Bis-choline tetrathiomolybdate for treating wilson disease

Abstract

To provide methods for treating Wilson Disease that are efficacious in improving Cu metabolism, reducing toxic free Cu, and maintaining normal Cu levels to improve patients' symptoms, without side-effects.SOLUTION: Methods for treatment may include administering 15 mg or between 30 and 90 mg of bis-choline tetrathiomolybdate once daily to a patient exhibiting NCC corrected, alanine aminotransferase (ALT), hemoglobin, platelets, or neutrophils levels meeting specified criteria. The methods may include modifying treatment by decreasing or increasing the daily dose of bis-choline tetrathiomolybdate or discontinuing treatment for a period of time.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to 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, each of which is incorporated by reference in its entirety for all purposes. [Background technology]

[0002] Wilson's disease (WD) is an autosomal recessive disorder of copper (Cu) metabolism. Mutations in the ATP7B gene result in insufficient production of the Cu-transporter ATPase2, leading to impaired Cu incorporation into ceruloplasmin, impaired biliary excretion of Cu, increased 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 WD is estimated at 1 in 30,000, corresponding to approximately 10,000 in the United States and 15,000 in the European Union.

[0003] The typical clinical presentation of WD is during adolescence to early adulthood. Genetic screening and genotype-phenotype correlations are complicated by the large number of associated ATP7B mutations, and most individuals with WD are compound heterozygotes. Early signs and symptoms of WD are primarily hepatic (~40%), neurological (~40%), or psychiatric (~20%), but patients often have combined hepatic and neuropsychiatric disorders. Untreated or inadequately treated patients have progressive morbidity, and mortality is usually secondary to decompensated cirrhosis and liver failure. Liver transplantation is the only effective treatment for acute liver failure associated with WD, and other causes of death associated with WD include hepatic malignancy and neurological deterioration with severe malnutrition.

[0004] The liver represents one of the major Cu storage organs in humans. In healthy individuals, intracellular Cu homeostasis is tightly controlled. Copper is taken up into cells by Cu transporter 1 (CTR1) and then transported from CTR1 to Cu chaperones such as Cu chaperone of antioxidant 1, cytochrome c oxidase, and superoxide dismutase. The copper associated with the chaperones is delivered to specific Cu-requiring enzymes. When excessive amounts of Cu appear, the excess Cu binds to metallothionein (MT) as monovalent Cu (Cu+) via Cu-thiolate bridges by abundant cysteine ​​residues in MT, thus leading to detoxification of Cu through a reduction in redox potential.

[0005] In WD patients, ATPase 2 deficiency impairs Cu excretion. This leads to Cu accumulation mainly in the liver and brain but also in other organs. Within the buffering capacity of MTs, there is no obvious toxicity of Cu because MTs tightly bind Cu. However, beyond the Cu buffering capacity of MTs, free Cu ions appear, and this excess of free intracellular Cu causes pro-oxidant properties, resulting in an increased risk of tissue / organ damage with clinical symptoms. It is assumed that Cu toxicity in WD is mediated by free or loosely bound Cu that is not tightly bound to MTs due to Cu overload.

[0006] The therapeutic goal in WD is to compensate for the impaired Cu excretion caused by ATPase2 deficiency. Current treatment for WD consists of the general chelator therapy D-pep. These are nicillamine (CUPRIMINE®, Valeant Pharmaceuticals; DEPEN®, Meda Pharmaceuticals) and trientine (SYPRINE®, Aton Pharma, Inc.), which nonspecifically chelate Cu and promote urinary Cu excretion. In addition, zinc (Zn), which blocks dietary uptake of Cu, is primarily used in maintenance therapy. Zinc impairs Cu absorption by induction of MT in the gastrointestinal (GI) tract.

[0007] Disease control in patients with neurological symptoms at the time of WD diagnosis is a particular area of ​​concern. More than one-third of patients with neurological symptoms show no improvement after 4 years of treatment with chelators. This failure to respond to chelation therapy with neurological symptoms may reflect irreversible damage to the nervous system. Also, in a recent study, approximately 50% of patients had residual neurological symptoms despite years of treatment with Cu-modulating agents. Deterioration of neurological symptoms at the initiation of treatment has been reported in approximately 25% of patients initiated with penicillamine and trientine, and up to 50% of these patients do not recover. The mechanism behind this “paradoxical” neurological deterioration is thought to be mobilization of Cu from the liver, leading to elevated Cu in the blood and central nervous system, which causes neurological deterioration. This theory is supported by non-clinical data.

[0008] Currently available drugs to treat WD have high rates of treatment discontinuation due to adverse events and treatment failure. Their adverse event profiles and complex dosing regimens lead to poor treatment compliance and high rates of treatment failure, which are major concerns in diseases such as WD that require lifelong treatment.

[0009] Tetrathiomolybdate in the form of its ammonium salt has been shown to provide control of Cu and improved liver function even after a single dose. The majority of clinical and nonclinical safety and toxicity studies of tetrathiomolybdate-based therapy have been conducted using ammonium as the cationic counterion.

[0010] Drug absorption of orally administered active agents can be affected by food ingested before or after the active agent is administered. Food can affect drug absorption through several mechanisms. Food can affect absorption by interacting with the active agent or pharmaceutical formulation in the gastrointestinal tract, stimulating bile flow, altering gastrointestinal pH, increasing splanchnic blood flow, or by delaying gastric emptying. Thus, the bioavailability of an active agent can be affected by the ingestion of food within about 2 hours before or about 1 hour after administration of the active agent.

[0011] Nevertheless, it is difficult to predict de novo whether a particular active agent or pharmaceutical formulation will exhibit a food effect. Moreover, even if present, the food effect on an active agent or pharmaceutical formulation may result in an increase or decrease in bioavailability under fed conditions compared to administration of an equivalent dose under fasting conditions. If a substantial food effect exists (i.e., food intake before or after administration of a dose causes a substantial increase or decrease in drug absorption compared to administration under fasting conditions), then a pharmaceutical formulation administered under fed conditions is not bioequivalent to the same pharmaceutical formulation administered under fasting conditions.

[0012] This lack of bioequivalence can have serious clinical consequences. For example, administering a pharmaceutical composition with food can provide dangerously high drug plasma levels of active agent, resulting in clinical side effects. Alternatively, administering a pharmaceutical composition under fasting conditions can provide an effective dose, while administering the composition with food can provide sub-therapeutic drug plasma levels such that the dose delivered is ineffective.

[0013] Thus, improving Cu metabolism without the side effects associated with currently available therapies, There is a need to develop an effective treatment for Wilson's disease that reduces toxic free Cu and maintains normal Cu levels to improve patient symptoms. Summary of the Invention

[0014] The present disclosure relates to methods of treating Wilson's disease with bischoline tetrathiomolybdate therapy. In some embodiments, the bischoline tetrathiomolybdate has the following structure: [ka]

[0015] In some embodiments, the disclosure relates to a method of treating Wilson's disease in a patient by administering 15 mg of bischoline tetrathiomolybdate once a day or once every day. In some embodiments, the disclosure relates to a method of treating Wilson's disease in a patient by administering 30-90 mg of bischoline tetrathiomolybdate daily. In further embodiments, the disclosure relates to a method of treating Wilson's disease in a patient by administering 30-90 mg of bischoline tetrathiomolybdate daily, wherein the patient has an NCC greater than 2.3 μm / L. 補正 , an alanine aminotransferase (ALT) level less than 80 IU / mL, hemoglobin greater than 8 g / dL, platelets greater than 30,000 / μL, or 1,000 / μL or 1x10 3 Have one or more neutrophils greater than 1 / μL.

[0016] In some embodiments, the present disclosure relates to methods of modifying bischoline tetrathiomolybdate administration to patients with Wilson's disease undergoing bischoline tetrathiomolybdate treatment by decreasing the daily dose of bischoline tetrathiomolybdate or increasing the daily dose of bischoline tetrathiomolybdate.

[0017] In one aspect, the present disclosure further provides a method of decreasing or increasing the daily dose of bischoline tetrathiomolybdate in patients exhibiting abnormal test results, optionally including discontinuing treatment for a period of time.

[0018] In another aspect, the present disclosure provides a pharmaceutical composition for treating Wilson's disease in a patient, comprising bischoline tetrathiomolybdate. In another aspect, the present disclosure provides a kit for treating Wilson's disease, comprising at least three sets of pharmaceutical dosage units and instructions for use.

[0019] In another aspect, the present disclosure relates to a method for treating Wilson's disease in a patient in need of such treatment, comprising administering bischoline tetrathiomolybdate in a fasting state.In certain aspects, bischoline tetrathiomolybdate is administered as an enteric coated formulation.

[0020] In yet another aspect, the disclosure relates to a method of treating Wilson's disease in a patient in need thereof, comprising administering bischoline tetrathiomolybdate for about 24 weeks or more, about 36 weeks or more, 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 more, or about 144 weeks or more.

[0021] In certain embodiments, the present disclosure relates to a pharmaceutical composition comprising 15mg of bischoline tetrathiomolybdate, which is used to treat Wilson's disease in a patient in need of treatment.In certain embodiments, the pharmaceutical composition comprising 15mg of bischoline tetrathiomolybdate is suitable for once-a-day administration.In further embodiments, the pharmaceutical composition is suitable for once-every-other-day administration.In still further embodiments, the pharmaceutical composition is a delayed-release pharmaceutical composition.In still further embodiments, the pharmaceutical composition is in the form of a tablet or capsule.In still further embodiments, the pharmaceutical composition is in the form of a tablet.In certain embodiments, the pharmaceutical composition is in the form of an enteric-coated tablet.

[0022] In certain embodiments of the present disclosure, the patient has an NCC of the patient as measured prior to administration, such as 20%, 35%, 50%, or 75%. 補正 NCC as measured after 24 weeks of treatment compared to 補正 reduction in patients' NCC as measured before administration 補正 NCC as measured after 24 weeks of treatment compared to 補正 This shows a decrease in

[0023] In certain embodiments of the present disclosure, the patient has an NCC of the patient as measured prior to administration, such as 20%, 35%, 50%, or 75%. 補正 NCC as measured after 48 weeks of treatment compared to 補正 reduction in patients' NCC as measured before administration 補正 NCC as measured after 48 weeks of treatment compared to 補正 This shows a decrease in

[0024] In certain embodiments of the present disclosure, the patient has an NCC of the patient as measured prior to administration, such as 20%, 35%, 50%, or 75%. 補正 NCC as measured after 72 weeks of treatment compared to 補正 reduction in patients' NCC as measured before administration 補正 NCC as measured after 72 weeks of treatment compared to 補正 This shows a decrease in

[0025] In certain embodiments, the present invention relates to a pharmaceutical composition comprising bischoline tetrathiomolybdate for use in treating Wilson's disease in a patient in need thereof, wherein 30, 45, 60, 75, or 90 mg of bischoline tetrathiomolybdate is administered daily, and the patient has one or more of the following: a) NCC greater than 2.3 μm / L 補正 , b) an alanine aminotransferase (ALT) level less than 80 IU / mL; c) hemoglobin greater than 8 g / dL; d) greater than 30,000 platelets / μL, or e)10 3 Neutrophils greater than / µL.

[0026] In certain embodiments, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in treating Wilson's disease in patients undergoing bischoline tetrathiomolybdate treatment, wherein the daily dose of bischoline tetrathiomolybdate is reduced when the patient exhibits an alanine aminotransferase (ALT) level that is at least twice the ALT level exhibited when starting bischoline tetrathiomolybdate treatment. In a particular embodiment, if the patient was on a 15 mg dose of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate every other day; if the patient was on a 30 mg dose of bischoline tetrathiomolybdate once a day, the dose is reduced to 15 mg of bischoline tetrathiomolybdate once a day; if the patient was on a 45 mg dose of bischoline tetrathiomolybdate once a day, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once a day; if the patient was on a 60 mg dose of bischoline tetrathiomolybdate once a day, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once a day; if the patient was on a 75 mg dose of bischoline tetrathiomolybdate once a day, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once a day; mg dose of bischoline tetrathiomolybdate, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once daily.

[0027] In a further embodiment, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for treating Wilson's disease in patients undergoing bischoline tetrathiomolybdate treatment, and the daily dose of bischoline tetrathiomolybdate is reduced when the patient shows an alanine aminotransferase (ALT) level at least twice the upper limit of normal (ULN).In yet a further embodiment, if the patient is on a bischoline tetrathiomolybdate dose of 15mg once a day, the dose is reduced to bischoline tetrathiomolybdate 15mg every other day; if the patient is on a bischoline tetrathiomolybdate dose of 30mg once a day, the dose is reduced to bischoline tetrathiomolybdate 15mg once a day; if the patient is on a bischoline tetrathiomolybdate dose of 45mg once a day, the dose is reduced to bischoline tetrathiomolybdate 30mg once a day. If the patent is on 60 mg dose of viscoline tetrathiomolybdate once a day, the dose is reduced to 45 mg dose of viscoline tetrathiomolybdate once a day, if the patent is on 75 mg dose of viscoline tetrathiomolybdate once a day, the dose is reduced to 60 mg dose of viscoline tetrathiomolybdate once a day, or if the patent is on 90 mg dose of viscoline tetrathiomolybdate once a day, the dose is reduced to 75 mg dose of viscoline tetrathiomolybdate once a day. In yet a further embodiment, the ULN is 30-45 IU / mL. In a more specific embodiment, the ULN is 34 IU / mL. In a further specific embodiment, the ULN is 40 IU / mL.

[0028] In a particular embodiment, the present disclosure relates to a pharmaceutical composition of viscoline tetrathiomolybdate for treating Wilson's disease in a patient undergoing viscoline tetrathiomolybdate treatment, and the daily dose of viscoline tetrathiomolybdate is reduced when the patient shows a hemoglobin level of 70% or less of the hemoglobin level shown when starting viscoline tetrathiomolybdate treatment.In a particular embodiment, if the patient is on a 15mg dose of viscoline tetrathiomolybdate once a day, the dose is reduced to 15mg of viscoline tetrathiomolybdate every other day; if the patient is on a 30mg dose of viscoline tetrathiomolybdate once a day, the dose is reduced to 15mg of viscoline tetrathiomolybdate once a day; if the patient is on a 45mg dose of viscoline tetrathiomolybdate once a day, the dose is reduced to 30mg of viscoline tetrathiomolybdate once a day. If the patent was on bischoline tetrathiomolybdate at a dose of 60 mg once daily, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once daily, if the patent was on bischoline tetrathiomolybdate at a dose of 75 mg once daily, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once daily, or if the patent was on bischoline tetrathiomolybdate at a dose of 90 mg once daily, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once daily.

[0029] In a particular embodiment, the present disclosure relates to a pharmaceutical composition of viscoline tetrathiomolybdate for treating Wilson's disease in patients undergoing viscoline tetrathiomolybdate treatment, and the daily dose of viscoline tetrathiomolybdate is reduced when the patient shows platelet level below 70% of the platelet level shown when starting viscoline tetrathiomolybdate treatment.In a particular embodiment, if the patient is on viscoline tetrathiomolybdate at a dose of 15mg once a day, the dose is reduced to viscoline tetrathiomolybdate at 15mg every other day, if the patient is on viscoline tetrathiomolybdate at a dose of 30mg once a day, the dose is reduced to viscoline tetrathiomolybdate at 15mg once a day, if the patient is on viscoline tetrathiomolybdate at a dose of 30mg once a day, the dose is reduced to viscoline tetrathiomolybdate at 15mg once a day, if the patient is on viscoline tetrathiomolybdate at a dose of 45 ... If the patent was on choline tetrathiomolybdate, the dose is reduced to 30 mg of bischoline tetrathiomolybdate once daily, if the patent was on a 60 mg dose of bischoline tetrathiomolybdate once daily, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once daily, if the patent was on a 75 mg dose of bischoline tetrathiomolybdate once daily, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once daily, or if the patent was on a 90 mg dose of bischoline tetrathiomolybdate once daily, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once daily.

[0030] In a particular embodiment, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in treating Wilson's disease in patients undergoing bischoline tetrathiomolybdate treatment, and the daily dose of bischoline tetrathiomolybdate is reduced when the patient shows neutrophil levels below 70% of the neutrophil levels shown when starting bischoline tetrathiomolybdate treatment.In a particular embodiment, if the patient is on a 15mg dose of bischoline tetrathiomolybdate once a day, the dose is reduced to 15mg of bischoline tetrathiomolybdate every other day; if the patient is on a 30mg dose of bischoline tetrathiomolybdate once a day, the dose is reduced to 15mg of bischoline tetrathiomolybdate once a day; if the patient is on a 45mg dose of bischoline tetrathiomolybdate once a day, the dose is reduced to 30mg of bischoline tetrathiomolybdate once a day. If the patent was on bischoline tetrathiomolybdate at a dose of 60 mg once daily, the dose is reduced to 45 mg of bischoline tetrathiomolybdate once daily, if the patent was on bischoline tetrathiomolybdate at a dose of 75 mg once daily, the dose is reduced to 60 mg of bischoline tetrathiomolybdate once daily, or if the patent was on bischoline tetrathiomolybdate at a dose of 90 mg once daily, the dose is reduced to 75 mg of bischoline tetrathiomolybdate once daily.

[0031] In a particular embodiment, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for treating Wilson's disease in a patient undergoing bischoline tetrathiomolybdate treatment, wherein the daily dose of bischoline tetrathiomolybdate is interrupted when the patient shows an alanine aminotransferase (ALT) level greater than 5 times the ALT level shown when starting bischoline tetrathiomolybdate treatment, and when the patient shows an ALT level less than 2 times the ALT level shown when starting bischoline tetrathiomolybdate treatment, and treatment is resumed with bischoline tetrathiomolybdate 15 mg every other day if the patient was on a bischoline tetrathiomolybdate dose of 15 mg every other day before interrupting bischoline tetrathiomolybdate, or with bischoline tetrathiomolybdate 15 mg a day if the patient was on a bischoline tetrathiomolybdate dose of 15 to 90 mg once a day before interrupting bischoline tetrathiomolybdate.

[0032] In a particular embodiment, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in treating Wilson's disease in a patient undergoing bischoline tetrathiomolybdate treatment, wherein the daily dose of bischoline tetrathiomolybdate is discontinued when the patient exhibits an alanine aminotransferase (ALT) level greater than 200 IU / mL and when the patient exhibits an ALT level less than twice the level exhibited when starting bischoline tetrathiomolybdate treatment, and the treatment is discontinued when the patient is on a 15 mg dose of bischoline tetrathiomolybdate every other day before discontinuing bischoline tetrathiomolybdate, or when the patient is on a 15-90 mg dose of bischoline tetrathiomolybdate once a day before discontinuing bischoline tetrathiomolybdate ... It is resumed with tratiomolybdate.

[0033] In certain embodiments, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for treating Wilson's disease in a patient undergoing bischoline tetrathiomolybdate treatment, wherein the daily dose of bischoline tetrathiomolybdate is interrupted when the patient shows a hemoglobin level less than 8 g / dL and when the patient shows a hemoglobin level equivalent to that shown when starting bischoline tetrathiomolybdate treatment, and treatment is resumed with bischoline tetrathiomolybdate 15 mg every other day if the patient was on bischoline tetrathiomolybdate 15 mg dose every other day before interrupting bischoline tetrathiomolybdate, or with bischoline tetrathiomolybdate 15 mg daily if the patient was on bischoline tetrathiomolybdate 15 to 90 mg dose once a day before interrupting bischoline tetrathiomolybdate.

[0034] In certain embodiments, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for treating Wilson's disease in a patient undergoing bischoline tetrathiomolybdate treatment, wherein the daily dose of bischoline tetrathiomolybdate is interrupted when the patient shows a platelet level less than 30,000 μL and when the patient shows a platelet level equivalent to that shown when starting bischoline tetrathiomolybdate treatment, and treatment is resumed with bischoline tetrathiomolybdate 15 mg every other day if the patient was on bischoline tetrathiomolybdate 15 mg dose every other day before interrupting bischoline tetrathiomolybdate, or bischoline tetrathiomolybdate 15 mg daily if the patient was on bischoline tetrathiomolybdate 15 to 90 mg dose once a day before interrupting bischoline tetrathiomolybdate.

