolybdate dosing regimen for a patient with Wilson's disease receiving bischoline tetrathiomolybdate treatment, wherein said patient has a measured bilirubin concentration greater than 2.4 mg/dl and an alanine aminotransferase (ALT) concentration greater than 120 IU/ml, including: a) withdrawal of bis-choline tetrathiomolybdate; b) reception 15 mg of bischoline tetrathiomolybdate every second day in a patient who received a dose of 15 mg of bischoline tetrathiomolybdate every second day before discontinuation of bischoline tetrathiomolybdate, or 15 mg/day of bischoline tetrathiomolybdate in a patient who received a dose of 15-90 mg once a day before discontinuation of bischoline tetrathiomolybdate, as soon as the indicated patient has a measured bilirubin concentration below the upper limit of normal. 37. A method of taking bischoline tetrathiomolybdate for the treatment of a patient with Wilson's disease, wherein said patient has impaired liver function, as determined by an abnormal test result, including: (a) taking by the patient the first dose, the value of which is from 15 to 90 mg of bis-choline tetrathiomolybdate per day during the first period of time, and the subsequent (b) receiving during the second period of time a second dose, the value of which is at least 15 mg of bis-choline tetrathiomolybdate per day less than the value of the first dose of bis-choline tetrathiomolybdate. 38. The method according to claim 37, characterized in that the value of the first dose is 15 mg of bis-choline tetrathiomolybdate per day, and the value of the second dose is less than 15 mg of bis-choline tetrathiomolybdate for two days. 39. The method according to claim 37, characterized in that the value of the first dose is 30 mg of bis-choline tetrathiomolybdate per day, and the value of the second dose is less than 15 mg of bis-choline tetrathiomolybdate per day. 40. The method according to claim 37, characterized in that the value of the first dose is 45 mg of bis-choline tetrathiomolybdate per day, and the value of the second dose is less than 30 mg of bis-choline tetrathiomolybdate per day. 41. The method according to claim 37, characterized in that the value of the first dose is 60 mg of bis-choline tetrathiomolybdate per day, and the value of the second dose is less than 45 mg of bis-choline tetrathiomolybdate per day. 42. The method according to claim 37, characterized in that the value of the first dose is 75 mg of bis-choline tetrathiomolybdate per day, and the value of the second dose is less than 60 mg of bis-choline tetrathiomolybdate per day. 43. The method according to claim 37, characterized in that the value of the first dose is 90 mg of bis-choline tetrathiomolybdate per day, and the value of the second dose is less than 75 mg of bis-choline tetrathiomolybdate per day. 44. The method according to any one of paragraphs. 37-43, characterized in that the abnormal test result includes an alanine aminotransferase (ALT) concentration at least two times the initial ALT concentration measured before taking bis-choline tetrathiomolybdate. 45. The method according to any one of paragraphs. 37-43, characterized in that the abnormal test result includes a hemoglobin concentration that is 70% or less of the initial hemoglobin concentration measured before taking bis-choline tetrathiomolybdate. 46. The method according to any one of paragraphs. 37-43, characterized in that the abnormal result of the study includes a platelet count that is 70% or less of the initial platelet count determined before taking bis-choline tetrathiomolybdate. 47. The method according to any one of paragraphs. 37-43, characterized in that the abnormal test result includes a neutrophil count that is 70% or less of the initial neutrophil count determined before taking bischoline tetrathiomolybdate. 48. The method according to any one of paragraphs. 37-43, characterized in that the abnormal test result includes an alanine aminotransferase (ALT) concentration greater than 68 IU/ml. 49. The method according to any one of paragraphs. 37-43, characterized in that the abnormal test result includes a hemoglobin concentration that is 70% or less of the normal hemoglobin concentration. 50. The method according to any one of paragraphs. 37-43, characterized in that the abnormal test result includes a platelet count that is 70% or less of the normal platelet count. 51. The method according to any one of paragraphs. 37-43, characterized in that the abnormal test result includes a neutrophil count that is 70% or less of the normal neutrophil count. 52. The method according to p. 37, characterized in that the abnormal result of the study includes an alanine aminotransferase (ALT) concentration at least five times the initial ALT concentration measured before taking bischoline tetrathiomolybdate, while additionally includes (c) discontinuation of treatment for a third period of time between step (a) and step (b) until the patient's alanine aminotransferase (ALT) concentration is determined to be two times lower than the initial ALT concentration measured before taking bischoline tetrathiomolybdate. 53. The method according to p. 37, characterized in that the abnormal result of the study includes an alanine aminotransferase (ALT) concentration of at least 200 IU / ml, while additionally includes (c) discontinuing treatment for a third time period between step (a) and step (b) until the patient has an alanine aminotransferase (ALT) concentration of less than 68 IU/mL. 54. The method according to p. 37, characterized in that the abnormal result of the study includes a hemoglobin concentration of less than 8 g / dl in the absence of bleeding, while additionally includes (c) discontinuing treatment for a third time period between step (a) and step (b) until the patient's hemoglobin concentration is determined to be equal to the baseline hemoglobin concentration measured prior to taking bischoline tetrathiomolybdate. 