[0035] In a particular embodiment, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in treating Wilson's disease in a patient undergoing bischoline tetrathiomolybdate therapy, the daily dose of bischoline tetrathiomolybdate being sufficient to maintain neutrophil levels in the patient below 1.0×10 3 / μL and if the patient exhibits neutrophil levels equivalent to those exhibited when starting bischoline tetrathiomolybdate treatment, treatment is discontinued and treatment is resumed with 15 mg of bischoline tetrathiomolybdate every other day if the patient was on a 15 mg dose of bischoline tetrathiomolybdate every other day before discontinuing bischoline tetrathiomolybdate, or with 15 mg of bischoline tetrathiomolybdate daily if the patient was on a 15 to 90 mg dose of bischoline tetrathiomolybdate once daily before discontinuing bischoline tetrathiomolybdate.

[0036] In a particular embodiment, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in treating Wilson's disease in a patient undergoing bischoline tetrathiomolybdate treatment, wherein the daily dose of bischoline tetrathiomolybdate is interrupted when the patient shows a bilirubin level of greater than 2.4 mg / dL and an alanine aminotransferase (ALT) level of greater than 120 IU / mL, and when the patient shows a bilirubin level below the upper limit of normal, and treatment is resumed with 15 mg of bischoline tetrathiomolybdate every other day if the patient was on a 15 mg dose of bischoline tetrathiomolybdate every other day before discontinuing bischoline tetrathiomolybdate, or with 15 mg of bischoline tetrathiomolybdate a day if the patient was on a 15-90 mg dose of bischoline tetrathiomolybdate once a day before discontinuing bischoline tetrathiomolybdate.

[0037] In a particular embodiment, the present disclosure relates to a pharmaceutical composition of bischoline tetrathiomolybdate for use in treating Wilson's disease in a patient undergoing bischoline tetrathiomolybdate therapy, the daily dose of bischoline tetrathiomolybdate being administered to the patient. If the patient exhibits a bilirubin level greater than two times the upper limit of normal for lirubin and an alanine aminotransferase (ALT) level greater than three times the ULN for ALT, and if the patient exhibits bilirubin below the upper limit of normal, treatment is discontinued and the patient is restarted with 15 mg of bischoline tetrathiomolybdate every other day if the patient was on a 15 mg dose of bischoline tetrathiomolybdate every other day before discontinuing bischoline tetrathiomolybdate, or with 15 mg of bischoline tetrathiomolybdate daily if the patient was on a 15 to 90 mg dose of bischoline tetrathiomolybdate once daily before discontinuing bischoline tetrathiomolybdate.

[0038] In certain embodiments, the present disclosure provides a composition comprising bischoline tetrathiomolybdate for use in a method for treating Wilson's disease in a patient. In some embodiments, the composition is defined according to any of the compositions disclosed herein. In some embodiments, the composition is for use in any of the methods disclosed herein. In some embodiments, the patient is defined as disclosed herein.

[0039] In certain embodiments, the present disclosure relates to the pharmaceutical composition of bischoline tetrathiomolybdate for use in Wilson's disease, and the composition is administered in fasting state.In further embodiments, the pharmaceutical composition comprises 15mg of bischoline tetrathiomolybdate.In yet further embodiments, the pharmaceutical composition is an enteric coated tablet.

[0040] In certain embodiments, the present disclosure relates to the above-mentioned methods of treating Wilson's disease, comprising administering bischoline tetrathiomolybdate to a patient having Wilson's disease, and modifying the bischoline tetrathiomolybdate to a patient having Wilson's disease, wherein the patient has cirrhosis of the liver.

[0041] In certain embodiments, the present disclosure relates to the above-mentioned methods of treating Wilson's disease, comprising administering bischoline tetrathiomolybdate to a patient with Wilson's disease, and modifying the bischoline tetrathiomolybdate to a patient with Wilson's disease, wherein the patient does not have cirrhosis.

[0042] In certain embodiments, the present disclosure relates to the above-mentioned method of treating Wilson's disease, comprising administering bischoline tetrathiomolybdate to a patient with Wilson's disease; and correcting the bischoline tetrathiomolybdate to a patient with Wilson's disease, wherein the patient exhibits one or more Wilson's disease phenotypes selected from total tremor, total gait, dystonia, limb agility and coordination, and rigidity, preferably, the patient exhibits total tremor, or limb agility and coordination, or both. In a further embodiment, a) the total tremor phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from rest tremor, head tremor, arm-postural and flapping tremor, postural-leg, and jaw tremor; b) the total gait phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from chair rise, postural-truncal dystonia, ataxia of stance, and parkinsonism, gait-leg dystonia, ataxia, and parkinsonism; and c) the dystonia phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from palatomandibular dystonia, cervical dystonia, and gait-leg dystonia. d) limb agility and coordination phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from finger tapping, rapid alternating hand movements, graphology, finger-nose test, and leg agility; and e) rigidity phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from arm, leg, and neck dystonia.

[0043] In still further embodiments, a) the total tremor phenotype is characterized by a UWDRS part III score of 30-45, b) the total gait phenotype is characterized by a UWDRS part III score of 20-32, c) the dystonia phenotype is characterized by a UWDRS part III score of 15-28, d) the limb dexterity and coordination phenotype is characterized by a UWDRS part III score of 20-36, and e) the rigidity phenotype is characterized by a UWDRS part III score of 10-20.

[0044] In certain embodiments, the disclosure relates to the above-mentioned method of treating Wilson's disease, comprising administering bischoline tetrathiomolybdate to a patient with Wilson's disease and modifying bischoline tetrathiomolybdate to a patient with Wilson's disease, wherein the patient exhibits a neurological symptom of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from handwriting, leg agility, and a combination thereof. In further embodiments, the patient exhibits a handwriting score according to UWDRS Part III of 2 to 4, a leg agility score according to UWDRS Part III of 2 to 8, or a handwriting and leg agility score according to UWDRS Part III of 4 to 12. In still further embodiments, the patient exhibits an improvement in one or more neurological symptoms of Wilson's disease according to UWDRS Part III after administration of the composition. In still further embodiments, the patient exhibits a decrease in UWDRS part III scores for one or more of: a) a total tremor phenotype of 5-25; b) a total gait phenotype of 5-20; c) a dystonia phenotype of 5-15; d) a limb agility and coordination phenotype of 5-20; and e) a rigidity phenotype of 5-15.

[0045] In yet other embodiments, the patient exhibits one or more of a decrease in UWDRS part III score for handwriting of 1 to 3, a decrease in UWDRS part III score for leg dexterity of 1 to 6, and a decrease in UWDRS part III score for handwriting and leg dexterity of 2 to 9.

[0046] In certain embodiments, the disclosure provides a composition as described herein for use in treating Wilson's Disease, wherein the patient exhibits one or more Wilson's Disease phenotypes selected from total tremor, total gait, dystonia, limb agility and coordination, and rigidity, preferably the patient exhibits total tremor, or limb agility and coordination, or both. In a further embodiment, a) the total tremor phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from rest tremor, head tremor, arm-postural and flapping tremor, postural-leg, and jaw tremor; b) the total gait phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from chair rise, postural-truncal dystonia, ataxia of stance, and parkinsonism, gait-leg dystonia, ataxia, and parkinsonism; and c) the dystonia phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from palatomandibular dystonia, cervical dystonia, and gait-leg dystonia. d) limb agility and coordination phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from finger tapping, rapid alternating hand movements, graphology, finger-nose test, and leg agility; and e) rigidity phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from arm, leg, and neck dystonia.

[0047] In yet a further embodiment, a) the total tremor phenotype is characterized by a UWDRS part III score of 30-45, b) the total gait phenotype is characterized by a UWDRS part III score of 20-32, and c) the dystonia phenotype is characterized by a UWDRS part III score of 15-28. III score of 20-36; and e) the rigidity phenotype is characterized by a UWDRS part III score of 10-20.

[0048] In certain embodiments, the disclosure provides a composition as described herein for use in treating Wilson's disease, wherein the patient exhibits a neurological symptom of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from handwriting, leg agility, and a combination thereof. In further embodiments, the patient exhibits a handwriting score according to UWDRS Part III of 2-4, a leg agility score according to UWDRS Part III of 2-8, or a handwriting and leg agility score according to UWDRS Part III of 4-12. In still further embodiments, the patient exhibits an improvement in one or more neurological symptoms of Wilson's disease according to UWDRS Part III after administration of the composition. In still further embodiments, the patient exhibits a reduction in one or more UWDRS Part III scores of a) total tremor phenotype of 5-25, b) total gait phenotype of 5-20, c) dystonia phenotype of 5-15, d) limb agility and coordination phenotype of 5-20, and e) rigidity phenotype of 5-15.

[0049] In yet other embodiments, the patient exhibits one or more of a decrease in UWDRS part III score for handwriting of 1 to 3, a decrease in UWDRS part III score for leg dexterity of 1 to 6, and a decrease in UWDRS part III score for handwriting and leg dexterity of 2 to 9.

[0050] In certain embodiments, the present disclosure provides a composition as described herein for use in treating Wilson's disease, wherein a patient has cirrhosis of the liver.

[0051] In certain embodiments, the present disclosure provides a composition as described herein for use in treating Wilson's disease, wherein the patient does not have cirrhosis.

[0052] Additional aspects and embodiments will become apparent from the following detailed description. [Brief description of the drawings]

[0053] [Figure 1] The clinical trial profile is shown. [Diagram 2] Changes in NCC-corrected concentrations over time are shown. Changes from baseline are least squares means (SE) of 19–25 patients at each time point. One patient discontinued treatment at week 23 but is within the specified window for including the NCC-corrected measurement as a value at week 24. p values ​​are relative to baseline. [Diagram 3] Changes in disability and neurological status over time are shown. Changes from baseline Unified Wilson's Disease Rating Scale (UWDRS part II) scores (disability; A) and part III scores (neurological signs; B) are least squares means (SE) for 21–28 patients. [Figure 4] NCC correction levels with once-daily WTX101 treatment are shown. [Diagram 5] 1 shows changes in measures of liver stability with once-daily WTX101 treatment. [Figure 6] Changes in disability and neurological signs with once-daily WTX101 treatment are shown. [Figure 7] The number of adverse events (AEs) reported during the core and extension periods are shown. [Figure 8] Figures 8A-8B show the mean ± standard error plasma concentrations of total Mo following administration of a single 60 mg (2 x 30 mg) dose of WTX101 EC tablet under fasted (Treatment A) and fed conditions (Treatment B), and UC + PPI under fasted conditions (Treatment C). Data are plotted on a linear axis (Figure 8A) and semi-logarithmic scale (Figure 8B). [Figure 9] Symptoms of UWDRS neurological conditions (part III) experienced by at least 50% of patients at baseline are shown. Data are expressed as percentage of patients in the enrolled population (N=28). [Figure 10A]Figure 10 shows the UWDRS Neurological Status (Part III) item scores for the study population. Figure 10A shows items with a maximum score of 4. Figure 10B shows items with a maximum score of 8. [Figure 10B] Figure 10 shows the UWDRS Neurological Status (Part III) item scores for the study population. Figure 10A shows items with a maximum score of 4. Figure 10B shows items with a maximum score of 8. [Figure 11A] The number of patients with change in UWDRS neurological status (part III) item scores between baseline and week 24 are shown. Data are from all patients with data for a given item, including those with a baseline score of zero (n=22 in each case). Figure 11A shows items with a maximum score of 4. Figure 11B shows items with a maximum score of 8. [Figure 11B] The number of patients with change in UWDRS neurological status (part III) item scores between baseline and week 24 are shown. Data are from all patients with data for a given item, including those with a baseline score of zero (n=22 in each case). Figure 11A shows items with a maximum score of 4. Figure 11B shows items with a maximum score of 8. [Figure 12] Patient flow for the extension study is shown. [Figure 13] NCC-corrected levels are shown for patients with and without cirrhosis. NCC levels are not corrected at baseline as they did not receive WTX101. BL, baseline; LLN, lower limit of normal reference range (0.8 μmol / L); ULN, upper limit of normal reference range (2.3 μmol / L); NCC-corrected, non-ceruloplasmin-bound copper corrected for the amount of copper bound to tetrathiomolybdate-copper-albumin complex; SEM, standard error of the mean. [Figure 14] ALT levels in patients with and without cirrhosis are shown. ALT, alanine aminotransferase; BL, baseline; SEM, standard error of the mean. [Figure 15]MELD scores (severity of liver disease; score range 6–40) are shown for patients with and without cirrhosis. BL, baseline; MELD, model for end-stage liver disease; SEM, standard error of the mean. [Figure 16] The modified Nazer score (prognostic index, score range, 0-20) of patients with and without cirrhosis is shown. [Figure 17A] 1 shows albumin levels in patients with and without cirrhosis. [Figure 17B] International normalized ratios for patients with and without cirrhosis are shown. BL, baseline; INR, international normalized ratio; SEM, standard error of the mean [Figure 18] Blood clotting times in patients with and without cirrhosis are shown. BL, baseline; INR, international normalized ratio; SEM, standard error of the mean. [Figure 19A] The UWDRS is shown for part II (measuring disability based on patient-reported activities of daily living; score range, 0-40) (Figure 19A) and part III (measuring neurological status as assessed by a clinician (score range; 0-143)) (Figure 19B). Higher scores indicate worse status. [Figure 19B] The UWDRS is shown for part II (measuring disability based on patient-reported activities of daily living; score range, 0-40) (Figure 19A) and part III (measuring neurological status as assessed by a clinician (score range; 0-143)) (Figure 19B). Higher scores indicate worse status. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] Certain aspects of the present disclosure are based on the surprising discovery that administering 15 mg of bischoline tetrathiomolybdate or modifying the daily dose of bischoline tetrathiomolybdate to control abnormal liver function in patients can reduce adverse events associated with the treatment of Wilson's disease. Ammonium salts of tetrathiomolybdate are commonly used. Initial Therapy of Patients with Wilson's Disease with Tetrathiomolybdate. Arch. Neurol. 48:42-47 (1991). According to the present disclosure, administration of bischoline tetrathiomolybdate at dosages the same or similar to those of ammonium tetrathiomolybdate commonly known in the art is associated with adverse events that the methods of the present disclosure reduce.

[0055] The present disclosure provides a method for administering a therapeutically effective dose of bischoline tetrathiomolybdate to a patient who has been showing abnormal test results after the patient has been treated with bischoline tetrathiomolybdate. Since abnormalities in liver function may indicate drug-induced liver damage (hepatotoxicity), it is important to determine whether the abnormality reflects liver damage or a limited toxicity that resolves over time as the drug continues to be taken. According to the present disclosure, even patients who show abnormal liver function can optionally continue to take bischoline tetrathiomolybdate at the same dose or at a reduced dose after discontinuing bischoline tetrathiomolybdate for a period of time. This administration regimen has the advantage of maximizing the time at full target dose of the drug, and therefore the potential for beneficial therapeutic effects.

[0056] The method of the present disclosure optionally includes identifying abnormal liver function in patients receiving bischoline tetrathiomolybdate, and monitoring liver test results in patients receiving reduced doses of bischoline tetrathiomolybdate.In any of the methods described herein, ALT can be elevated to a level of, for example, greater than 34IU / mL or 64IU / mL or 170IU / mL before dose reduction.Alternatively, hemoglobin can be reduced, or platelets can be reduced, or neutrophils can be reduced before dose reduction.

[0057] The disclosed method optionally includes measuring the copper level in the body. Various means of measuring the copper level in the body are known in the art. In one embodiment, the free copper concentration in serum or plasma ultrafiltrate is measured by inductively coupled mass spectrometry to aid in the diagnosis and monitoring of Wilson's disease. In another embodiment, the free concentration in urine is determined. In another embodiment, the biliary secretion of copper is determined by measuring the copper concentration in feces. In another embodiment, the copper content of hair is determined. In a further embodiment, the amount of free serum copper is determined as the amount of unbound copper circulating in the blood, which is copper unbound by ceruloplasmin. It should be understood that this is copper that is free to accumulate in the liver and other organs. In a preferred embodiment, non-ceruloplasmin bound copper or NCC is determined by inductively coupled mass spectrometry or other methods known in the art. In any of the methods described herein, NCC is determined by measuring ... 補正 can be increased, for example, to greater than 2.3 μm / L.

[0058] The test results and level ranges in healthy individuals described above can vary depending on the test conditions and test methods, but generally, healthy individuals will have ALT levels within the ranges of 6-34 U / L, 9-34 U / L, or 6-41 U / L, hemoglobin within the ranges of 11.6-16.4 g / dL, 13.6-18.0 g / dL, or 12.0-16.0 g / dL, and serum glucose levels within the ranges of 140-400×10 3 Platelets / µL range, 1.96–7.23 × 10 3 Wilson disease is known to show neutrophils in the range of 0.2 to 1.2 mg / dL, or bilirubin in the range of 0.10 to 1.10 mg / dL. Further information on laboratory test methods for the diagnosis and treatment of Wilson disease can be found at the European Association This is provided in the Clinical Practice Guidelines for the Study of the Liver (EASL): Wilson's Disease; J. Hepatology 56:671-685 (2012). is incorporated in its entirety into this disclosure.

[0059] In some embodiments, the present disclosure relates to a method for treating Wilson's disease in patients by administering 15mg of bischoline tetrathiomolybdate once a day or once every day.The once a day dose can be given in the form of a single dose, or two doses, two doses that are optionally divided equally, or three doses, or four doses, or five doses.The dose can be delivered orally, intravenously, intramuscularly, or by other methods known in the art.

[0060] In some embodiments, the disclosure relates to a method of treating Wilson's disease in a patient by administering 30-90 mg of bischoline tetrathiomolybdate daily, wherein the patient has an NCC greater than 2.3 μm / L. 補正 , an alanine aminotransferase (ALT) level less than 80 IU / mL, hemoglobin greater than 8 g / dL, platelets greater than 30,000 / μL, or 1,000 / μL or 1x10 3 Patients have one or more neutrophil counts greater than 2.3 μm / L. 補正 and alanine aminotransferase (ALT) levels less than 80 IU / mL, or NCC greater than 2.3 μm / L. 補正 and hemoglobin greater than 8 g / dL, or any other combination of two or more of these parameters. In some embodiments, one or more parameters will be measured. In one embodiment, NCC 補正 are measured. In another embodiment, two or more of the parameters are measured. In another embodiment, all of the parameters are measured.

[0061] In some embodiments, the disclosure relates to a method of treating Wilson's disease in a patient by administering 30-90 mg of bischoline tetrathiomolybdate daily, wherein the patient has an NCC greater than 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 μg / L. 補正 , or N.C.C. 補正alanine aminotransferase (ALT) levels less than 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 IU / mL, or two times the upper limit of normal (ULN) for ALT; hemoglobin greater than 6, 7, 8, 9, or 10 g / dL; platelets greater than 20,000, 25,000, 30,000, 35,000, or 40,000 / μL; or 0.5x10 3 , 1x10 3 , 1.5x10 3 , 2x10 3 , or 2.5x10 3 In certain embodiments, the patient may have a combination of two or more of these parameters. In some embodiments, one or more parameters will be measured. In another embodiment, the NCC 補正 are measured. In further embodiments, two or more of the parameters are measured. In further embodiments, all are measured.

[0062] In some embodiments, the present disclosure relates to a method for modifying bischoline tetrathiomolybdate administration to patients with Wilson's disease undergoing bischoline tetrathiomolybdate treatment by increasing the daily dose of bischoline tetrathiomolybdate.In some embodiments of the present disclosure, the dose of bischoline tetrathiomolybdate is increased in patients who show certain test results.In some embodiments, the daily dose of bischoline tetrathiomolybdate is increased in increments of 15 mg.In some embodiments, the present disclosure relates to a method for modifying bischoline tetrathiomolybdate administration to patients with Wilson's disease undergoing bischoline tetrathiomolybdate treatment by increasing the daily dose of bischoline tetrathiomolybdate. 補正 , an alanine aminotransferase (ALT) level less than 80 IU / mL, hemoglobin greater than 8 g / dL, platelets greater than 30,000 / μL, or 1,000 / μL or 1x10 3 In a further embodiment, the disclosure provides for a patient having one or more of the following: NCC greater than 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 μg / L. 補正 , or N.C.C.補正 Alanine aminotransferase (ALT) levels less than 2x the upper limit of normal (ULN), 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 IU / mL, or ALT levels above normal (ULN) hemoglobin greater than 2x the normal limit, 6, 7, 8, 9, or 10 g / dL; platelets greater than 20,000, 25,000, 30,000, 35,000, or 40,000 / μL; or 0.5x10 3 , 1x10 3 , 1.5x10 3 , 2x10 3 , or 2.5x10 3 The daily dose is increased if the patient has one or more of the following: NCC greater than 2.3 μm / L. 補正 and alanine aminotransferase (ALT) levels less than 80 IU / mL, or NCC greater than 2.3 μm / L. 補正 and hemoglobin greater than 8 g / dL, or any other combination of two or more of these parameters. In some embodiments, one or more parameters will be measured. In one embodiment, NCC 補正 is measured. In another embodiment, two or more of the parameters are measured. In another embodiment, all parameters are measured. In a particular embodiment, the daily dose is increased in increments of 15 mg of bischoline tetrathiomolybdate. In a particular embodiment, the daily dose is increased during the initiation of treatment, typically during the first 3, 4, 5, or 6 months of treatment with bischoline tetrathiomolybdate. In a particular aspect of the present disclosure, the patient's dose is increased once. In a further aspect of the present disclosure, the patient's dose is increased twice. In a further aspect of the present disclosure, the patient's dose is increased three or more times.

[0063] In some embodiments, the present disclosure relates to a method for modifying the administration of bischoline tetrathiomolybdate to the patient with Wilson's disease undergoing bischoline tetrathiomolybdate treatment by reducing the daily dose of bischoline tetrathiomolybdate.In some embodiments, the daily dose of bischoline tetrathiomolybdate is reduced by 15mg increments.In one embodiment, the daily dose is reduced by administering a dose every other day.In another embodiment, the daily dose is reduced by administering 15mg every other day, so that the patient receives an average of 7.5mg of bischoline tetrathiomolybdate per day.

[0064] In one aspect, the present disclosure further provides a method for reducing the daily dose of bischoline tetrathiomolybdate in patients who show abnormal test results. In certain aspects of the present disclosure, when a patient shows certain abnormal test results, administration of bischoline tetrathiomolybdate is temporarily suspended, and optionally resumed at a lower dose when the patient shows improved test results. In one embodiment, the test is a test of liver function. Any test of liver function known in the art can be used. In one embodiment, alanine aminotransferase (ALT) or bilirubin level is used. In one embodiment, the test is a test of bone marrow suppression caused by prolonged excessive decopperization leading to cytopenia. In one embodiment, hemoglobin level, platelet level, or neutrophil level can be used as the test. In one embodiment, the test results of two or more tests are used. In one embodiment, several tests are used. In certain embodiments, the dose is reduced when two consecutive test results are abnormal.

[0065] In certain embodiments, the daily dose of bischoline tetrathiomolybdate in patients showing abnormal test results is reduced by 15 mg, such that the dose of patients taking 15 mg of bischoline tetrathiomolybdate per day before abnormal test results is reduced to 15 mg of bischoline tetrathiomolybdate every other day, the dose of patients taking 30 mg of bischoline tetrathiomolybdate per day before abnormal test results is reduced to 15 mg per day, the dose of patients taking 45 mg of bischoline tetrathiomolybdate per day before abnormal test results is reduced to 30 mg per day, the dose of patients taking 60 mg of bischoline tetrathiomolybdate per day before abnormal test results is reduced to 45 mg per day, the dose of patients taking 75 mg of bischoline tetrathiomolybdate per day before abnormal test results is reduced to 60 mg per day, and the dose of patients taking 90 mg of bischoline tetrathiomolybdate per day before abnormal test results is reduced to 75 mg per day.In other embodiments, the dose of bischoline tetrathiomolybdate in patients showing abnormal test results is reduced to 75 mg per day. The daily dose of choline tetrathiomolybdate is reduced by half. In yet another embodiment, the dose of choline tetrathiomolybdate in patients showing abnormal test results who are taking 30-90 mg of choline tetrathiomolybdate per day before the abnormal test results is reduced to a dose of 15 mg of choline tetrathiomolybdate per day, and the dose of choline tetrathiomolybdate in patients showing abnormal test results who are taking 15 mg of choline tetrathiomolybdate per day before the abnormal test results is reduced to a dose of 15 mg of choline tetrathiomolybdate every other day.

[0066] In certain embodiments, when a patient shows a certain abnormal test result, administration of bischoline tetrathiomolybdate is temporarily suspended and resumed when the test result meets a certain threshold. In certain embodiments, dosing is suspended when two consecutive test results are abnormal. In further embodiments, dosing is resumed when two consecutive test results meet a certain threshold. In certain embodiments, the daily dose of bischoline tetrathiomolybdate is resumed at the level before the suspension. In further embodiments, the daily dose of bischoline tetrathiomolybdate is resumed at a reduced dosage level as described above. In still further embodiments of the present disclosure, the daily dose is resumed at 15 mg of bischoline tetrathiomolybdate. In still further embodiments of the present disclosure, if the patient was taking 30-90 mg of bischoline tetrathiomolybdate per day prior to the abnormal test result, the daily dose is resumed at 15 mg of bischoline tetrathiomolybdate. In yet a further embodiment of the present disclosure, if the patient was taking 15 mg of bischoline tetrathiomolybdate daily prior to the abnormal test result, the dose is resumed at 15 mg of bischoline tetrathiomolybdate every other day.

[0067] Abnormal test results may be defined as above or below a set threshold, and liver or bone marrow function is said to be normal. In any aspect, an upper limit of normal (ULN) is defined for the test results. In any aspect, dosing is modified if the patient shows two consecutive abnormal test results. Administration of bischoline tetrathiomolybdate may be modified by a test result of liver function greater than the ULN, or 2 times the ULN, or 3 times the ULN, or 4 times the ULN, or 5 times the ULN, or any multiple of the ULN, or greater than a small multiple of the ULN between 1 times, 2 times, 3 times, 4 times, or 5 times the ULN. In one embodiment, if the test result is 2 to 5 times the ULN, daily administration of bischoline tetrathiomolybdate is discontinued if the test result is greater than 5 times the ULN. In another embodiment, the liver function test is ALT. Optionally, if ALT is less than twice the ULN, administration of bischoline tetrathiomolybdate is resumed. Optionally, if ALT is less than twice the ULN, daily doses of bischoline tetrathiomolybdate are resumed at a lower dose. In one embodiment, the ULN and lower limit of normal (LLN) of ALT depend on the particular assay used. In one embodiment, the ULN of ALT 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 ULN of ALT is 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 IU / mL, or any fraction therebetween. In another embodiment, the ULN for ALT is 34 IU / mL.In another embodiment, the ULN for ALT is 40 IU / mL.

[0068] In another optional embodiment, the daily dose of bischoline tetrathiomolybdate is modified if the hepatic results are below the baseline measurements of the test performed before starting administration of bischoline tetrathiomolybdate. Optionally, this baseline is patient-specific. Optionally, this baseline is determined by medical judgment. Optionally, this baseline is determined by clinical trial results. Optionally, dosing is adjusted if the patient has two consecutive abnormal tests. In one embodiment, the threshold value for modifying the dose of bischoline tetrathiomolybdate is 50% or 60% or 70% or 80% or 90% of baseline, or any percentage therebetween. In another embodiment, the threshold value is 65% or 70% or 75% of baseline. In one embodiment, the threshold value is 70% of baseline. In any aspect, if the patient's hemoglobin level is less than 70% of the patient's baseline hemoglobin, the dose of bischoline tetrathiomolybdate is modified. In any other aspect, the threshold value is 70% of baseline platelets or 70% of baseline neutrophils.

[0069] In a further embodiment, the dose of viscoline tetrathiomolybdate is reduced or temporarily suspended if the patient's hemoglobin level is less than 6, 7, 8, 9, or 10 g / dL. In yet a further embodiment, the dose of viscoline tetrathiomolybdate is reduced or temporarily suspended if the patient's hemoglobin level is less than 8 g / dL. In another embodiment, the dose of viscoline tetrathiomolybdate is reduced or temporarily suspended if the platelets are less than 20,000, 25,000, 30,000, 35,000, or 40,000 / μL. In yet another embodiment, the dose of viscoline tetrathiomolybdate is reduced or temporarily suspended if the platelets are less than 30,000 / μL. In yet another embodiment, the dose of viscoline tetrathiomolybdate is reduced or temporarily suspended if the neutrophils are less than 0.5×10 3 , 1×10 3 , 1.5×10 3 , 2×10 3 , or 2.5 × 10 3If the neutrophil count is less than 1×10 / μL, the dose of bischoline tetrathiomolybdate is reduced or temporarily discontinued. 3 If the serum creatinine concentration is less than 100 mg / μL, the dose of bischoline tetrathiomolybdate is reduced or temporarily discontinued. Optionally, dosing is modified if the patient exhibits two consecutive abnormal test results.

[0070] In certain embodiments, when the dose of bischoline tetrathiomolybdate is temporarily discontinued, the patient experiences a hemoglobin level of 6, 7, 8, 9, or 10 g / dL or greater, a platelet count of 20,000, 25,000, 30,000, 35,000, or 40,000 / μL or greater, and / or a platelet count of 0.5×10 3 , 1x10 3 , 1.5x10 3 , 2x10 3 , or 2.5x10 3 In a further embodiment, if the dose of bischoline tetrathiomolybdate is temporarily suspended, the patient exhibits one or more of the following: a hemoglobin level of 8 g / dL or more, a platelet count of 30,000 / μL or more, and / or a neutrophil count of 1×10 3 Dosing is resumed if the patient exhibits one or more of the following baseline levels: hemoglobin, platelets, or neutrophils / μL or more. In a further embodiment, if the dose of bischoline tetrathiomolybdate is temporarily suspended, dosing is resumed if the patient exhibits baseline levels of one or more of hemoglobin, platelets, or neutrophils.

[0071] Those skilled in the art will understand that this detailed description of liver function or bone marrow suppression tests is intended to be non-limiting. Other tests of liver function or bone marrow suppression can be performed. New tests of liver function or bone marrow suppression can be developed and used in place of the currently disclosed liver function tests.

[0072] In another aspect, the present disclosure further provides a method for reducing the daily dose of bischoline tetrathiomolybdate in patients exhibiting neurological deterioration. In one embodiment, neurological deterioration is assessed using UWDRS part III score. In one embodiment, baseline UWDRS part III is determined before administration of bischoline tetrathiomolybdate. In one embodiment, neurological deterioration is defined as an increase in UWDRS part III score above baseline of 1, 2, 3, 4, 5, 6, 7, or 8 points. In another embodiment, neurological deterioration is defined as an increase in UWDRS part III score above baseline of 4, 5, or 6. In another embodiment, neurological deterioration is defined as an increase in UWDRS part III score above baseline of 4 when baseline UWDRS part III is less than 20. In another embodiment, neurological deterioration is defined as an increase in UWDRS part III score above baseline of 6 when baseline UWDRS part III is 20 or more. In any aspect, the modification comprises discontinuing bischoline tetrathiomolybdate. In any aspect, the modification comprises administering a modified dose of bischoline tetrathiomolybdate after the patient no longer shows neurological deterioration. In certain aspects, the patient does not show neurological deterioration when the patient's UWDRS part III score is determined to be stable. In one embodiment, the modified dose is a reduced dose. In some embodiments, the modified dose is half the daily dose administered before the patient shows neurological deterioration. In other embodiments, the modified dose is less than the daily dose administered before the patient shows neurological deterioration, for example, 15 mg less than the daily dose administered before the patient shows neurological deterioration. In some embodiments, if the patient was on a 15 mg dose of bischoline tetrathiomolybdate once a day, 15 mg of bischoline tetrathiomolybdate every other day; if the patient was on a 30 mg dose of bischoline tetrathiomolybdate once a day, 15 mg of bischoline tetrathiomolybdate once a day; if the patient was on a 45 mg dose of bischoline tetrathiomolybdate once a day, 15 to 30 mg of bischoline tetrathiomolybdate once a day. If the patent was on bischoline tetrathiomolybdate at a dose of 60 mg once a day, it would be 30 mg of bischoline tetrathiomolybdate once a day; if the patent was on bischoline tetrathiomolybdate at a dose of 75 mg once a day, it would be 30 to 45 mg of bischoline tetrathiomolybdate once a day; or if the patent was on bischoline tetrathiomolybdate at a dose of 90 mg once a day, it would be 45 mg of bischoline tetrathiomolybdate once a day.

[0073] In some embodiments, the disclosure relates to increasing or decreasing the dose of bischoline tetrathiomolybdate in regular increments. In one embodiment, the method comprises administering to a patient a first dose level comprising about 15 to about 90 mg of bischoline tetrathiomolybdate per day for a period of time, followed by administration of a second dose level comprising at least about 15 mg less bischoline tetrathiomolybdate per day than the amount of bischoline tetrathiomolybdate in the first dose level for a second period of time. In one embodiment, the second dose level is 15 mg every other day. Dose level and daily dose may be used interchangeably. Dose level may include 1, 2, 3, 4, 5, or more doses given at different times or at the same time of day. A dose may optionally be one tablet or two tablets. Optionally, a dose may be provided as a tablet, capsule, or other pill. Optionally, a dose may be in liquid form.

[0074] In some embodiments, the first dose level is 15 mg, or 30 mg, or 45 mg, or 60 mg, or 75 mg, or 90 mg. In any aspect, the first dose level can be greater than 90 mg. In some embodiments, the second dose level is 15 mg, or 30 mg, or 45 mg, or 60 mg, or 75 mg, or 90 mg. In any aspect, the second dose level can be greater than 90 mg. One of skill in the art will appreciate that this recitation of dose levels is non-limiting. Optionally, the dose can be adjusted based on the subject's body weight. Optionally, the dose can be adjusted by measuring the bioavailability of the drug, such as by measuring the serum concentration of tetrathiomolybdate after administration of bischoline tetrathiomolybdate. Optionally, the dose can be adjusted by measuring the copper in the patient's serum. Optionally, the dose can be adjusted based on the NCC 補正 can be adjusted by measuring

[0075] In one embodiment, the first dose level is 90 mg and the second dose level is 15 mg. In one embodiment, the first dose level is 90 mg and the second dose level is 75 mg. In other embodiments, the first dose level is 90 mg, or 75 mg, or 6 In one embodiment, the second dose level is 15 mg less than the first dose level. In another embodiment, the second dose level is 30 mg less than the first dose level. In another embodiment, the treatment with bischoline tetrathiomolybdate is interrupted between the first dose level and the second dose level. In one embodiment, the treatment is interrupted after an abnormal test result. In one embodiment, the treatment with the second dose level is performed after the patient does not show abnormal test results.

[0076] In another aspect, the present disclosure provides a pharmaceutical composition for treating Wilson's disease in patients, comprising bischoline tetrathiomolybdate.The specific pharmaceutical composition of bischoline tetrathiomolybdate is provided by United States Patent No. 7,189,865, which is incorporated by reference in its entirety.Pharmaceutical compositions are generally described in Remington: The Science and Practice of Pharmacy, 22nd edition (2012).

[0077] In some embodiments, the pharmaceutical composition comprises bischoline tetrathiomolybdate and a second pharmacoactive ingredient. In one embodiment, the second pharmacoactive ingredient is zinc. Zinc can be provided as zinc acetate or zinc sulfite. In one embodiment, the second pharmacoactive ingredient is a tetrathiomolybdate salt other than a bischoline salt. Optionally, the second pharmacoactive ingredient is ammonium tetrathiomolybdate. In another embodiment, the second pharmacoactive ingredient is a copper chelator. In any embodiment, the second pharmacoactive ingredient is 2,3,2-tetramine or D-penicillamine.

[0078] In some embodiments, the disclosed compositions and methods relate to salts of tetrathiomolybdate other than the bischoline salt of tetrathiomolybdate.In some embodiments, the tetrathiomolybdate salt is a salt of tetrathiomolybdate and any pharma- ceutically acceptable counterion.Exemplary counterions include, but are not limited to, ammonium, choline, and acetylcholine.Counterions can be, for example, positively charged organic acids.Dosage is adjusted according to the molecular weight of the salt.

[0079] In another aspect, the present disclosure provides a kit for treating Wilson's disease, comprising at least three sets of pharmaceutical dosage units and instructions for use. In one embodiment, the kit comprises sufficient tablets for a 7-day or 30-day or 90-day course of treatment together with instructions for use. In one embodiment, the instructions for use indicate liver function and threshold tests for increasing or decreasing the number of pharmaceutical dosage units or subunits of pharmaceutical dosage units administered each day. In one embodiment, the kit further comprises zinc tablets. In one embodiment, the kit further comprises a copper chelator other than bischoline tetrathiomolybdate. In another aspect, the present disclosure provides a composition for use in any of the methods of the present disclosure. In another aspect, the present disclosure provides a composition for use in the manufacture of a medicament for use in any of the methods of the present disclosure.

[0080] For oral administration, the pharmaceutical compositions of the present disclosure may take the form of solid dosage forms, for example, tablets (both swallowable and chewable forms), capsules, or gelcaps, prepared by conventional means with pharma- ceutically acceptable excipients and carriers, such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.), fillers (e.g., lactose, microcrystalline cellulose, calcium phosphate, etc.), lubricants (e.g., magnesium stearate, talc, silica, etc.), disintegrants (e.g., potato starch, sodium starch glycolate, etc.), wetting agents (e.g., sodium lauryl sulfate), and the like. Such tablets may also be coated by methods well known in the art.

[0081] The dose to be administered will depend on the age, weight, and condition of the patient, as well as the route of administration, dosage form, and The dosage may be adjusted according to the regimen and desired outcome, hi some embodiments, the dose administered to a subject is titrated until a desired endpoint is reached.

[0082] The compositions described above may be administered in the dosage forms described above in single or divided doses from one to four times daily.

[0083] Dosage units, including tablets, capsules, and caplets of various sizes, can be prepared, for example, in total weights of about 2 to 10,000 mg, containing one or both of the active substances within the ranges mentioned above, the remainder being a physiologically acceptable carrier of the other substance according to accepted pharmaceutical practice. These tablets can of course be scored to provide smaller doses. Gelatin capsules can be similarly formulated.

[0084] In some embodiments, bischoline tetrathiomolybdate is provided in the form of a divisible dosage unit with the same dosage unit.For example, in some embodiments, a scored tablet can provide the dosage unit.Under the direction of a physician or other medical professional, a subject can be instructed to take one portion of a dosage unit, one portion providing the desired dosage level at a given interval.At the following intervals, a patient can be instructed to take two or more portions of a dosage unit, two or more portions providing the desired dosage level at that interval.

[0085] Liquid formulations can also be prepared by dissolving or suspending one or a combination of active agents in a conventional liquid vehicle acceptable for pharmaceutical administration to provide the desired dosage in 1 to 4 teaspoons.

[0086] Such dosage forms may be administered to the patient on a regimen of 1 to 4 times per day.

[0087] Certain aspects of the present disclosure are based on the surprising discovery that administration of bischoline tetrathiomolybdate in a fed state reduces absorption by 60% to 75% compared to administration of bischoline tetrathiomolybdate under fasting conditions. In one aspect of the present disclosure, bischoline tetrathiomolybdate is administered to a patient suffering from Wilson's disease in a fasting state. In other embodiments, bischoline tetrathiomolybdate is administered after an overnight fast. In yet other embodiments, bischoline tetrathiomolybdate is administered on an empty stomach after about 1, 2, 3, 4, 5, 6, 7, or 8 hours of fasting. In certain embodiments, bischoline tetrathiomolybdate is administered as an enteric coated formulation.

[0088] Any feature described herein (including any attached claims, abstracts, and drawings), and / or any step of any method disclosed in such a manner may be combined with any of the above-mentioned embodiments in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. In particular, any of the active agents and compositions described herein may be used in any of the described treatment methods. Any and all combinations are expressly contemplated as forming part of the present invention.

[0089] As used herein, the following terms shall have the following meanings:

[0090] "Bischoline tetrathiomolybdate" refers to the bischoline salt of tetrathiomolybdate or its pharmaceutical composition. Bischoline tetrathiomolybdate is also known as choline tetrathiomolybdate, or ATN-224, or WTX101, or WTX-101, or DECUPRATE (trademark). "WD" refers to Wilson's disease.

[0091] "QOD" or "quaque altera die" refers to administering a treatment every other day, e.g., a QOD of 15 mg is understood in the art to indicate administering a 15 mg dose every other day. "QD" or "quaque die" refers to administering a treatment once a day, e.g., a QD of 15 mg is understood in the art to indicate administering a 15 mg dose once a day. "SoC" refers to standard of care.

[0092] "Sequential test results" or "sequential abnormal test results" refer to two or more measurements of the same parameter taken at two different time points. In certain embodiments, the measurements are taken one week apart. In other embodiments, the measurements are taken two weeks apart.