55. The method according to p. 37, characterized in that the abnormal result of the study includes a platelet count of less than 30,000 / μl, while additionally includes (c) discontinuing treatment for a third period of time between step (a) and step (b) until the patient's platelet count is determined to be equal to the baseline platelet count determined prior to taking bischoline tetrathiomolybdate. 56. The method according to p. 37, characterized in that the abnormal result of the study includes the number of neutrophils, which is less than 1.0 × 10 ³ / μl, while additionally includes (c) discontinuing treatment for a third time period between step (a) and step (b) until the patient's neutrophil count is determined to be equal to the baseline neutrophil count determined prior to taking bischoline tetrathiomolybdate. 57. The method according to any one of paragraphs. 52-56, characterized in that the second dose is 15 mg per day. 58. The method according to any one of paragraphs. 52-56, characterized in that the second dose is 15 mg every second day. 59. The method according to any one of paragraphs. 7-58, characterized in that it additionally includes an assessment of the patient at least one of the following indicators: a) NCM concentration _corrected ; b) concentration of alanine aminotransferase (ALT); c) hemoglobin concentration; d) the number of platelets; and e) the number of neutrophils. 60. A method for modifying the regimen for taking bischoline tetrathiomolybdate for a patient with Wilson's disease receiving treatment with bischoline tetrathiomolybdate, wherein said patient has worsening neurological symptoms, characterized in that the patient's baseline UWDRS score (part III) is less than 20 before taking bischoline tetrathiomolybdate, and characterized in that said worsening of neurological symptoms includes an increase in the UWDRS (Part III) score of at least 4 points relative to the specified baseline UWDRS (Part III) score, including: a) withdrawal of bis-choline tetrathiomolybdate; b) reception by the specified patient in the absence of aggravation of neurological symptoms: 15 mg of bischoline tetrathiomolybdate every second day if the patient took a dose of 15 mg of bischoline tetrathiomolybdate once a day; 15 mg of bischoline tetrathiomolybdate once daily if the patient was taking a dose of 30 mg of bischoline tetrathiomolybdate once daily; 15 or 30 mg of bischoline tetrathiomolybdate once a day if the patient received a dose of 45 mg of bischoline tetrathiomolybdate once a day; 30 mg of bischoline tetrathiomolybdate once daily if the patient was taking a dose of 60 mg of bischoline tetrathiomolybdate once daily; 30-45 mg of bischoline tetrathiomolybdate once a day if the patient took a dose of 75 mg of bischoline tetrathiomolybdate once a day; 45 mg of bischoline tetrathiomolybdate once daily if the patient was taking a dose of 90 mg of bischoline tetrathiomolybdate once daily. 61. The method according to claim 5, characterized in that the tablet is an enteric-coated tablet. 62. The method according to any one of paragraphs. 1-61, characterized in that the patient has cirrhosis. 63. The method according to any one of paragraphs. 1-61, characterized in that the patient does not have cirrhosis. 64. The method according to any one of paragraphs. 1-63, characterized in that the patient has one or more of the phenotypes of Wilson's disease, selected from the general tremor; general gait; dystonia; mobility and coordination of limbs; and rigidity; preferably, characterized in that the patient has a general tremor phenotype or limb mobility and coordination phenotype, or both. 65. The method according to p. 64, characterized in that the patient has a phenotype of general tremor or mobility and limb coordination, or both phenotypes. 66. The method according to claim 64 or 65, characterized in that: a) the phenotype of general tremor includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: resting tremor; head tremor; postural tremor and tremor of the "wing flap" type (hands); postural tremor (legs); and jaw tremor; b) the phenotype of the general gait includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: rising from a chair; body position - torsion dystonia, postural ataxia and parkinsonism; gait - dystonia of the legs, ataxia and parkinsonism; c) the dystonia phenotype includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: oromandibular dystonia; cervical dystonia; dystonia of the arm and hand; torsion dystonia; and gait - dystonia of the legs; d) the mobility and coordination phenotype of the limbs includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: finger tapping; quick alternating hand movements; handwriting finger-nose test and leg mobility; e) the rigidity phenotype includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from the neurological manifestations of the arms, legs, and neck. 67. The method according to p. 66, characterized in that: a) the total tremor phenotype score on the UWDRS scale (part III) is 30-45; b) the overall gait phenotype score on the UWDRS scale (part III) is 20-32; c) dystonia phenotype score on the UWDRS scale (part III) is 15-28; d) phenotype score of limb mobility and coordination on the UWDRS scale (part III) is 20-36; e) the rigidity phenotype score on the UWDRS scale (part III) is 10-20. 68. The method according to any one of paragraphs. 1-67, characterized in that the patient's neurological manifestation of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS) is selected from handwriting, leg mobility, and a combination thereof. 69. The method according to p. 68, characterized in that the patient's handwriting score on the UWDRS scale (part III) is 2-4; leg mobility score on the UWDRS (Part III) scale is 2-8 or handwriting and leg mobility score on the UWDRS scale (Part III) is 4-12. 