[0093] "Non-ceruloplasmin-bound copper" or "NCC" refers to the concentration of free copper in serum. In plasma, copper is bound to ceruloplasmin or loosely bound to other plasma proteins, such as albumin or smaller circulating peptides. Loosely bound copper that is not bound to ceruloplasmin (i.e., non-ceruloplasmin-bound copper, or NCC) is sometimes referred to as "free" copper. In healthy situations (i.e., without Wilson's disease), generally more than 70% of total plasma copper is bound to ceruloplasmin. Due to Wilson's disease, ceruloplasmin-bound copper levels are typically low in Wilson's disease, which may explain the overall low total plasma copper levels observed in Wilson's disease patients. However, when free (i.e., non-ceruloplasmin-bound) copper is calculated by subtracting ceruloplasmin copper from the total serum copper level, it is found that this is usually elevated above the upper limit of normal (>15 mg / dL). In untreated Wilson's disease patients, NCC levels are typically greater than 25 μg / dL. To calculate NCC levels (μg / dL), ceruloplasmin (mg / dL) is multiplied by 3 and this value is then subtracted from total serum copper level (μg / dL).

[0094] "N.C.C. 補正 " or "NCC corr" refers to NCC corrected for copper in the tetrathiomolybdate-copper-albumin complex. NCC corr Exemplary methods for determining copper are provided in Weiss et al. Lancet Gastroenterol Hepatol. 2:869-876 (2017), which is incorporated in its entirety by reference herein. The mechanism of copper incorporation into ceruloplasmin is described in Hellman et al. J. Bio. Chem. 48:46632-38 (2002).

[0095] "Model for End-Stage Liver Disease" or "MELD" refers to a scoring system for assessing the severity of chronic liver disease. MELD uses a subject's serum bilirubin level, serum creatinine level, and the international normalized ratio (INR) of prothrombin time to predict survival. It is calculated according to the following formula: MELD = 3.78 x ln[serum bilirubin (mg / dL)] + 11.2 x ln[INR] + 9.57 x ln[serum creatinine (mg / dL)] + 6.43

[0096] The "modified Nazer score" refers to an assessment of liver status and consists of a combination of five laboratory parameters: aspartate aminotransferase, international normalized ratio, bilirubin, albumin, and white blood cell count. The score ranges from 0 to 20 in total, with lower values ​​indicating improvement.

[0097] "Fibrosis-4 Index / Transient Elastography" or "FIB-4 Index" refers to a formula used to predict liver fibrosis based on standard biochemical values ​​(ALT, aspartate aminotransferase, and platelet count) and age.

[0098] "Transient elastography" is a non-invasive imaging technique that uses a sonogram to assess the degree of hepatic fibrosis or fatty deposits in the liver by measuring the speed of sound waves passing through the liver. Point.

[0099] "Ceruloplasmin" refers to the ferroxidase enzyme, which in humans is encoded by the CP gene. Ceruloplasmin is the major copper-transporting protein in the blood and also plays a role in iron metabolism.

[0100] "Total copper and total molybdenum" or "total copper and total molybdenum analysis" refers to the measurement of the total copper and total molybdenum (Mo) concentrations in a patient's serum.

[0101] "Speciation profiling" refers to Mo, Cu, and protein complex profiling by size exclusion chromatography.

[0102] "Unified Wilson's Disease Rating Scale" or "UWDRS" refers to a clinical rating scale designed to assess the neurological symptoms of WD, which can be generally categorized into three movement disorder syndromes: a. dystonia, b. ataxia, and c. parkinsonism. The UWDRS consists of three parts: UWDRS Part I (consciousness, item 1), UWDRS Part II (history review of daily activities items [impairment], items 2-11), and UWDRS Part III (neurological examination, items 12-34). UWDRS Part I and Part III are typically assessed by a neurologist. UWDRS Part II is typically reported by the subject or a family member. The UWDRS is described in Czlonkowska A et al. Neurol Neurochir Pol 41:1-12 (2007), which is incorporated in its entirety into this disclosure.

[0103] "Clinical Global Impressions-Severity Scale" or "CGI-S" refers to a 7-point scale that requires clinicians to rate the severity of a subject's illness at the time of evaluation in comparison to their previous experience with subjects with the same diagnosis. Taking into account the total clinical experience, subjects are rated for severity of illness at the time of evaluation as follows: 1, normal, not ill at all; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.

[0104] The "Clinical Global Impression-Improvement Scale" or "CGI-I" refers to a 7-point scale that requires clinicians to rate how much the target illness has improved or worsened compared to the baseline state at the start of the intervention, rated as follows: 1, very improved; 2, greatly improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, greatly worse; or 7, very worse.

[0105] The "Brief Psychiatric Rating Scale-24" or "BPRS-24" refers to a 24-item instrument that allows assessors to measure the severity of psychiatric symptoms. The BPRS-24 assesses 24 psychiatric symptoms. The presence and severity of psychiatric symptoms are rated on a Likert scale ranging from 1 (absent) to 7 (extremely severe). The BPRS-24 can be administered by a trained physician.

[0106] "EuroQoL 5 Dimensions" or "EQ-5D" refers to a test consisting of the EQ-5D-5L descriptor system and the EQ visual analogue scale. The descriptor system consists of five dimensions (mobility, self-care, usual activities, pain / discomfort, anxiety / depression), each with five levels of severity (no problems / mild problems / moderate problems / severe problems / extreme problems). For a score in the EQ-5D-5L descriptor system, respondents are asked to indicate their health status by checking (or placing a cross) the most appropriate statement in each of the five dimensions. This decision results in a one-digit number representing the level chosen for that dimension. The five dimension digits are combined into a five-digit number describing the respondent's health status. It is possible to do so.

[0107] "Treatment Satisfaction Questionnaire for Medication-Based Therapy" or "TSQM-9" refers to a score used to assess the overall level of satisfaction or dissatisfaction of subjects receiving medication. This composite scale is composed of two items from the TSQM-9 survey: How satisfied are you with the good points of this medication that outweigh the bad points? All things considered, how satisfied or dissatisfied are you with this medication?

[0108] "Three most bothersome symptoms" refers to the subject's three most bothersome symptoms. Each subject, or subject and caregiver, will identify their three most bothersome symptoms, which will also be documented in written form as to the impact of these symptoms on activities of daily living. The three most bothersome symptoms will be recorded via videotape from consenting subjects, where feasible and appropriate.

[0109] "Timed 25F Walk Test" refers to a quantitative mobility and leg function performance test based on a timed 25 foot walk. Subjects are instructed to walk to one end of a clearly marked 25 foot course and walk 25 feet as quickly and safely as possible. Time is calculated from the beginning of the start command and ends when the subject reaches the 25 foot mark. The task is then immediately performed again by having the subject walk the same distance back. The score for the Timed 25F Walk Test is the average of the two trials. Subjects may use assistive devices when performing this task.

[0110] The "9-Hole Peg Test" or "9-HPT" refers to a brief, standardized, quantitative test of upper limb function. Both dominant and non-dominant hands are tested twice. The subject is seated at a table equipped with a small shallow container holding nine pegs and a wooden or plastic block with nine empty holes. At a starting command when a stopwatch is started, the subject picks up the nine pegs, one at a time, and places them in the nine holes, and once they are in the holes, removes them again, one at a time, as quickly as possible and places them back into the shallow container. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The score on the 9-HPT is the average of the four trials.

[0111] "Nonverbal Stroop interference test" refers to a valid measurement of executive function, planning, planning, application of knowledge, and decision-making abilities. In psychology, the Stroop effect is the demonstration of interference in the reaction time of a task. There is no verbal communication during this test. The test is taught with nonverbal instructions, using gestures and demonstrations.

[0112] "Digit Span Test" refers to a test measured for forward and reverse (backward) recall of digit sequences and digit span sequencing. Digit sequences are presented starting at a length of two digits, and two trials are presented at increasing enumeration lengths. The test ends when the subject is unable to accurately report trials at one sequence length or when the maximum enumeration length (9 digits, 8 backwards) is reached.

[0113] "Adverse event" refers to an untoward medical occurrence in a clinical investigational subject administered a medicinal product, not necessarily causally related to this treatment. Thus, an adverse event may be any untoward and / or unintended sign (including abnormal laboratory findings), symptoms, or disease that is temporally associated with the use of an investigational drug, whether or not related to the investigational drug. Clinically significant abnormal laboratory findings or other examination findings, including neurological examination findings, are reported as adverse events. A person skilled in the art exercises his or her medical and scientific judgment in determining whether an abnormal laboratory finding or other abnormal evaluation is clinically significant. An abnormal test determined to be an error need not be reported as an adverse event.

[0114] The severity of all adverse events will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE). These criteria can be found at http: / / ctep.cancer.gov / reporting / ctc.html. For adverse events not listed in the CTCAE, the following grading system will be used: Mild (CTCAE Grade 1): Transient symptoms, signs / symptoms that are easily tolerated and do not interfere with the subject's daily activities. Moderate (CTCAE Grade 2): Marked signs / symptoms that interfere with the subject's normal activities but are still tolerable. Severe (CTCAE Grade 3): Signs / symptoms that cause unacceptable and substantial interference with the subject's daily activities, preventing normal life. Life-threatening (CTCAE Grade 4): Life-threatening or disabling adverse event. Death (CTCAE Grade 5): Death-related adverse event.

[0115] "Adverse (drug) response" refers to any harmful and unintended reaction to a medicinal product associated with any dose, which is considered an adverse drug reaction. A "response" to a medicinal product means that a causal relationship between the medicinal product and the adverse event is at least reasonably possible, i.e., the relationship cannot be excluded.

[0116] "Unexpected Adverse Drug Reaction" refers to an adverse reaction, the nature or severity of which is inconsistent with the applicable product information.

[0117] "Pharmacological properties" refers to the need to consider the absorption, distribution, metabolism, and excretion of a drug.

[0118] "Adverse event of special interest" refers to any new neurological symptom or clinically significant worsening of an ongoing neurological symptom after initiation of study medication, whether serious or nonserious, to be designated as an AESI.

[0119] "Serious adverse event" refers to an adverse event or adverse response that results in any of the following: death or a life-threatening adverse event, hospitalization or prolongation of an ongoing hospitalization, permanent or significant disability / incapacity or substantial disruption of the ability to perform normal life functions, birth abnormality / birth defect, or a significant medical event.

[0120] An adverse event or side effect is considered "life-threatening" if, in the eyes of either the investigator or sponsor, its occurrence poses an immediate risk of death to the subject. It does not include events that, if occurring in a more severe form, could result in death.

[0121] A stay of at least 1 night is considered an inpatient hospitalization. Emergency room visits without hospitalization are not recorded as SAEs under this criterion, nor are scheduled or planned hospitalizations for procedures prior to signing informed consent. However, unexpected complications occurring during elective surgery and / or extended hospital stays should be recorded as adverse events and assessed for severity. Admission to a hospital for social or situational reasons (i.e., no place to stay, living too far away to travel to the hospital) is not considered an inpatient hospitalization.

[0122] Non-fatal, life-threatening, or significant medical events that require hospitalization may be considered SAEs if, based on appropriate medical judgment, they may endanger the subject and require medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm that requires intensive treatment in the emergency room or at home, poor circulation that does not result in inpatient hospitalization, convulsions, the development of drug dependency, etc.

[0123] "Medical history" refers to information regarding previous and current medications, previous and current diagnoses, conditions, and surgeries that qualify as significant tobacco, alcohol, or drug use.

[0124] "Clinical laboratory evaluation" or "clinical laboratory measurements" include chemistry, hematology, coagulation, and urinalysis (by microscopy).

[0125] "Electrocardiogram parameters" refers to heart rate, RR interval, PR interval, QRS width, and QT interval.

[0126] "Vital signs" refers to heart rate, blood pressure, respiratory rate, temperature, and weight.

[0127] "Physical examination" refers to evaluation of the general appearance, respiratory system, cardiovascular system, abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, and musculoskeletal (including spine and limbs) systems. The Unified Wilson Disease Assessment Scale Part III is the neurological examination used in this study.

[0128] The term "score" as used herein refers to the relative value, level, strength, or extent of an assay result. It can be created artificially by a person skilled in the art or using an algorithm, possibly using samples with known analytes, optionally using samples with known concentrations or titers of known analytes. It can be a number assigned manually by a person skilled in the art, or a number generated by a formula or algorithm. Also, symbols such as "-", "+", "++" can be used. Scores can be generated from calculations using a formula or algorithm, or assigned by visual inspection, measurement, or estimation of the assay results. When samples with known concentrations or titers of known analytes are used, such samples can be assayed in diluted and undiluted conditions to generate a range of scores or a standard curve of scores, which in some embodiments can be used in the same assay to assign or estimate the scores of unknown samples analyzed for the same analyte. EXAMPLES

[0129] Example 1: Bischoline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicenter, phase 2 trial. background Wilson's disease is an inherited disorder in which copper accumulates in the liver, brain, and other tissues. Treatment has been limited by efficacy, safety concerns, and multiple daily dosing. Bischoline tetrathiomolybdate (WTX101) is an orally administered, first-in-class copper protein-aggregating molecule that targets hepatic intracellular copper, reducing plasma nonceruloplasmin-bound copper (NCC) by forming a ternary complex with albumin and increasing copper excretion in the bile. The efficacy and safety of WTX101 were evaluated in patients with Wilson's disease as initial or early treatment.

[0130] method This open-label, phase 2 study was conducted at 11 hospitals in the United States and Europe. Patients (≥18 years of age) with Wilson's disease who were treatment-naïve or had not received treatment with chelators or zinc for >24 months, had a Leipzig score of ≥4, and had NCC concentrations above the lower limit of the normal reference range (≥0·8 μmol / L) were enrolled. Eligible patients received WTX101 monotherapy at a starting dose of 15–60 mg / day based on baseline NCC concentrations for the first 4–8 weeks, with response-guided individualized dosing for the remaining weeks up to 24 weeks. Investigators, other hospital personnel, and patients were blinded to the identity of the treatments. The primary endpoint was the survival of tetrathiomolybdate-copper-albumin complex (NCC) at 24 weeks. 補正 ) is the change in baseline NCC concentration corrected for copper, and treatment success is measured by the normalized NCC 補正 Achievement or maintenance of NCC (≤2·3 μmol / L [upper limit of normal]) or NCC from baseline at 24 weeks 補正 The primary endpoint was defined as achieving at least a 25% reduction in baseline serum glucose (GGT) levels. This study is registered with ClinicalTrials.gov, no. NCT02273596.

[0131] findings Twenty-eight patients were enrolled and received WTX101, with 22 (79%) patients completing the study up to week 24. At 24 weeks, 20 of 28 patients (71%, 95% CI 51·3 to 86·8; p < 0·0001) met criteria for treatment success, with 16 (57%) treated with WTX101 achieving or maintaining normalized NCC-corrected concentrations and 4 (14%) achieving at least a 25% reduction from baseline NCC correction. The mean NCC correction decreased by 72% from baseline to week 24 (least squares mean difference −2·4 μmol / L [SE 0·4], 95% CI −3·2 to −1·6; p < 0·0001). Surprisingly, no cases of paradoxical drug-related neurological deterioration were recorded. Liver function remained stable in all patients, but asymptomatic reversible increases in alanine, or aspartate aminotransferase, or gamma-glutamyltransferase concentrations, but not bilirubin, occurred in 11 (39%) of 28 patients who received at least 30 mg / day WTX101. Eleven serious adverse events were reported in seven patients (25%), including psychiatric disorders (six events in four patients), gait disturbance (one event), elevated hepatic aminotransferases (two events in two patients, one with agranulocytosis), and decline in neurological function (one event likely due to natural disease progression, although causal relationships could not be excluded). Seven serious adverse events classified as psychiatric disorders and gait disturbance were assessed as unlikely to be related to the study drug, whereas the remaining four events were possibly or probably related.

[0132] interpretation The results indicated that WTX101 may be a promising new therapeutic approach for Wilson's disease with a unique mechanism of action. Given its once-daily dosing and favorable safety profile, WTX101 may improve the treatment of patients with this debilitating condition.

[0133] introduction Wilson's disease is an autosomal recessive disorder of copper transport disorder leading to accumulation of copper in the liver, brain, and other tissues. The disease is caused by mutations in the ATP7B gene, which encodes a copper-transporting ATPase. Decreased ATP7B function reduces copper incorporation into ceruloplasmin and impairs excretion of copper in the bile. Wilson's disease affects approximately 1 in 30,000 individuals, but prevalence varies across populations and can be significantly underdiagnosed. Clinical manifestations vary widely and include forms of liver disease, neurological and psychiatric symptoms, and Kayser-Fleischer arcus. Abnormal laboratory findings include elevated concentrations of free nonceruloplasmin-bound copper (NCC) in plasma and low concentrations of circulating ceruloplasmin.

[0134] If left undiagnosed and untreated, Wilson's disease is universally fatal. Oral treatments approved decades ago to lower copper levels include chelating agents (penicillamine and trientine), which increase urinary excretion of copper or zinc and inhibit gastrointestinal copper absorption.

[0135] Few prospective studies have been conducted with these treatments, and there is a significant unmet need regarding efficacy, safety, and simplicity of dosing regimens. Furthermore, patients with neurological symptoms who begin treatment with penicillamine or trientine are at increased risk of developing neurological disease. This can be accompanied by paradoxical early deterioration, where new neurological signs appear rapidly or existing neurological signs worsen, leading to significant disability. In clinical studies, the percentage of neurological Wilson's disease patients affected by early deterioration after initiation of chelators ranges from 19% to 35%. Early neurological deterioration may be irreversible and may be due to rapid mobilization of free copper.

[0136] Bischoline tetrathiomolybdate (WTX101) is an oral, first-in-class copper protein-binding molecule under investigation as a once-daily monotherapy for Wilson's disease. The previous form of the drug, ammonium tetrathiomolybdate, rapidly controlled copper concentrations in clinical studies but was too unstable for routine use. The bischoline moiety represents a major advancement due to its improved stability, and unlike other available treatments, WTX101 appears to have direct intracellular activity in hepatocytes, binding excess copper and promoting copper excretion in the bile. WTX101 also rapidly binds copper in free plasma, forming a stable ternary complex of tetrathiomolybdate with copper and albumin.

[0137] method An open-label, phase 2 study was conducted at 11 hospitals. Eligible patients were aged 18 years or older and had a diagnosis of Wilson's disease with a Leipzig score of 4 or higher. At enrollment, patients had no previous treatment for Wilson's disease or had been treated with a chelator or zinc within 24 months and had NCC concentrations above the lower limit of the normal reference range (≥0·8 μmol / L). Patients with decompensated cirrhosis, a MELD score of 11 or a modified Nazer score of 6 or higher were excluded.

[0138] The protocol and all amendments were approved by the local Institutional Review Board and Ethics Committee. Study conduct was monitored by an independent Data and Safety Monitoring Board. All participants provided written informed consent in accordance with the Declaration of Helsinki.

[0139] The investigators, other hospital personnel, patients, and sponsors were aware of the identity of the treatments. Previously treated patients had a 48-h washout period before initiation of WTX101. Patients received a starting dose of 15–60 mg / day of WTX101 based on baseline NCC concentrations for the first 4–8 weeks, followed by response-guided individualized dosing for the remaining weeks of the 24-week period. Administration of WTX101 was initially twice daily, but an early protocol amendment implemented once-daily dosing (if deemed appropriate by the investigator).

[0140] Following elevated alanine aminotransferase (ALT) concentrations in a patient receiving 120 mg / day, the dose regimen was modified to reduce the maximum dose from 300 mg / day to 60 mg / day.

[0141] At the investigator's discretion, the dose of WTX101 could be adjusted in predefined increments based on various factors, including clinical chemistry and hematology, clinical evaluation, safety, and NCC concentration. Titration was gradual, with each increase limited to twice the previous dose, and was not allowed if NCC was within or below the normal range. The dose was temporarily reduced or discontinued after two consecutive reports of ALT or aspartate aminotransferase (AST) concentrations at least 2-5 times above the normal range, a 30% or greater decrease in baseline hemoglobin, or a 4-point or greater increase in neurological signs based on the Unified Wilson's Disease Rating Scale (UWDRS) Part III, an approved and validated quantitative neurological scoring system developed specifically for Wilson's disease.

[0142] Using the values ​​of plasma total copper concentration and ceruloplasmin concentration, NCC was calculated from total copper concentration to ceruloplasmin concentration. The NCC was calculated by subtracting the amount of copper bound to tetrathiomolybdate-copper-albumin complexes after WTX101 treatment, as this is not part of the reactive toxic copper pool. The NCC measurements were corrected by subtracting the amount of copper bound to tetrathiomolybdate-copper-albumin complexes after WTX101 treatment, as this is not part of the reactive toxic copper pool. The correction method used the average molar ratio of molybdenum to copper in the ternary complex, determined using the relationship between NCC and plasma molybdenum concentrations and confirmed by two independent methods. The NCC correction method was validated using random selection of test and validation samples.

[0143] The primary endpoint was NCC from baseline to 24 weeks. 補正 The change in the copper-tetrathiomolybdate complex (NCC 補正 The success of treatment was measured as NCC concentration corrected for copper in the sucrose solution. 補正 Achievement or maintenance of a normalized concentration of ≤2·3 μmol / L [upper limit of normal] or NCC from baseline at 24 weeks 補正 Clinical outcome was defined as achievement of at least a 25% reduction in

[0144] Secondary endpoints were NCC 補正Levels clinical neurological disease, liver function, clinical symptoms, health-related quality of life (HRQoL), mental status, pharmacokinetic and exchangeable copper, speciation profiling, safety and tolerability, changes and time to normalization of urinary copper. Mental status, pharmacokinetic data, and copper endpoints were also measured. Neurological disease was assessed as patient-reported impairment measured with the UWDRS part II and as trained assessor neurological status measured with the UWDRS part III. Liver synthetic function was assessed by monitoring the International Normalized Ratio (INR) and albumin concentrations. In addition, changes in liver function were assessed by the modified Nazer score (based on bilirubin, INR, AST, albumin, and white blood cell count) and, in post-hoc analyses, by the MELD score (based on bilirubin, creatinine, INR, and cause of liver disease). HRQoL was measured with the EuroQoL 5 Dimensions Visual Analogue Scale (EQ VAS).

[0145] Adverse event (AE) data were collected regarding onset, duration, severity, and severity in relation to the study drug as determined by the investigator.

[0146] The planned enrollment was 30 patients, with at least 15 patients expected to have received limited (≤90 days) prior treatment with chelators or zinc. No formal power calculations were performed, as the study objective was primarily to present descriptive statistics. Changes in copper concentrations and scores were summarized over time with descriptive statistics. A mixed-model repeated measures analysis with fixed-effect terms was applied at clinic visits, and a spatial power covariance structure was applied to model within-participant error. A spatial power covariance structure was chosen because we assume that within-participant correlations decay as the time distance between repeated measures increases. SAS (version 9.3) was utilized to provide least-squares means changes over time, as well as associated 95% CIs, SEs, and two-sided p-values.

[0147] Twenty-eight patients were enrolled and treated with WTX101, with 22 (79%) patients completing the study up to week 24 (Figure 1). At baseline, 15 (54%) patients were female and the mean age was 34·1 years (SD 11·86), ranging from 18 to 64 years. Nine (32%) patients had not received prior treatment for Wilson's disease. Nine (32%) patients had been treated for fewer than 28 days, and 10 (36%) patients had been treated for between 28 days and 2 years (median 100 days [range 7–714]). Most patients had neurological signs of varying severity at enrollment, with dysarthria (19 [68%]), postural tremor (18 [64%]), impaired hand coordination (18 [64%]), and abnormal gait (17 [61%]), with abnormal gait mainly caused by ataxia (12 [43%]) being the most common. The mean score for neurological abnormalities was 22.8 (SD 21.0; range 0–83), with only 3 (11%) patients scoring 0 (no neurological abnormalities). At baseline, 13 (46%) patients had cirrhosis based on medical history (7 patients) or estimate of AST-to-platelet ratio index (6 patients). Fourteen (50%) patients had 26 liver test abnormalities at study entry (12 ALT, 9 AST, 1 bilirubin, and 4 INR). Of these abnormalities, 24 were within 1–2 times the upper limit of normal and 2 were within 3–5 times the upper limit.

[0148] At week 24, or last dose for patients who discontinued early, the daily dose was 15 mg in 6 (21%) patients, 30 mg in 13 (46%) patients, and 60 mg in 9 (32%) patients. More than 80% of total WTX101 dosing in the study was once daily.

[0149] Treatment with WTX101 was 補正 was associated with rapid improvement in mean NCC 補正Concentrations fell below the upper limit of normal by week 12 (Figure 2). At 24 weeks, 20 of 28 patients (71%, 95% CI 51·3 to 86·8; p < 0·0001) had achieved treatment success, with 16 (57%) having normalised NCC. 補正 Four patients (14%) achieved or maintained NCC from baseline. 補正 decreased by at least 25%. Overall, the average NCC 補正 reduced by 72% from baseline to week 24 (least squares mean difference -2·4 μmol / L [SE 0·4], 95% CI -3·2 to -1·6; p<0·0001; Table 1, Figure 2). [Table 1] [Table 2]

[0150] Disease-related disability improved significantly after treatment with WTX101 (Table 1, Figure 3). Mean UWDRS part II score improved from 6 6 (SD 10 0) at baseline to 4 1 (8 2) at week 24 (Table 1, Figure 3A). UWDRS part II score improved by at least 1 point in 12 (57%) patients, remained unchanged in 9 (43%) patients, and no patient reported a worsening, except for one patient who discontinued treatment at 21 weeks due to further deterioration of pre-existing neurological disease.

[0151] The mean UWDRS part III score improved significantly from 22 8 (21 0) at baseline to 16 6 (17 7) at week 24 (Table 1, Figure 3B). The UWDRS part III score improved by 4 points or more at week 24 in 14 (67%) patients and remained stable (within 3 points of baseline) in 5 (24%) patients. A worsening of 5 points was present in 2 (10%) patients, one patient scored 19 at baseline with a fluctuation of 16 to 27 during the study, and a second patient scored 3 at baseline and 8 at weeks 18 to 24; these patients rated their disability as 0 throughout. In total, no cases of paradoxical neurological deterioration attributable to the study drug were recorded 12 weeks after initiation of treatment.

[0152] Although the improvements in INR and albumin from baseline to week 24 were statistically significant, they were numerically small, indicating stable liver function (Table 1). Liver status, as estimated by MELD and modified Nazer score, changed little throughout the study (Table 1).

[0153] Clinical improvement was reflected by a significantly increased mean EQ VAS score (Table 1).

[0154] Treatment with WTX101 was generally well tolerated, with most adverse events being of mild or moderate intensity (summarized in Table 2). Increased enzyme concentrations, primarily ALT, AST, or γ-glutamyltransferase, without concomitant increases in bilirubin, were recorded in 11 of 28 patients (39%) who received ≥30 mg / day WTX101. These increases usually occurred after 4–10 weeks, were mostly mild or moderate, all were asymptomatic, and normalized within 1–2 weeks after dose adjustment or treatment interruption for up to 6 weeks. The median peak ALT in these 11 patients was 197 U / L (range 101–1341), a 7·2-fold increase from baseline. Three patients (11%) with ALT increases of 14·3- to 29·3-fold from baseline discontinued treatment. A second high ALT signal (615 U / L) occurred in one of the first enrolled patients who received WTX101 at 120 mg / day. The per-protocol dose regimen was subsequently amended to reduce the maximum dose to 60 mg / day. The patient with the most prominent ALT signal (1341 U / L) received WTX101 at 30 mg / day and had previously had elevated ALT (peak 400 U / L) with penicillamine treatment before enrollment. In the three patients who discontinued the drug due to increased ALT concentrations, the abnormal results from liver tests were reversible and were not associated with a significant increase in bilirubin. [Table 3]

[0155] Treatment-emergent adverse events reported by the investigator in at least two patients and all treatment-emergent serious adverse events were listed. Patients may have had more than one adverse event or serious adverse event. Seven serious adverse events, classified as psychiatric and gait disorders, were assessed as unlikely to be related to the study drug, whereas the remaining four events were possibly or probably related. One patient reported adjustment disorder and recorded worsening of acute status disorder 6 weeks later (listed here as one serious adverse event). Another patient reported mania on two separate occasions within 3 weeks during the 24-week study (listed here as one serious adverse event). ALT refers to alanine aminotransferase. GGT refers to gamma-glutamyltransferase. AST = aspartate aminotransferase.

[0156] Two (7%) patients had leukopenia and one (4%) had thrombocytopenia reported as possibly, possibly, or definitely related to the study drug, but all resolved after dose adjustment. Few patients reported gastrointestinal or skin adverse events related to study treatment. There were almost none (Table 2).

[0157] Seven patients (25%) reported 11 serious adverse events: psychiatric disorders (six events in four patients), elevated hepatic aminotransferases (two events in two patients, one with agranulocytosis), gait disturbance (one event), and decreased neurological function (one event; Table 2). The psychiatric serious adverse events and gait disturbance were assessed as remote or unlikely to be related to the study drug because of symptoms of preexisting neurological or psychiatric illness, whereas the other four serious adverse events were possibly or likely to be related to treatment.

[0158] One previously treated patient who showed neurological deterioration before enrollment showed further neurological decline after week 12 despite study treatment and was discontinued at week 21, with a 3-point increase in UWDRS part II and an 11-point increase in UWDRS part III from baseline. Although causality could not be excluded, the neurological decline was assessed as probably due to natural disease progression. Investigators discontinued treatment in two (7%) patients because of psychiatric or behavioral symptoms that prevented them from following the protocol. These patients did not improve or change their UWDRS part III scores.

[0159] Discussion The results showed that WTX101 significantly reduced NCC after approximately three months. 補正 It induces rapid copper control with a reduction in copper levels, resulting in early and significant improvement in neurological symptoms and function in most patients. This study is the first multinational prospective trial conducted in patients with Wilson's disease, and aims to evaluate treatment with the new oral drug WTX101, which has significant advantages in administration and dosing.

[0160] Previously available treatments may take several years to show clinical improvement in patients with Wilson's disease. While liver function may normalize within 1-2 years of a previous treatment regimen in most patients with liver disease or compensated cirrhosis, symptom improvement in those with neurological disease may be slower and may not improve or resolve as quickly as liver function. Without being bound to any particular theory, the rapid biochemical and clinical improvement we observed with WTX101 may be associated with its novel copper-specific and direct hepatic mechanism of action, which reduces the concentration of toxic free copper in plasma. Treating patients with neurological symptoms has been particularly challenging because, even after years of chelation therapy, approximately half of patients with neurological disease at the time of presentation still have residual signs. Furthermore, paradoxical early neurological deterioration may be observed in patients with neurological Wilson's disease even after initiation of treatment with standard chelators, and neurological deficits may be irreversible in one-third to one-half of patients. A study by Litwin and colleagues observed early neurological deterioration in 12 of 42 (29%) patients with neurological Wilson's disease treated with penicillamine, with a mean of 2–3 months of neurological deterioration from the start. Litwin et al. Early neurological worsening in patients with Wilson's disease. J. Neurol Sci 355:162-67 (2015). Potentially, WTX101 binding to copper in inactive, large protein complexes that cannot be redistributed to the CNS could account for the apparent lack of early neurological deterioration within the first 12 weeks of treatment. One possibility is that previously treated patients may have received chelation therapy for a long enough period that they did not observe neurological deterioration with subsequent WTX101 treatment; however, no cases of early neurological deterioration have been documented in treatment-naive patients. One previously treated patient (zinc for <28 days) with neurological deterioration prior to enrollment had further neurological decline despite dose escalation due to an inadequate clinical response to WTX101, and study treatment was discontinued at week 21. We assessed the neurological decline as possibly due to natural disease progression, although a causal relationship could not be excluded.In addition to the patient who discontinued at week 21, two other participants discontinued treatment for neurological or psychiatric reasons. Treatment with TX101 was discontinued. Neurological, psychiatric, or both neurological and psychiatric symptoms occurred frequently in patients with Wilson's disease and were the cause of these two participants' failure to comply with study procedures. Pre-existing psychiatric illnesses also necessitated several hospital admissions during the study, which we documented as serious adverse events by definition. Indeed, 8 of the 11 reported serious adverse events were neurological or psychiatric in nature and occurred in 5 patients.

[0161] Composite liver function appeared stable with WTX101 over the 24-week study, as indicated by INR and albumin concentration results. This finding was observed in all patients, regardless of whether they had evidence of cirrhosis. Of note, reversible increases in liver function tests were observed in 39% of patients in the study, regardless of stage of liver disease. Increases occurred at 30 mg / day or higher 4–10 weeks after initiation and were mostly mild or moderate. All patients with elevations were asymptomatic with respect to liver disease. Results from liver function tests normalized within 1–2 weeks after dose adjustment or treatment interruption. Patients with increased liver function test results, including those who discontinued the drug, did not experience a significant increase in bilirubin, indicating the absence of severe drug-induced liver injury. Similar dose-dependent and early reversible increases in aminotransferases occurred in patients with Wilson's disease treated with ammonium tetrathiomolybdate, which also responded to dose reductions or treatment interruptions. However, in patients without liver disease or primary biliary cirrhosis, we did not report similar liver test abnormalities using tetrathiomolybdate, suggesting that the effects observed are specific to Wilson's disease. One mechanism by which liver enzyme levels increase in response to WTX101 treatment may be related to its copper-regulating activity, such as by removing copper from hepatic pools containing metallothionein, leading to a subsequent transient increase in hepatic aminotransferases. However, the exact mechanism remains to be elucidated.

[0162] Previously available treatments for Wilson's disease were subject to other potentially serious adverse events that frequently led to treatment interruptions and changes. In a retrospective study, 32% of patients using chelators and 11% using zinc discontinued treatment due to adverse events. Penicillamine is associated with early sensitivity reactions such as fever, rash, and various skin reactions, as well as late reactions such as lupus-like syndromes and nephrotoxicity. Gastrointestinal adverse events are frequently reported with zinc treatment, and 40% of children treated with zinc had gastrointestinal adverse events in a Polish cohort. Wiernicka et al.,Gastrointestinal side effects in children with Wilson's disease treated with zinc sulphate.World J Gastroenterol 19:4356-62(2013). In the study, two patients each reported nausea or dry skin considered related to study treatment, but these were generally mild or moderate and did not lead to discontinuation. Six patients discontinued study treatment. These interruptions reflect the chronic, life-limiting nature of symptomatic patients with Wilson's disease, with most enrolled patients exhibiting varying degrees of neurological or psychiatric symptoms that necessitated modifications to the initial medication regimen, an exploratory approach.

[0163] Previously available medications for Wilson's disease are prescribed in multiple daily doses, up to four times a day, and must be taken without food. Studies suggest that up to 45% of patients treated with current therapies have poor or problematic long-term adherence. Non-adherence to lifelong therapy can lead to recurrence of symptoms and progression of liver disease, or neurological or psychiatric symptoms, although time frames vary among individuals. WTX101 allows for once-daily oral dosing, which may lead to improved adherence to treatment and improved patient outcomes.

[0164] The sample size is sufficient for a phase 2 trial in an incurable disease, but relatively small when evaluating outcomes in a clinically heterogeneous disease. However, all results were consistent regardless of the assessment parameters applied, supporting the overall beneficial effect of WTX101 in the study population. Patients with decompensated liver disease with elevated MELD scores were excluded. Due to the enrollment difficulties associated with rare diseases, and because Wilson's disease is often treated very quickly after diagnosis, a mixed population of treatment-naïve and previously treated patients was necessary. The inclusion of this population in the study also allowed for the evaluation of the effect of WTX101 in patients who had previously received chelation therapy or zinc. The trial was uncontrolled and open-label. Although internal controls are desirable, this is not always feasible in early drug development for rare diseases. However, there were improvements in outcomes that are less susceptible to bias, including copper control and liver function. Although the trial duration was relatively short, an extension study is ongoing to further explore the long-term safety and efficacy of WTX101.

[0165] In conclusion, WTX101 treatment rapidly lowered free copper in patients with Wilson's disease, and this copper control was associated with reduced disability, improved neurological status, and stable liver function over 24 weeks. With dose adjustment, WTX101 demonstrated a good safety profile with a simple once-daily oral dosing regimen with no food effect. Thus, WTX101 has the potential to address several unmet clinical needs.

[0166] Example 2: Long-term efficacy and safety of WTX101 in Wilson's disease: Data from a continuing extension of a Phase 2 study. In Example 1, oral once-daily WTX101 monotherapy rapidly reduced and controlled NCC and improved disability and neurological status, without early drug-induced neurological deterioration and stabilization of liver function in patients with WD after 24 weeks. The 72-week efficacy and safety data from the ongoing extension period of the Phase 2 study represent the first prospective report of long-term disease management with WTX101 in WD.

[0167] Example 1 is an open-label, multicenter, single-arm, phase 2 trial conducted in 28 adults with an established WD diagnosis by a Leipzig score of ≥4. If included, NCC levels had to exceed the lower limit of the normal reference range (≥0.8 μM). Participants were either previously untreated for WD (n=9) or previously treated with chelation or zinc for ≤24 months (<28 days, n=9; 28 days to 2 years, n=10). Participants received WTX101 for 24 weeks using a response-guided dosing regimen with individualized doses between 15 and 120 mg / day based on NCC levels, clinical assessments, and safety criteria.

[0168] Data are (a) NCC levels corrected for bound copper in the tetrathiomolybdate-copper-albumin complex (NCC 補正 ), (b) hepatic status as measured using standard laboratory measurements and by the Model for End-Stage Liver Disease (MELD) score (based on bilirubin, creatinine, and International Normalized Ratio [INR]), (c) patient-reported disability using the Unified Wilson's Disease Rating Scale (UWDRS) part II and neurological status using UWDRS part III, and (d) safety parameters as shown below were collected from the first 72 weeks of the extension period.

[0169] At baseline in the core study, 46% of patients had cirrhosis based on medical history (n=7) or AST to platelet ratio index (n=6). At week 24 or when patients received their final dose with early discontinuation, the daily dose was 15 mg in 6 patients, 30 mg in 13 patients, and 60 mg in 9 patients. All 22 patients who completed the initial 24-week core study participated in the extension period described in this example.

[0170] Twenty patients completed treatment by 72 weeks. One patient discontinued treatment because she was hoping to become pregnant. Treatment was discontinued. One patient was unable to comply with study procedures due to a progressive disease course despite continuing treatment. [Table 4]

[0171] Unless otherwise stated, mean ± SEM Plasma free copper levels Mean (SEM) increase in NCC at baseline 補正 (3.6 [0.4] μM), was reduced at week 24 (0.9 [0.2] μM), and remained controlled at week 72 (0.5 [0.2] μM) (Figure 4).

[0172] Liver function Mean INR, albumin, ALT levels, and MELD scores appeared to improve or remain unchanged between weeks 24 and 72, indicating stability of liver function (Figure 5).

[0173] Reversible ALT elevations requiring dose adjustments, as observed in 39% of patients (>= 30 mg / day) at Week 24 (Example 1), were not observed with the extension.

[0174] Patients demonstrated continued improvement in mean UWDRS disability scores and neurological sign scores from week 24 to week 72 (Figure 6).

[0175] WTX101 was generally well tolerated over 72 weeks of treatment. Overall, the number of reported adverse events (AEs) and serious AEs (SAEs) decreased by approximately 50% from weeks 1–24 to weeks 25–72 (Figure 7, Table 4). Between weeks 24 and 72, 89% of AEs were mild or moderate, and 89% were considered unrelated or unlikely to be related to treatment.

[0176] Decreases in platelet (56%) and neutrophil (32%) counts were common at baseline, with similar reports throughout follow-up. Most occurrences were not accompanied by low NCC levels and are unlikely to reflect copper deficiency. Over the follow-up period, low hemoglobin was rare, with 5.2% of measurements below the normal range, and seven patients had low hemoglobin at some point, but not measurements below 100 g / L. Two subjects had evidence of mild anemia and neutropenia with low NCC levels, each potentially consistent with copper deficiency between weeks 36 and 72, and both responded rapidly to dose reduction. [Table 5]

[0177] Initial improvements in free copper levels, and hepatic and neurological status were maintained or even improved from 24 to 72 weeks with WTX101, indicating that once-daily WTX101 provides long-term disease control of WD. WTX101 is well tolerated beyond 24 weeks of treatment in patients with WD. These findings, together with its simple dosing regimen, Here we show that WTX101 addresses several unmet needs in the treatment of WD.