70. The method according to any one of paragraphs. 1-67, characterized in that the patient has a decrease in one or more of the neurological manifestations of Wilson's disease on the UWDRS scale (part III) after taking the composition. 71. The method according to p. 70, characterized in that the patient has a decrease in the score of one or more of the neurological manifestations on the UWDRS scale (part III) by: a) 5-25 points for the general tremor phenotype; b) 5-20 points for the general gait phenotype; c) 5-15 points for dystonia phenotype; d) 5-20 points for the phenotype of mobility and limb coordination; and e) 5-15 points for the rigidity phenotype. 72. The method according to p. 70, characterized in that the patient has a decrease in the score of one or more of the neurological manifestations on the UWDRS scale (part III): handwriting score by 1-3 points; leg mobility score by 1-6 points and handwriting and leg mobility score by 2-9 points. 73. Use of a composition containing bischoline tetrathiomolybdate in a method for treating Wilson's disease in a patient wherein bischoline tetrathiomolybdate is taken on an empty stomach. 74. Use according to claim 73, wherein the method includes taking 15-120 mg of bis-choline tetrathiomolybdate per day or every other day. 75. Application according to any one of paragraphs. 73 or 74, wherein the method comprises taking bis-choline tetrathiomolybdate once a day or once every second day. 76. Application according to any one of paragraphs. 73-75, wherein the patient has one or more of the Wilson's disease phenotypes selected from general tremor; general gait; dystonia; mobility and coordination of limbs; and rigidity; preferably, where the patient has a general tremor or limb mobility and coordination phenotype, or both. 77. Application according to paragraph 76, where: a) the phenotype of general tremor includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: resting tremor; head tremor; postural tremor and tremor of the "wing flap" type (hands); postural tremor (legs); and jaw tremor; b) the phenotype of the general gait includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: rising from a chair; body position - torsion dystonia, postural ataxia and parkinsonism; gait - dystonia of the legs, ataxia and parkinsonism; c) the dystonia phenotype includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: oromandibular dystonia; cervical dystonia; dystonia of the arm and hand; torsion dystonia; and gait - dystonia of the legs; d) the mobility and coordination phenotype of the limbs includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from: finger tapping; quick alternating hand movements; handwriting finger-nose test and leg mobility; e) the rigidity phenotype includes one or more of the neurological manifestations of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS), selected from the neurological manifestations of the arms, legs, and neck. 78. Application according to paragraph 77, where: a) the total tremor phenotype score on the UWDRS scale (part III) is 30-45; b) the overall gait phenotype score on the UWDRS scale (part III) is 20-32; c) dystonia phenotype score on the UWDRS scale (part III) is 15-28; d) phenotype score of limb mobility and coordination on the UWDRS scale (part III) is 20-36; e) the rigidity phenotype score on the UWDRS scale (part III) is 10-20. 79. Application according to any one of paragraphs. 73-78, where the patient has a neurological manifestation of Wilson's disease according to Part III of the Unified Wilson's Disease Symptom Severity Rating Scale (UWDRS) selected from handwriting, leg mobility, and a combination thereof. 80. Use according to claim 79, where the patient's handwriting score on the UWDRS scale (part III) is 2-4; leg mobility score on the UWDRS (Part III) scale is 2-8 or handwriting and leg mobility score on the UWDRS scale (Part III) is 4-12. 81. Application according to any one of paragraphs. 77-80, where the patient has a decrease in one or more of the neurological manifestations of Wilson's disease on the UWDRS scale (Part III) after taking the composition. 82. Use according to claim 81, where the patient has a decrease in the score of one or more of the neurological manifestations on the UWDRS scale (part III) by: a) 5-25 points for the general tremor phenotype; b) 5-20 points for the general gait phenotype; c) 5-15 points for dystonia phenotype; d) 5-20 points for the phenotype of mobility and limb coordination; and e) 5-15 points for the rigidity phenotype. 83. Use according to claim 81, where the patient has a decrease in the score of one or more of the neurological manifestations on the UWDRS scale (part III): handwriting score by 1-3 points; leg mobility score by 1-6 points and handwriting and leg mobility score by 2-9 points. 84. Application according to any one of paragraphs. 73-83, characterized in that the patient has cirrhosis. 85. Use according to claim 84, wherein the patient has a decrease in the NCM _adjusted value measured after 24 weeks of administration, in comparison with the patient's NCM _adjusted value measured before admission. 86. The use according to claim 84, wherein the patient has a decrease in the NCM _adjusted value measured after 48 weeks of administration, in comparison with the patient's NCM _adjusted value measured before admission. 87. Use according to claim 84, where the patient has one or more of the following indicators: a) the NCM _corrected value is greater than 2.3 µmol/l; b) concentration of alanine aminotransferase (ALT) - less than 80 IU/ml; c) hemoglobin concentration exceeds 8 g/dl; d) the number of platelets exceeds 30,000/µl; and e) the number of neutrophils exceeds 10 ³ /µl.

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