[0178] Example 3: A phase 3, randomized, assessor-blinded, multicenter study evaluating the efficacy and safety of WTX 101 administered for 48 weeks in patients with Wilson's disease aged 18 years or older with an extension period of up to 60 months. Summary of study design We conducted a randomized, assessor-blinded, multicenter study evaluating the efficacy and safety of individualized WTX101 dosing regimens administered for 48 weeks compared with SoC in subjects aged 18 years or older with WD.

[0179] Approximately 102 subjects will be enrolled at approximately 5-10 North American sites and 15-25 other sites worldwide.

[0180] Eligible subjects with WD who were receiving >28 days of SoC therapy (i.e., penicillamine or trientine chelation therapy, Zn therapy, or a combination of both chelation and Zn therapy) (Cohort 1), or who were untreated or receiving ≦28 days of SoC therapy (i.e., penicillamine or trientine chelation therapy, Zn therapy, or a combination of both chelation and Zn therapy) (Cohort 2), were randomized in a 2:1 ratio to treatment with WTX101 or SoC (as continuation therapy in Cohort 1, or as continuation or initial therapy in Cohort 2). Randomization was stratified by prior SoC therapy.

[0181] Subjects who met all inclusion criteria and no exclusion criteria were enrolled in the study and studied as outpatients. Previously treated subjects randomized to receive WTX101 must undergo a ≥ 48 hour washout of prior SoC therapy immediately prior to the initiation of treatment with WTX101. Eligible subjects randomized to WTX101 will receive WTX 101 as a delayed-release tablet for oral administration at doses ranging from 15 mg to 60 mg QD every other day (QOD). A maximum dose of up to 90 mg QD must be discussed and agreed upon with the medical monitor only if the following criteria are met: NCC 補正 > upper limit of normal (ULN), alanine aminotransferase (ALT) < 2 × ULN, and hematological parameters (hemoglobin, platelets, neutrophils) remain above the thresholds requiring dose modification according to Table 1. Efficacy and safety assessments will be performed at scheduled visits, while adverse events and concomitant medications will be continuously monitored throughout the study.

[0182] The visit scheme consisted of a screening visit, an enrolment visit, a treatment phase, and an end-of-study (EOS) (or early termination [ET]) visit. The visit schedule is summarised below:

[0183] The screening visit occurred within 28 days of the enrollment visit (Day 1). After the Day 1 visit, telephone assessments were conducted at weeks 1, 2, 30, and 42 (Days 8, 15, 211, and 295, respectively), followed by study visits at weeks 4, 6, 8, 12, 18, 24, 36, and 48 (Days 29, 43, 57, 85, 127, 169, 253, and 337, respectively).

[0184] Subjects who complete the 48-week treatment period will be offered the opportunity to participate in an extension phase of the study to evaluate the long-term safety and tolerability of the therapeutic effects of WTX101. If a subject does not choose to participate in this extension phase, he / she will be supported in transitioning to SoC for WD under the guidance of a local physician.

[0185] The EOS visit will occur at Week 52 (Day 365) only for subjects not entering the extension phase. For each subject not entering the extension phase, the main study phase will end approximately 52 weeks (approximately 365 days) after treatment initiation on Day 1 (48 weeks of treatment with an EOS visit 4 weeks after the last dose date). For each subject entering the extension phase, the main study phase will end approximately 48 weeks (Day 337) after treatment initiation on Day 1.

[0186] Dose Modifications for Individual Subjects Detailed criteria for temporary interruption of WTX101 dosing or restriction of dose escalation are detailed in Table 5. [Table 6] [Table 7] [Table 8] [Table 9]

[0187] Two consecutive results (i.e., obtained at two consecutive study visits) for a particular laboratory parameter or pre-specified parameters consistent with UWDRS Part III toxicity or exacerbation must be obtained in order for dose adjustment criteria to apply. Weekly repeat testing will continue until results return to baseline or within normal range limits. Testing will then be repeated two weeks later. If results remain at baseline or within normal range limits, then per-protocol schedule timing will be resumed.

[0188] Research period For each subject, the primary study period will end approximately 52 weeks (approximately 365 days) after initiation of treatment on Study Day 1 (48 weeks of treatment with an EOS visit 4 weeks after the last dose date if the subject does not enter the extension period). Subjects who complete the 48-week treatment period will be offered the opportunity to participate in an extension period to evaluate the long-term safety and efficacy of WTX101. If the subject does not choose to participate in this extension period, he / she will be supported in transitioning to SoC for WD under the guidance of a local physician.

[0189] Unscheduled visits may occur if additional clinical evaluation outside of the scheduled visits is deemed necessary by the investigator or if the subject meets dose adjustment criteria. Additionally, if there is overt neurological deterioration, as indicated by signs or symptoms of neurological deterioration, additional neurological evaluations will be performed at the investigator's discretion.

[0190] All subjects who complete 48 weeks of randomized treatment in WTX101-301 will be offered the opportunity to participate in an open-label extension phase of up to 60 months, in which they will receive WTX101 therapy. The purpose of the extension phase is to evaluate the tolerability and establish the long-term safety and efficacy of WTX101. Subjects are eligible to remain in the extension phase until WTX101 is commercially available in their respective countries.

[0191] treatment group Subjects will be treated with 15 mg QD to 60 mg QD of WTX101 or SoC therapy. Subjects will be randomized into one of two cohorts: Cohort 1 - subjects treated with >28 days of chelation or Zn therapy, or a combination of chelation and Zn therapy, or Cohort 2 - untreated or subjects treated with ≤28 days of prior chelation or Zn therapy, or a combination of both chelation and Zn therapy. The subject being investigated.

[0192] Rationale for Medication The dose of WTX101 will be adjusted in individual subjects as necessary based on the guidelines specified in the protocol. A detailed dosing guide for WTX101 dose modifications is outlined in Table 5.

[0193] The starting dose of WTX101 is 15 mg QD for all subjects. After 4 weeks, subsequent WTX101 dosing will be individualized. Dosing guidance will be based on clinical chemistry and hematology, clinical evaluation, safety, and NCC. 補正 Based on various factors including:

[0194] Dose escalation is permitted at the investigator's discretion, at 15 mg increments at least every 4 weeks if disease is not adequately controlled, and NCC / NCC 補正 No dose adjustment criteria will be applied, taking into account the subject's clinical condition and free blood Cu levels measured by. After dose escalation, subjects will be monitored for adverse events and laboratory evaluations every 2 weeks for a period of 4 weeks. If regular study visits are not scheduled during this period, home care nurses may complete these evaluations.

[0195] NCC 補正 If levels fall within the normal range (<2.3 μmol / L) and the subject's clinical condition is stable or improving on two consecutive assessments, the WTX101 dose may be maintained or reduced at the discretion of the principal investigator. To avoid overtreatment, if the subject's clinical condition indicates the possibility of overtreatment and / or NCC / NCC 補正If values ​​are below the normal range, the dose can be reduced at any time as directed by the principal investigator. However, NCC is not used as a criterion for dose adjustment. 補正 Use of ACE inhibitors is optional and reflects differing clinical practice across arms of the global study. If any of the dose adjustment criteria are met, the dose should be lowered or discontinued.

[0196] Study drug administration WTX101 will be provided as a tablet containing 15 mg bischoline tetrathiomolybdate for oral administration. WTX101 will be administered in doses ranging from 15 mg QOD to 60 mg QD. A maximum dose of up to 90 mg QD should be discussed and agreed with the medical monitor only if the following criteria are met: NCC correction is >ULN, ALT is <2×ULN, and hematological parameters (hemoglobin, platelets, neutrophils) remain above thresholds requiring dose modification according to Table 1.

[0197] WTX101 will be administered QD or QOD (taken in the morning) and in the fasted state (1 hour before or 2 hours after a meal) for a 48-week treatment period. Further details on WTX101 administration are included below.

[0198] Individualized WTX101 dosing will be utilized throughout the study based on the following parameters: Clinical Criteria: Dose titration based on hepatic and neurological status, NCC 補正 Dose titration indicated based on NCC levels adjusted for the amount of Cu bound to WTX101 TPC, and safety monitoring: dose adjustment criteria based on regularly scheduled evaluation of observed hematological effects of Cu reduction, liver studies, and neurological studies.

[0199] The WTX101 dose may also be reduced if adverse events occur requiring dose reduction. Dosing guidance related to specific events will be provided in the dose adjustment criteria (Table 5), and dose reductions for other events will be handled by the site's Principal Investigator (or Co-Investigator, if applicable) in coordination with the Medical Monitor, as appropriate.

[0200] In all subjects, WTX101 will be administered at a starting dose of 15 mg QD on day 1 and continued for the first 4 weeks. If the disease is not adequately controlled after 4 weeks, a titration escalation to 30 mg QD may be performed at the discretion of the principal investigator, taking into account the subject's clinical status and free blood Cu levels as measured by NCC / NCC correction, and no dose adjustment criteria will be applied. Further dose escalations are possible at the discretion of the principal investigator, in increments of 15 mg at least 4-week intervals, following the same criteria as above.

[0201] NCC 補正 If levels fall within the normal range (<2.3 μmol / L) and / or the subject's clinical condition is stable or improving on two consecutive assessments, the WTX101 dose may be maintained or reduced at the discretion of the principal investigator. To avoid overtreatment, if the subject's clinical condition indicates the possibility of overtreatment and / or NCC / NCC 補正 If values ​​are below the normal range, the dose can be reduced at any time as directed by the principal investigator. However, NCC is not used as a criterion for dose adjustment. 補正 Use of ACE inhibitors is optional and reflects differing clinical practice across arms of the global study. If any of the dose adjustment criteria are met, the dose should be lowered or discontinued.

[0202] The expected maximum dose is 60 mg QD, but higher doses may be considered as appropriate in conjunction with the medical monitor. A maximum dose of up to 90 mg QD should be discussed and agreed with the medical monitor only if the following criteria are met: NCC 補正>ULN, ALT <2×ULN, and hematological parameters (hemoglobin, platelets, neutrophils) remain above the thresholds requiring dose modification according to Table 5.

[0203] The accuracy of the measurements was subject to the following parameters: Estrogens may interfere with biliary Cu excretion. Vitamin E is used as an adjunct therapy in WD treatment regimens. Subjects should not use vitamins or minerals containing Cu, Zn, or Mo. Gadolinium and iodine-containing contrast agents are known to interfere with testing for Mo. Gadolinium and iodine-containing contrast agents were requested not to be used within 96 hours prior to Mo testing. Barium-containing contrast agents are known to interfere with testing for Cu. Barium-containing contrast agents were requested not to be used within 96 hours prior to Cu testing. Subjects should avoid foods and beverages high in Cu for the duration of the study.

[0204] After randomization and washout (if applicable), subjects will return for visits and treatment: Week 1-30 visits and Week 42 visits will occur within ±3 days of the scheduled time, and Week 36-48 visits will occur within ±7 days of the scheduled time.

[0205] Efficacy evaluation The primary efficacy assessment will be the control of free Cu, measured as the percent change in NCC levels from baseline (day 1) to week 48. For subjects treated with WTX101, NCC levels will be corrected for the amount of Cu bound to the WTX101 ternary complex (TPC).

[0206] Secondary efficacy assessments included: hepatic status using MELD score, disability using UWDRS part II, neurological status using UWDRS part III, clinical status using the Clinical Global Impression Scale (scale items 1 and 2), and NCC responder rate.

[0207] Tertiary efficacy assessments included: individualized assessment of each subject's three most bothersome symptoms, liver fibrosis using the FIB-4 index and transient elastography, corrected Na liver status using the zer score, psychiatric symptoms using the BPRS-24, and QoL / PRO endpoint measurements using the EQ-5D and TSQM-9. Exploratory efficacy assessments included:

[0208] Assessment of Cu control using exploratory measures of plasma total Cu, free Cu, PUF-Cu, and Cu speciation; assessment of Mo plasma levels; assessment of 24-h urinary Cu and urinary Mo; assessment of the Timed 25F Walk Test; assessment of the 9-HPT; assessment of the Non-Verbal Stroop Interference Test; and assessment of the Quantitative Span Test.

[0209] statistics All statistical analyses are performed according to art-recognized procedures. A general description of the statistical methods used to analyze efficacy and safety data is outlined below. Statistical analyses will be performed using SAS®, version 9.3 or later, SAS Institute, Cary, North Carolina, USA.

[0210] The primary endpoint was Cu control, assessed as the percentage change from baseline to 48 weeks in NCC levels; for subjects treated with WTX101, NCC levels were corrected for the amount of Cu bound to WTX101 TPC.

[0211] Percent change from baseline in NCC levels was analyzed using mixed model repeated measures (MMRM) analysis stratified by cohort and prior SoC treatment. Change from baseline at weeks 4, 8, 12, 24, 36, and 48 will be included. Restricted maximum likelihood estimation will be used. Models were stratified by cohort and prior SoC treatment. To better normalize the data, NCC may be log transformed prior to analysis. Fixed effect terms are included for randomized treatment (WTX101 or SoC), visit and randomized treatment by visit interaction, as well as baseline NCC level as covariates. Treatment by visit interaction will remain in the model regardless of significance. An unstructured covariance matrix will be used to model within-subject error, and the Kenward-Roger approximation will be used to estimate degrees of freedom. If the fit of the unstructured covariance structure does not converge, the following covariance structures will be tried in order until convergence is reached: Toeplitz with heterogeneity, autoregressive with heterogeneity, Toeplitz, and autoregressive. The primary contrast of interest is between subjects treated with WTX101 versus SoC at week 48. Model-based estimates, two-sided 95% confidence intervals (CIs), and p-values ​​of the difference between randomized treatments in the mean percent change in NCC levels at week 48 are provided. Non-inferiority is concluded in the overall study population for WTX101 relative to SoC if the low two-sided 95% CI excludes a difference of -15%, and superiority is concluded in the overall study population for WTX101 across SoC if the low two-sided 95% CI excludes a difference of 0%. Least squares (LS) extracts changes from baseline and associated standard errors (SE) at early time points (i.e., weeks 4, 8, 12, 24, and 36) and display graphically by arm over time.

[0212] The supportive analysis of the primary endpoint within cohort 1 mirrors that described for the overall population analysis, except that the analysis was not stratified for cohort.

[0213] Percent change from baseline in NCC levels was analyzed descriptively using MMRM analysis, with no formal statistical comparisons made between randomized treatment arms. Percent change from baseline at weeks 4, 8, 12, 24, 36, and 48 were estimated using the same model terms described in the analysis of Cohort 1 subjects. Primary outputs of interest were LS means, SEs, and p-values ​​for the percent change from baseline in NCC levels within each of the 48 weeks. Mean changes in LS within arms and SEs from early baseline time points (i.e., weeks 4, 8, 12, 24, and 36) were extracted and compared by arm over time. Each is displayed in a graph.

[0214] Secondary efficacy endpoints included: change from baseline in liver status at 48 weeks as assessed by MELD score, change from baseline to 48 weeks in UWDRS part II score, change from baseline to 48 weeks in UWDRS part III score, change from baseline to 48 weeks in CGI-I and CGI-S, and NCC responder rate at 48 weeks.

[0215] Secondary efficacy endpoints will be analyzed in the same manner as the primary endpoints via cohort-stratified MMRM analysis with a key contrast between SoC vs. WTX101-treated subjects at week 48. Supportive and comparative analyses will also be performed for Cohort 1 subjects, and within-arm supportive and descriptive analyses will be performed for Cohort 2 subjects. For endpoints b, c, and d, total scores will be analyzed.

[0216] The NCC response is NCC or NCC 補正 Achieve or maintain normalized levels of 0.8 μM-2.3 μM or NCC or NCC at 48 weeks 補正 The NCC level was defined as the proportion of subjects achieving at least a 25% reduction in NCC. For subjects treated with WTX101, NCC levels will be corrected for the amount of Cu bound to WTX101 TPC.

[0217] Subjects without 48-week values ​​will be considered non-responders. These data will be analyzed via cohort-stratified logistic regression with duration of randomized treatment and baseline NCC levels. Again, supportive and comparative analyses will be performed for cohort 1 subjects, and within-arm supportive and descriptive analyses will be performed for cohort 2 subjects.

[0218] Example 4: Absorption of bischoline tetrathiomolybdate following a single dose of enteric coated formulation with and without food and uncoated formulation co-administered with a proton pump inhibitor without food A single-center, open-label, randomized, three-period, three-treatment, six-sequence crossover study was conducted to evaluate the PK (pharmacokinetics) of a single dose of bischoline tetrathiomolybdate in healthy subjects based on measurements of plasma total Mo concentrations. As described in the study diagram shown in Figures 8A and 8B, 18 healthy nonsmokers using adult male and female subjects received treatment A, B, or C over a three-period course. Subjects received each treatment one time. Subjects were randomized into one of six treatment sequences: ABC, ACB, BAC, BCA, CAB, and CBA. All study medications were taken orally with approximately 240 mL of water. Subjects were instructed not to crush, split, or chew the study medication. Treatment A: 60 mg of bischoline tetrathiomolybdate (2x bischoline tetrathiomolybdate enteric coated (EC) tablets, 30 mg, see Table 6) at time 0 on day 1 after an overnight fast. Treatment B: 60 mg of bischoline tetrathiomolybdate (2x bischoline tetrathiomolybdate 1 EC tablet, 30 mg) at time 0 on day 1, preceded by an overnight fast and 30 minutes after the start of a high-fat breakfast. Treatment C: 20 mg omeprazole (1x 20 mg delayed-release capsule of PPI (proton pump inhibitor)) QD in the morning on days -5 to -1 after an overnight fast, 20 mg omeprazole delayed-release capsule at time -1 on day 1 after an overnight fast, and 60 mg bischoline tetrathiomolybdate (2x bischoline tetrathiomolybdate uncoated (UC) capsules, 30 mg, see Table 7) at time 0 on day 1. [Table 10] [Table 11]

[0219] All 18 subjects who enrolled and completed the study included safety and PK analyses. However, no measurable predose plasma total Mo concentrations were observed in the corresponding C max One subject was excluded from the PK descriptive statistics and statistical analyses for Treatment B due to >40% (maximum measured plasma concentration). Thus, the PK analysis population consisted of 18 subjects on the fasted EC tablet (Treatment A) and fasted UC+PPI (Treatment C) and 17 subjects on the fed EC tablet (Treatment B).

[0220] Pharmacokinetic Results PK parameters for plasma total Mo were calculated as follows: AUC 0-t : Area under the plasma concentration versus time curve from time 0 to the last measurable concentration, calculated by the linear trapezoidal method. AUC 0-inf : Area under the plasma concentration versus time curve from time 0 to infinity. AUC 0-inf is the AUC 0-t The elimination rate was calculated as the sum of the last measurable plasma concentration plus the ratio of the last measurable plasma concentration to the elimination rate constant. C max : The maximum measured plasma concentration over a specified span of time. t max t: Time of maximum measured plasma concentration. If maxima occur at multiple time points, t max was defined as the first time point with this value. λz: apparent first-order terminal elimination rate constant calculated from a semi-logarithmic plot of the plasma concentration versus time curve. The maximum number of points in the terminal log-linear phase (e.g., 3 or more nonzero plasma concentrations), starting from the last nonzero concentration, was used to calculate the parameter by linear least-squares regression analysis. t 1 / 2 The apparent first-order terminal elimination half-life was calculated to be 0.693 / λz. T lag Absorption delay time CL / F: apparent oral clearance Vz / F: Apparent oral volume of distribution

[0221] As shown in Figures 8A and 8B, the mean ± standard error plasma concentrations of total Mo were slightly lower following administration of the EC tablet in the fasted state (Treatment A) compared to the uncoated capsule (UC) + PPI in the fasted state (Treatment C). However, there was variability between subjects, with 3 of 18 showing much lower concentrations for the EC tablet, 5 showing the same pattern as the mean data, and 10 showing comparable or superimposable concentrations for both treatments.

[0222] Consistent with the mean plasma concentration, C max , AUC 0-t , and AUC inf The arithmetic (Table 8) and geometric (Table 7) means of T were lower for the fasted EC tablet (Treatment A) than for the fasted UC capsule + PPI (Treatment C). The GMRs ranged from 75.81% to 87.16%, with associated lower limits of 90% CIs of <80.00% (Table 9), indicating reduced exposure on average. max The median values ​​for were similar for both treatments at 4.54 and 4.50 hours, respectively, with comparable ranges (Table 8).

[0223] Four (4) of 18 subjects had an absorption lag time following administration of the EC tablet in the fasting state, with a median (range) of 2.00 hours (2.00 to 3.00 hours) (Table 8).

[0224] Administration of EC tablets with food (treatment B) resulted in a significant reduction in mean plasma total Mo concentrations (Figure 5). This was observed in all but 2 of the 17 evaluable subjects on this treatment. max , AUC 0-t , and AUC inf was lower after administration of the EC tablet with food (Tables 4 and 5), and the GMR ranged from 25.20% to 40.49%, indicating a significant decrease in absorption. max The median absorption lag time was comparable with 4.55 and 4.54 hours with and without food, respectively, with a comparable range (Table 8). Compared with the fasted EC tablet (Treatment A), more subjects (6 subjects) had an absorption lag time, with an increased median (range) of 3.00 hours (2.00-5.00 hours) (Table 8).

[0225] average t 1 / 2 was essentially the same for all three treatments (Table 8), with an overall average of approximately 48 hours or 2 days. CL / F and Vz / F were also similar for the two fasting treatments, but were higher in that treatment due to lower bioavailability following administration of the EC tablet in the fed state.

[0226] C max , AUC 0-t , and AUC inf The lowest between-subject coefficient of variation (BSCV) for was observed with UC capsule + PPI (treatment C) in the fasted state, with values ​​ranging from 15.8% to 19.1% (Table 8). Administration of the EC tablet in the fasted state (treatment A) resulted in higher BSCV ​​(26.1% to 35.2%; Table 8). When the EC tablet was administered after a high-calorie / high-fat meal, the BSCV ​​was much higher, especially for AUC 0-t and AUC inf The BSCV ​​for AUC was approximately 2.2-fold higher when the EC tablet was administered under fed conditions compared to the fasted EC tablet (Table 8).

[0227] As shown in Figures 8A and 8B, there was a small decrease in mean ± standard error plasma concentrations of total Mo after administration of the EC tablet (Treatment A) in the fasted state compared to UC+PPI (Treatment C) in the fasted state. max Similar trends were observed for AUC(0-t), AUC(inf) (Tables 6 and 7). Nevertheless, when examining individual subject data, while we observed similar patterns in some individual subjects, the majority had total Mo concentration time profiles that were comparable for bischoline tetrathiomolybdate EC tablets and bischoline tetrathiomolybdate UC+PPI when both were administered under fasting conditions. However, administration of bischoline tetrathiomolybdate EC tablets (Treatment B) in the fed state resulted in a 60%-75% decrease in absorption that was consistent among the majority of subjects. [Table 12] [Table 13] [Table 14]

[0228] Example 5: Neurological Improvement with WTX101 Treatment in a Phase 2, Multicenter, Open-Label Study of Wilson's Disease Data collected during the Phase 2 study described in Example 1 were further analyzed to characterize specific neurological changes following 24 weeks of treatment with WTX101.

[0229] method Adult patients with WD (untreated or on chelation or zinc therapy for ≤2 years) received response-guided individualized dosing of WTX101 (15-120 mg daily) for 24 weeks. Changes in neurological status were characterized using the Unified Wilson's Disease Rating Scale (UWDRS).

[0230] result Of the 28 patients enrolled, 25 had neurological symptoms. Baseline mean UWDRS part II (disability) and 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, the mean [SD] UWDRS part II score (4.1 [8.2]; p Both Part II and Part III scores (16.6 [17.7]; p < 0.0001) improved over time. There was a highly significant predictive relationship between Part II and Part III total scores over time (p < 0.0001). The most common UWDRS Part III abnormalities at baseline were postural arm tremor (71%), dysarthria (68%), gait (61%) and limb dexterity and coordination scale items, e.g., alternating hand movements (71%), finger tapping (57%), handwriting (54%), and leg agility (54%). The most severely affected items were handwriting and dysarthria (mean [SD] scores 2.0 [0.8] and 1.8 [0.9], respectively). The greatest mean improvements (% change) over 24 weeks were observed in handwriting (51.4%), leg dexterity (40.8%), postural arm tremor (39.5%), and alternating hand movements (35.0%). Grouping total tremor or limb dexterity and coordination items showed similar improvements (34.2% and 29.2%, respectively). WTX101 was generally well tolerated, and no early drug-induced neurological deterioration was observed.

[0231] conclusion Neurological symptoms were common in this cohort of patients with WD. WTX101 treatment rapidly improved disability and neurological status in a 24-week phase 2 prospective trial in WD. Improvement in neurological status after WTX101 treatment correlated with a reduction in patient-reported disability.

[0232] Example 6: Neurological Improvement with WTX101 Treatment in a Phase 2, Multicenter, Open-Label Study of Wilson's Disease The Phase 2 study of Example 1 was further analyzed to characterize the neurological symptoms in Wilson's disease (WD) patients and the specific neurological changes after 24 weeks of treatment with WTX101. Analysis of this data was generally performed as described in Example 5.

[0233] Neurological symptoms can be incapacitated very quickly, but previous existing treatments do not always alleviate symptoms, sometimes cause a notoriously paradoxical early worsening of the neurological disease, and / or are 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 (NCC) levels, and a favorable safety profile with mean NCC levels below the upper limit of normal by 12 weeks.

[0234] Analysis of neurological symptoms assessed using the Unified Wilson's Disease Rating Scale (UWDRS) showed symptomatic improvement without paradoxical early worsening. Changes in neurological symptoms in the study were probed using data from Part III (neurological status) of the UWDRS. Additionally, this example explores the quantitative relationship between patients' reported Wilson's disease (Part II) and clinically assessed (Part III) neurological symptoms.

[0235] method Adults (≥18 years) diagnosed with Wilson disease (Leipzig score of ≥4), who had not received prior treatment for Wilson disease or had received chelation or zinc therapy for ≤24 months, and had NCC concentrations above the lower limit of the normal reference range (i.e., ≥0.8 μmol / L). Patients were excluded if they had decompensated cirrhosis, a model for end-stage liver disease (MELD) score of >11, or a modified Nazer score (revised King's score) of >6.

[0236] A 24-week, phase 2, open-label study was conducted in Europe and the United States. During the first 4-8 weeks, patients were randomized to receive 100 mg of ... Patients received 15–60 mg of WTX101 once daily, depending on CC concentration, after which dosing was adjusted according to laboratory (including NCC concentration adjusted for plasma molybdenum) and clinical evaluations (maximum daily dose administered: 120 mg).

[0237] Disability and neurological status were assessed using UWDRS parts II and III, respectively, at baseline and at weeks 4, 8, 12, 18, and 24. Disability (part II): a 10-item patient-reported questionnaire (total score range: 0–40; higher scores indicate greater disability). Neurological status (part III): a 23-item clinician-rated score (total score range: 0–143; higher scores indicate worse neurological status). Data (UWDRS parts II and III total scores, as well as AEs) were briefly summarized for outcome status.

[0238] The relationship between disability and neurological status total scores was explored to better understand and quantify the impact of treatment on neurological symptoms in order to provide optimal treatment regimens while minimizing AEs. UWDRS neurological status scores for baseline, week 24, and change from baseline to week 24 were calculated for any individual item and for item groups (i.e., a collection of individual items that can be considered representative of a particular patient phenotype [Table 11]) experienced by at least 50% of patients. [Table 15]

[0239] Least squares means (standard error [SE], 95% confidence interval [CI]) values ​​were calculated for changes from baseline in UWDRS total scores using mixed-model repeated measures analyses, and significance was assessed using two-sided p-values. To explore and quantify the relationships between UWDRS total scores for parts II and III, random coefficient analyses were performed using each patient's scores from all study visits. Summary statistics were calculated for other outcomes.

[0240] result In total, 28 patients received WTX101 (Table 12). Six patients discontinued treatment: three experienced AEs of a non-neurological nature, two had psychiatric disorders and were unable to comply with the protocol, and one had neurological deterioration due to disease progression. [Table 16]

[0241] UWDRS Disability and Neurological Status: Total Score The mean (SD) total scores improved by 4.1 (8.2) for disability and 16.6 (17.7) for neurological status at week 24. Improvements were significant in both cases (least squares mean [SE, 95% CI] change from baseline), by -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 part III total scores (p<0.0001).

[0242] UWDRS Neurological Status: Individual Items and Item Groups Baseline Individual items: Of the six items affecting at least 50% of patients, postural arm tremor, rapid alternating hand movements, and dysarthria (voice) were the most common (Figure 9). Considering the maximum possible score difference between items (i.e., 4 or 8), handwriting and speech were the most severely affected (Figures 10A and 10B).

[0243] Item groups: Tremor was reported in the highest proportion of patients (23 patients, 82%), followed by gait (17 patients, 61%), dystonia (15 patients, 54%), agility and coordination of the limbs (15 patients, 54%), and rigidity (12 patients, 43%). Considering the maximum possible score differences between item groups (Table ​ (Table11),11), rigidity was the most severely affected (mean [standard deviation, SD] ​​score: 3.5 [2.9]), followed by tremor (7.4 [7.0]), dystonia (3.9 [4.4]), gait (4.4 [4.1]), and agility and coordination of the limbs (1.3 [0.5]).

[0244] Change from baseline to week 24 Individual items: Based on descriptive statistics, the mean percent improvement was greatest for handwriting and leg dexterity (Figures 11A and 11B), with fewer patients showing a worsening of any of the scores ( (Figure 12). Two patients had a 2-point deterioration (finger tap), all others had a 1-point deterioration.

[0245] Improvements in the group of items: tremor (mean [SD], 34.2% [61.7]) and limb agility and coordination (29.2% [72.2]) were generally similar to the improvements in the individual items. Of the 22 patients in the analysis, 5 showed a decrease in scores of 4 and 3, respectively (worsening by 1 point in 5 cases, 3 points in 1 case [tremor], and 4 points in 1 case [limb agility and coordination]). The overall deteriorations in stiffness (26.9% [169.6]), dystonia (15.0% [135.2]), and gait (4.2% [77.8]) were 4, 3, and 6, respectively, attributable to the individual (worsening between 1 and 8 points for stiffness, 2 and 4 points for dystonia, and 1 and 6 points for total gait).

[0246] conclusion Phase 2 studies have demonstrated that WTX101 treatment has the potential to address an important unmet need in Wilson's disease. Improvement in neurological status after WTX101 treatment correlated with a reduction in patient-reported disability. WTX101 was associated with reduced disability and improved neurological status and was well tolerated.

[0247] Example 7: Analysis of patients with and without cirrhosis Mortality in Wilson's disease is usually secondary to decompensated cirrhosis and liver failure, therefore liver function is an important factor in determining the appropriate treatment regimen. Results of patients with and without cirrhosis used in the patient pool of Example 1 were supplemented and analyzed with 48-week data generated in the 3-year extension phase of the initial trial. Example 1 was an open-label, single-arm, 24-week extension study using WTX101 at 15-60 mg / day initially, followed by response-guided individualized dosing (maximum dose of 120 mg / day). The extension phase was an open-label, single-arm, 3-year study using continued response-guided individualized dosing of WTX101 once daily.

[0248] In the analysis described in this example, patients were characterized as having cirrhosis based on medical history (biopsy or imaging) or estimate of the AST to platelet ratio index (APRI) (AST refers to aspartate aminotransferase). Summary statistics included baseline demographics, NCC 補正 Levels, ALT levels, MELD and modified Nazer scores, albumin concentration, International Normalized Ratio (INR), disability and neurological status using the Unified Wilson Disease Rating Scale, and adverse events (AEs) were calculated. Of the 15 patients with cirrhosis, 13 completed the core study, all of which are continuing in the extension study. Of the 13 patients without cirrhosis, 9 completed the core study, all of which are continuing in the extension study. Patient flow through the extension study is shown in Figure 12.

[0249] NCC at baseline 補正 The mean NCC score was 3.6 μmol / L in patients with cirrhosis and 3.7 μmol / L in patients without cirrhosis. WTX101 reduced NCC from baseline to 24 weeks in patients with and without cirrhosis. 補正 The improvement seen at 24 weeks was maintained through 48 weeks. NCC 補正 The levels are shown in FIG.

[0250] In the core study, ALT elevations requiring dose adjustment occurred in five patients with cirrhosis and seven patients without cirrhosis. ALT elevations were associated with study discontinuation in three patients without cirrhosis. ALT elevations during the core study were not accompanied by increases in bilirubin levels. From weeks 24 to 48, no ALT elevations requiring dose adjustment occurred, and ALT levels remained stable regardless of cirrhosis status. ALT levels in patients with and without cirrhosis are shown in Figure 14. MELD score (severity of liver disease; score range, The pulmonary circulation parameters were 6-40) (Figure 15) and modified Nazer score (prognostic index; score range, 0-20) (Figure 16) were low at baseline and stable through the core examination and at week 48.

[0251] Mean albumin concentration (Figure 17A) and international normalized ratio (INR) (Figure 17B) remained stable in the core study and through week 48 in patients with and without cirrhosis. Mean albumin concentration (Figure 17A) and blood clotting time (Figure 18) were within normal range at baseline. These remained stable in the core study and through week 48 in patients with and without cirrhosis. UWDRS is used to evaluate patient-reported disability and clinician-assessed neurological status. Improvements occurred during the core study and through week 48, regardless of cirrhosis status (Figures 19A and 19B). The tolerability profile of WTX101 was good and similar in patients with and without cirrhosis. Adverse events (AEs) occurred in 10 patients with cirrhosis and 12 patients without cirrhosis during the core study. The most common AEs were increased ALT and GGT levels (in three patients with cirrhosis and five patients without cirrhosis, respectively), increased AST levels (four patients in each group), and tremor (four patients without cirrhosis). Fewer patients experienced AEs during the extension phase compared to the core study (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 during weeks 0-48. During the extension phase, two patients in the cirrhosis group experienced SAEs possibly related to WTX101. One patient had neutropenia and one patient had hepatolenticular degeneration.

[0252] In this analysis, improved control of copper levels with WTX101 treatment compared to baseline was maintained from week 24 to week 48 of WTX101 treatment in both patient groups. With WTX101, liver function remained stable up to 48 weeks in patients with and without cirrhosis. The tolerability profile of WTX101 was good and was not affected by the presence of cirrhosis. Thus, WTX101 treatment remains effective and well tolerated regardless of whether treated patients had or did not have cirrhosis prior to treatment.

[0253] Those of skill in the art will understand that the particular thresholds disclosed herein may vary somewhat depending on the particular conditions of the test and assay method. Moreover, those of skill in the art will understand that a threshold value described as "greater than" or "less than" will, in certain embodiments, be "equal to or greater than" or "equal to or less than," respectively. Similarly, those of skill in the art will understand that a threshold value described as "greater than or equal to" or "less than or equal to" will, in certain embodiments, be "greater than" or "less than," respectively.

[0254] The foregoing detailed description has been given for clarity of understanding only, and no unnecessary limitations should be understood therefrom since modifications will be apparent to those skilled in the art.

[0255] While the invention has been described in relation to specific embodiments thereof, it is capable of further modifications, and it will be understood that this application is generally intended to cover any variations, uses, or adaptations of the invention in accordance with the principles of the disclosure, and includes such departures from the disclosure as are within known or customary practice in the art to which the invention pertains and as are applicable to the essential features set forth above and below within the scope of the appended claims.

[0256] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, reference to any references, articles, publications, patents, patent publications, and patent applications cited herein constitutes part of the common general knowledge in any country throughout the world. This disclosure is not, and should not be construed as, an admission that any of the present disclosure constitutes valid prior art or as any form of suggestion.

Claims

1. 1. A method of treating Wilson's disease in a patient in need of such treatment, comprising administering 15 mg of bischoline tetrathiomolybdate once daily.

2. 1. A method of treating Wilson's disease in a patient in need of such treatment, comprising administering 15 mg of bischoline tetrathiomolybdate once daily.

3. 3. The method of claim 1 or 2, wherein the 15 mg of bischoline tetrathiomolybdate is administered as a delayed release dosage form.

4. The method of claim 1 or 3, wherein the dosage form is a tablet or a capsule.

5. The method of claim 4 , wherein the dosage form is a tablet.

6. The patient's NCC when measured prior to administration 補正 NCC as measured after 24 weeks of treatment compared to 補正 The method of any one of claims 1 to 5, which exhibits a decrease in

7. The patient's NCC when measured prior to administration 補正 NCC as measured after 24 weeks of treatment compared to 補正 7. The method of claim 6, wherein the antibody exhibits at least a 20% reduction in

8. The patient's NCC when measured prior to administration 補正 NCC as measured after 24 weeks of treatment compared to 補正 7. The method of claim 6, wherein the antibody exhibits at least a 35% reduction in

9. The patient's NCC when measured prior to administration 補正 NCC as measured after 24 weeks of treatment compared to 補正 7. The method of claim 6, wherein the antibody exhibits at least a 50% reduction in

10. The patient's NCC when measured prior to administration 補正 NCC as measured after 24 weeks of treatment compared to 補正 7. The method of claim 6, wherein the antibody exhibits at least a 75% reduction in

11. The patient's NCC when measured prior to administration 補正 NCC as measured after 48 weeks of treatment compared to 補正 The method of any one of claims 1 to 5, which exhibits a decrease in

12. The patient's NCC when measured prior to administration 補正 NCC as measured after 48 weeks of treatment compared to 補正 The method of claim 11 , wherein the antibody exhibits at least a 20% reduction in

13. The patient's NCC when measured prior to administration 補正 NCC as measured after 48 weeks of treatment compared to 補正 12. The method of claim 11 , wherein the antibody exhibits at least a 35% reduction in

14. The patient's NCC when measured prior to administration 補正 NCC as measured after 48 weeks of treatment compared to 補正 The method of claim 11 , wherein the antibody exhibits at least a 50% reduction in

15. The patient's NCC when measured prior to administration 補正 Compared with 48 weeks of treatment NCC when measured after administration 補正 12. The method of claim 11 , wherein the antibody exhibits at least a 75% reduction in

16. 1. A method of treating Wilson's disease in a patient in need of such treatment, comprising administering 30-90 mg of bischoline tetrathiomolybdate daily, wherein the patient: a) NCC greater than 2.3 μm / L 補正 , b) alanine aminotransferase (ALT) levels less than 80 IU / mL; c) hemoglobin greater than 8 g / dL; d) greater than 30,000 platelets / μL; and e) 10 ３ / μL or greater neutrophils.

17. 17. The method of claim 16, comprising administering 30 mg of bischoline tetrathiomolybdate per day.

18. 17. The method of claim 16, comprising administering 45 mg of bischoline tetrathiomolybdate per day.

19. 17. The method of claim 16, comprising administering 60 mg of bischoline tetrathiomolybdate per day.

20. 17. The method of claim 16, comprising administering 75 mg of bischoline tetrathiomolybdate per day.

21. 17. The method of claim 16, comprising administering 90 mg of bischoline tetrathiomolybdate per day.

22. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient having Wilson's disease undergoing viscoline tetrathiomolybdate treatment, the patient exhibiting an alanine aminotransferase (ALT) level that is at least twice the ALT level exhibited when viscoline tetrathiomolybdate treatment is initiated, the method comprising: Reducing the bischoline tetrathiomolybdate dose, if said patient is on a dose of 15 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate every other day; if said patient is on a dose of 30 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate once daily; If the patent was on a 45 mg dose of bischoline tetrathiomolybdate once daily, reducing said dose to 30 mg of bischoline tetrathiomolybdate once daily; If the patent was on a dose of 60 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 45 mg of bischoline tetrathiomolybdate once daily; If the patent was for a dose of 75 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 60 mg of bischoline tetrathiomolybdate once daily; or If the patent was for a dose of 90 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 75 mg of bischoline tetrathiomolybdate once daily, comprising:

23. Bisphosphonate therapy for patients with Wilson's disease receiving bisphosphonate tetrathiomolybdate therapy 1. A method of modifying scholine tetrathiomolybdate administration, the method comprising the steps of: Reducing the bischoline tetrathiomolybdate dose, if said patient is on a dose of 15 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate every other day; if said patient is on a dose of 30 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate once daily; If the patent was on a 45 mg dose of bischoline tetrathiomolybdate once daily, reducing said dose to 30 mg of bischoline tetrathiomolybdate once daily; If the patent was on a dose of 60 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 45 mg of bischoline tetrathiomolybdate once daily; If the patent was for a dose of 75 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 60 mg of bischoline tetrathiomolybdate once daily; or If the patent was for a dose of 90 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 75 mg of bischoline tetrathiomolybdate once daily, comprising:

24. 24. The method of claim 23, wherein the ULN is 30-45 IU / mL.

25. 24. The method of claim 23, wherein the ULN is 34 IU / mL.

26. 24. The method of claim 23, wherein the ULN is 40 IU / mL.

25. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient having Wilson's disease undergoing viscoline tetrathiomolybdate treatment, said patient exhibiting a hemoglobin level that is 70% or less of the hemoglobin level exhibited when starting viscoline tetrathiomolybdate treatment, said method comprising: Reducing the bischoline tetrathiomolybdate dose, if said patient is on a dose of 15 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate every other day; if said patient is on a dose of 30 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate once daily; If the patent was on a 45 mg dose of bischoline tetrathiomolybdate once daily, reducing said dose to 30 mg of bischoline tetrathiomolybdate once daily; If the patent was on a dose of 60 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 45 mg of bischoline tetrathiomolybdate once daily; If the patent was for a dose of 75 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 60 mg of bischoline tetrathiomolybdate once daily; or If the patent was for a dose of 90 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 75 mg of bischoline tetrathiomolybdate once daily, comprising:

26. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient with Wilson's disease undergoing viscoline tetrathiomolybdate treatment, the patient exhibiting platelet levels that are 70% or less than the platelet levels exhibited when starting viscoline tetrathiomolybdate treatment, the method comprising: Reducing the bischoline tetrathiomolybdate dose, if said patient is on a dose of 15 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate every other day; if said patient is on a dose of 30 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate once daily; If the patent was on a 45 mg dose of bischoline tetrathiomolybdate once daily, reducing said dose to 30 mg of bischoline tetrathiomolybdate once daily; If the patent was on a dose of 60 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 45 mg of bischoline tetrathiomolybdate once daily; If the patent was for a dose of 75 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 60 mg of bischoline tetrathiomolybdate once daily; or If the patent was for a dose of 90 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 75 mg of bischoline tetrathiomolybdate once daily, comprising:

27. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient having Wilson's disease undergoing viscoline tetrathiomolybdate treatment, said patient exhibiting neutrophil levels that are 70% or less than the neutrophil levels exhibited when starting viscoline tetrathiomolybdate treatment, said method comprising: Reducing the bischoline tetrathiomolybdate dose, if said patient is on a dose of 15 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate every other day; if said patient is on a dose of 30 mg bischoline tetrathiomolybdate once daily, reducing said dose to 15 mg bischoline tetrathiomolybdate once daily; If the patent was on a 45 mg dose of bischoline tetrathiomolybdate once daily, reducing said dose to 30 mg of bischoline tetrathiomolybdate once daily; If the patent was on a dose of 60 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 45 mg of bischoline tetrathiomolybdate once daily; If the patent was for a dose of 75 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 60 mg of bischoline tetrathiomolybdate once daily; or If the patent was for a dose of 90 mg of bischoline tetrathiomolybdate once daily, reducing the dose to 75 mg of bischoline tetrathiomolybdate once daily, comprising:

28. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient with Wilson's disease undergoing viscoline tetrathiomolybdate treatment, the method comprising the steps of: and wherein the ALT level is greater than 5 times that observed at the start of the treatment, and the method further comprises: a) discontinuing bischoline tetrathiomolybdate; b) after the patient exhibits ALT levels less than twice the levels exhibited when bischoline tetrathiomolybdate treatment is initiated; administering 15 mg of bischoline tetrathiomolybdate every other day if the patient was on a dose of 15 mg of bischoline tetrathiomolybdate every other day prior to discontinuing bischoline tetrathiomolybdate; or If the patient was on a dose of 15-90 mg bischoline tetrathiomolybdate once daily prior to discontinuing the bischoline tetrathiomolybdate, administering 15 mg bischoline tetrathiomolybdate daily.

29. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient with Wilson's disease undergoing viscoline tetrathiomolybdate treatment, the patient exhibiting an alanine aminotransferase (ALT) level greater than 200 IU / mL, the method comprising: a) discontinuing bischoline tetrathiomolybdate; b) after the patient exhibits ALT levels less than twice the levels exhibited when bischoline tetrathiomolybdate treatment is initiated; administering 15 mg of bischoline tetrathiomolybdate every other day if the patient was on a dose of 15 mg of bischoline tetrathiomolybdate every other day prior to discontinuing bischoline tetrathiomolybdate; or If the patient was on a dose of 15-90 mg bischoline tetrathiomolybdate once daily prior to discontinuing the bischoline tetrathiomolybdate, administering 15 mg bischoline tetrathiomolybdate daily.

30. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient with Wilson's disease undergoing viscoline tetrathiomolybdate treatment, the patient exhibiting a hemoglobin level of less than 8 g / dL in the absence of bleeding, the method comprising: a) discontinuing bischoline tetrathiomolybdate; b) after said patient exhibits a hemoglobin level equivalent to that exhibited when starting bischoline tetrathiomolybdate treatment; administering 15 mg of bischoline tetrathiomolybdate every other day if the patient was on a dose of 15 mg of bischoline tetrathiomolybdate every other day prior to discontinuing bischoline tetrathiomolybdate; or If the patient was on a dose of 15-90 mg bischoline tetrathiomolybdate once daily prior to discontinuing the bischoline tetrathiomolybdate, administering 15 mg bischoline tetrathiomolybdate daily.

31. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient with Wilson's disease undergoing viscoline tetrathiomolybdate treatment, said patient exhibiting a platelet level of less than 30,000 μL, said method comprising: a) discontinuing bischoline tetrathiomolybdate; b) after said patient exhibits platelet levels equivalent to those exhibited when starting bischoline tetrathiomolybdate therapy; administering 15 mg of bischoline tetrathiomolybdate every other day if the patient was on a dose of 15 mg of bischoline tetrathiomolybdate every other day prior to discontinuing bischoline tetrathiomolybdate; or If the patient was on a dose of 15-90 mg bischoline tetrathiomolybdate once daily prior to discontinuing the bischoline tetrathiomolybdate, administering 15 mg bischoline tetrathiomolybdate daily.

32. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient with Wilson's disease undergoing viscoline tetrathiomolybdate treatment, comprising: ３ / μL, said method comprising: a) discontinuing bischoline tetrathiomolybdate; b) after said patient exhibits neutrophil levels equivalent to those exhibited when starting bischoline tetrathiomolybdate treatment; administering 15 mg of bischoline tetrathiomolybdate every other day if the patient was on a dose of 15 mg of bischoline tetrathiomolybdate every other day prior to discontinuing bischoline tetrathiomolybdate; or If the patient was on a dose of 15-90 mg bischoline tetrathiomolybdate once daily prior to discontinuing the bischoline tetrathiomolybdate, administering 15 mg bischoline tetrathiomolybdate daily.

33. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient with Wilson's disease undergoing viscoline tetrathiomolybdate treatment, the patient exhibiting a bilirubin level greater than 2.4 mg / dL and an alanine aminotransferase (ALT) level greater than 120 IU / mL, the method comprising: a) discontinuing bischoline tetrathiomolybdate; b) after the patient exhibits a bilirubin level below the upper limit of normal; administering 15 mg of bischoline tetrathiomolybdate every other day if the patient was on a dose of 15 mg of bischoline tetrathiomolybdate every other day prior to discontinuing bischoline tetrathiomolybdate; or If the patient was on a dose of 15-90 mg bischoline tetrathiomolybdate once daily prior to discontinuing the bischoline tetrathiomolybdate, administering 15 mg bischoline tetrathiomolybdate daily.

34. 1. A method of administering bischoline tetrathiomolybdate to treat a patient having Wilson's disease, said patient exhibiting abnormal test results, said method comprising: (a) administering to said patient a first dose level comprising about 15 to about 90 mg of bischoline tetrathiomolybdate per day for a first period of time; followed by (b) administering a second dose level comprising at least about 15 mg / day less bischoline tetrathiomolybdate per day than said first dose level for a second period of time.

35. 35. The method of claim 34, wherein the first dose level comprises about 15 mg of bischoline tetrathiomolybdate per day and the second dose level comprises less than about 15 mg of bischoline tetrathiomolybdate per two days.

36. 35. The method of claim 34, wherein the first dose level comprises about 30 mg of bischoline tetrathiomolybdate per day and the second dose level comprises less than about 15 mg of bischoline tetrathiomolybdate per day.

37. 35. The method of claim 34, wherein the first dose level comprises about 45 mg of bischoline tetrathiomolybdate per day and the second dose level comprises less than about 30 mg of bischoline tetrathiomolybdate per day.

38. 35. The method of claim 34, wherein the first dose level comprises about 60 mg of bischoline tetrathiomolybdate per day and the second dose level comprises less than about 45 mg of bischoline tetrathiomolybdate per day.

39. 35. The method of claim 34, wherein the first dose level comprises about 75 mg of bischoline tetrathiomolybdate per day and the second dose level comprises less than about 60 mg of bischoline tetrathiomolybdate per day.

40. 35. The method of claim 34, wherein the first dose level comprises about 90 mg of bischoline tetrathiomolybdate per day and the second dose level comprises less than about 75 mg of bischoline tetrathiomolybdate per day.

41. The method of any of claims 34-40, wherein the abnormal test result comprises an alanine aminotransferase (ALT) level that is at least twice the baseline ALT measured prior to administration of bischoline tetrathiomolybdate.

42. The method of any of claims 34-40, wherein the abnormal test result comprises a hemoglobin level that is 70% or less of the baseline hemoglobin level measured prior to administration of bischoline tetrathiomolybdate.

43. The method of any of claims 34-40, wherein the abnormal test result comprises a platelet level below 70% of the baseline platelet level measured prior to administration of bischoline tetrathiomolybdate.

44. The method of any of claims 34-40, wherein the abnormal test result comprises a neutrophil level that is 70% or less of the baseline neutrophil level measured prior to administration of bischoline tetrathiomolybdate.

45. 41. The method of any of claims 34-40, wherein the abnormal test result comprises an alanine aminotransferase (ALT) level greater than 68 IU / mL.

46. The method of any of claims 34-40, wherein the abnormal test result comprises a hemoglobin level below 70% of a normal hemoglobin level.

47. The method of any of claims 34-40, wherein the abnormal test result comprises a platelet level below 70% of the normal platelet level.

48. The method of any of claims 34-40, wherein the abnormal test result comprises a neutrophil level below 70% of a normal neutrophil level.

49. and wherein the abnormal test result comprises an alanine aminotransferase (ALT) level that is at least 5-fold higher than a baseline ALT level measured prior to administration of bischoline tetrathiomolybdate, and the method further comprises:

35. The method of claim 34, further comprising: (c) discontinuing treatment during a third period between steps (a) and (b) until the patient exhibits an alanine aminotransferase (ALT) level that is less than twice the baseline ALT level measured prior to administration of bischoline tetrathiomolybdate.

50. the abnormal test result comprises an alanine aminotransferase (ALT) level of at least 200 IU / mL, 35. The method of claim 34, further comprising: (c) discontinuing treatment during a third period between steps (a) and (b) until the patient exhibits an alanine aminotransferase (ALT) level of less than 68 IU / mL.

51. the abnormal test results include a hemoglobin level of less than 8 g / dL in the absence of bleeding; 35. The method of claim 34, wherein (c) the treatment is interrupted during a third period between steps (a) and (b) until the patient exhibits a hemoglobin level equivalent to the hemoglobin level measured before administration of bischoline tetrathiomolybdate.

52. The abnormal test result comprises a platelet level less than 30,000 μL, and the method further comprises:

35. The method of claim 34, further comprising: (c) discontinuing treatment during a third period between steps (a) and (b) until the patient exhibits platelet levels equivalent to the platelet levels measured prior to administration of bischoline tetrathiomolybdate.

53. the abnormal test results include a neutrophil level less than 1.0 x 103 / μL; 35. The method of claim 34, wherein (c) treatment is interrupted during a third period between steps (a) and (b) until the patient exhibits neutrophil levels equivalent to the neutrophil levels measured prior to administration of bischoline tetrathiomolybdate.

54. 54. The method of any of claims 49-53, wherein the second dose is 15 mg per day.

55. 54. The method of any of claims 49-53, wherein the second dose is 15 mg every other day.

56. The patient a) NCC 補正 level, b) alanine aminotransferase (ALT) levels; c) hemoglobin level; d) platelet levels, and The method of any of claims 6 to 55, further comprising measuring at least one of the following: e) neutrophil levels.

57. 1. A method of modifying viscoline tetrathiomolybdate administration to a patient with Wilson's disease undergoing viscoline tetrathiomolybdate treatment, said patient exhibiting neurological deterioration, said patient exhibiting a baseline UWDRS Part III score of less than 20 measured prior to viscoline tetrathiomolybdate administration, said neurological deterioration comprising an increase in baseline UWDRS Part III score of at least 4 points over said baseline UWDRS Part III score, said method comprising: a) discontinuing bischoline tetrathiomolybdate; b) after the patient no longer shows neurological deterioration; if the patient is on a 15 mg dose of bischoline tetrathiomolybdate once daily, administering 15 mg of bischoline tetrathiomolybdate every other day; if the patient is on a dose of 30 mg bischoline tetrathiomolybdate once daily, administering 15 mg bischoline tetrathiomolybdate once daily; administering 15 or 30 mg of bischoline tetrathiomolybdate once daily, where the patent was on bischoline tetrathiomolybdate at a dose of 45 mg once daily; Whereas the patent was on bischoline tetrathiomolybdate at a dose of 60 mg once daily, administering bischoline tetrathiomolybdate at a dose of 30 mg once daily; Whereas the patent was on bischoline tetrathiomolybdate at a dose of 75 mg once daily, administering bischoline tetrathiomolybdate at a dose of 30-45 mg once daily; or Whereas the patent was for a 90 mg dose of bischoline tetrathiomolybdate once daily, the method includes administering 45 mg of bischoline tetrathiomolybdate once daily.

58. 2. The method of claim 1, wherein bischoline tetrathiomolybdate is administered in the fasted state.

59. The method of claim 5, wherein the tablet is an enteric coated tablet.

60. The method of any one of claims 1 to 59, wherein the patient has cirrhosis.

61. The method of any one of claims 1 to 59, wherein the patient does not have cirrhosis.

62. 2. A composition comprising bischoline tetrathiomolybdate for use in a method of treating Wilson's disease in a patient.

63. 63. The composition for use according to claim 62, wherein said method comprises administering 15 mg to 120 mg of bischoline tetrathiomolybdate per day or every other day.

64. 64. A composition for use according to claim 62 or 63, wherein the method comprises administering bischoline tetrathiomolybdate once a day or once every other day.

65. 65. The composition for use according to any one of claims 62 to 64, wherein said patient exhibits one or more Wilson's Disease phenotypes selected from total tremor, total gait, dystonia, limb agility and coordination, and rigidity, preferably said patient exhibits total tremor, or limb agility and coordination, or both.

66. a) the total tremor phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from rest tremor, head tremor, arm-postural and flapping tremor, postural-leg, and jaw tremor; b) the total gait phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from chair rise, postural-truncal dystonia, stance ataxia, and parkinsonism, gait-leg dystonia, ataxia, and parkinsonism; c) the dystonia phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from palatomandibular dystonia, cervical dystonia, arm and hand dystonia, truncal dystonia, and gait-leg dystonia; d) the limb dexterity and coordination phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from finger tapping, rapid alternating hand movements, graphology, finger-nose test, and leg dexterity; 66. The composition for use of claim 65, wherein e) the stiffness phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from the arms, legs, and neck.

67. a) the total tremor phenotype is characterized by a UWDRS part III score of 30-45; b) the total walking phenotype is characterized by a UWDRS part III score of 20-32; c) the dystonia phenotype is characterized by a UWDRS part III score of 15-28; d) limb dexterity and coordination phenotype is characterized by a UWDRS part III score of 20-36; e) The composition for use according to claim 66, wherein the rigid phenotype is characterized by a UWDRS part III score of 10-20.

68. 68. The composition for use according to any one of claims 62 to 67, wherein the patient exhibits neurological symptoms of Wilson's Disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from handwriting, leg dexterity, and combinations thereof.

69. 69. The composition for use according to claim 68, wherein the patient exhibits a handwriting score according to the UWDRS part III of 2 to 4, a leg dexterity score according to the UWDRS part III of 2 to 8, or a handwriting and leg dexterity score according to the UWDRS part III of 4 to 12.

70. 70. The composition for use according to any one of claims 66 to 69, wherein the patient shows improvement in one or more neurological symptoms of Wilson's disease according to UWDRS part III following administration of the composition.

71. The patient, a) total tremor phenotype of 5-25; b) 5-20 total walking phenotypes; c) dystonia phenotypes 5-15; d) 5-20 limb agility and coordination phenotype; and e) a reduction in UWDRS part III score of one or more of the stiffness phenotypes from 5 to 15.

72. 71. The composition for use of claim 70, wherein the patient exhibits one or more of a reduction in UWDRS part III score for handwriting from 1 to 3, a reduction in UWDRS part III score for leg dexterity from 1 to 6, and a reduction in UWDRS part III score for handwriting and leg dexterity from 2 to 9.

73. The composition for use according to any one of claims 62 to 72, wherein the patient has cirrhosis of the liver.

74. The patient has a NCC measured prior to administration. 補正 NCC measured after 24 weeks of treatment compared to 補正 74. The composition for use according to claim 73, which exhibits a reduction in

75. The patient has a NCC measured prior to administration. 補正 NCC measured after 48 weeks of treatment compared with 補正 74. The composition for use according to claim 73, which exhibits a reduction in

76. The patient, a) NCC greater than 2.3 μm / L 補正 , b) alanine aminotransferase (ALT) levels less than 80 IU / mL; c) hemoglobin greater than 8 g / dL; d) greater than 30,000 platelets / μL; and e) 10 ３ 74. The composition for use of claim 73, having one or more of the following: neutrophils greater than 100 / μL.

77. 62. The method of any one of claims 1-61, wherein said patient exhibits one or more Wilson's Disease phenotypes selected from total tremor, total gait, dystonia, limb agility and coordination, and rigidity, preferably said patient exhibits total tremor, or limb agility and coordination, or both.

78. 78. The method of claim 77, wherein the patient exhibits a total tremor, or limb agility and coordination, or both.

79. a) the total tremor phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from rest tremor, head tremor, arm-postural and flapping tremor, postural-leg, and jaw tremor; b) the total gait phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from chair rise, postural-truncal dystonia, stance ataxia, and parkinsonism, gait-leg dystonia, ataxia, and parkinsonism; c) the dystonia phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from palatomandibular dystonia, cervical dystonia, arm and hand dystonia, truncal dystonia, and gait-leg dystonia; d) the limb dexterity and coordination phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from finger tapping, rapid alternating hand movements, graphology, finger-nose test, and leg dexterity; 80. The method of claim 77 or 78, wherein e) the stiffness phenotype comprises one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from the arms, legs, and neck.

80. a) the total tremor phenotype is characterized by a UWDRS part III score of 30-45; b) the total walking phenotype is characterized by a UWDRS part III score of 20-32; c) the dystonia phenotype is characterized by a UWDRS part III score of 15-28; d) limb dexterity and coordination phenotype is characterized by a UWDRS part III score of 20-36; e) The method of claim 79, wherein the rigid phenotype is characterized by a UWDRS part III score of 10-20.

81. 81. The method of claims 1-61 or 77-80, wherein the patient exhibits neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III selected from handwriting, leg dexterity, and combinations thereof.

82. 82. The method of claim 81, wherein the patient exhibits a handwriting score according to UWDRS part III of 2 to 4, a leg dexterity score according to UWDRS part III of 2 to 8, or a handwriting and leg dexterity score according to UWDRS part III of 4 to 12.

83. 81. The method of claims 1-61 or 77-80, wherein the patient exhibits improvement in one or more neurological symptoms of Wilson's disease according to UWDRS part III following administration of the composition.

84. The patient, a) total tremor phenotype of 5-25; b) 5-20 total walking phenotypes; c) dystonia phenotypes 5-15; d) 5-20 limb agility and coordination phenotype; and e) exhibiting a decrease in UWDRS part III score of one or more of the stiffness phenotypes from 5 to 15.

85. 84. The method of claim 83, wherein the patient exhibits one or more of a decrease in UWDRS part III score for handwriting from 1 to 3, a decrease in UWDRS part III score for leg dexterity from 1 to 6, and a decrease in UWDRS part III score for handwriting and leg dexterity from 2 to 9.

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