Viscoletetrathiomolybate for treating Wilson's disease

Abstract

The present invention provides a pharmaceutical composition for treating Wilson's disease that is effective in improving patient symptoms by improving Cu metabolism, reducing toxic free Cu, and maintaining normal Cu levels, without causing side effects. [Solution] A pharmaceutical composition for use in treating Wilson's disease in a patient requiring treatment is provided, wherein the pharmaceutical composition comprises biscolinetetrathiomolybdate, which is administered once daily in an amount of 15 mg as a delayed-release enteric-coated tablet, wherein a) the patient exhibits one or more Wilson's disease phenotypes selected from total tremor, total gait, dystonia, limb agility and coordination, and / or b) the patient has cirrhosis of the liver.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 594,184 filed on 4 December 2017, U.S. Provisional Application No. 62 / 646,553 filed on 22 March 2018, U.S. Provisional Application No. 62 / 655,568 filed on 10 April 2018, U.S. Provisional Application No. 62 / 669,095 filed on 9 May 2018, U.S. Provisional Application No. 62 / 741,313 filed on 4 October 2018, and U.S. Provisional Application No. 62 / 750,595 filed on 25 October 2018, each of which is incorporated herein by reference in whole 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 uptake of Cu 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 people, which corresponds to approximately 10,000 people in the United States and approximately 15,000 people in the European Union.

[0003] The typical clinical manifestations of WD occur in adolescence or early adulthood. Genetic screening and genotype-phenotype correlations are complicated by numerous associated ATP7B mutations, and most individuals with WD are compound heterozygotes. The initial signs and symptoms of WD are primarily hepatic (approximately 40%), neurological (approximately 40%), or psychiatric (approximately 20%), but patients often have a complex of hepatic disease and neuropsychiatric disorders. Patients who remain untreated or receive inadequate treatment have a 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 malignancies with severe malnutrition and neurological deterioration.

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

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

[0006] The treatment goal in WD is focused on compensating for impaired Cu efflux caused by ATPase2 deficiency. Current treatment for WD is general chelating therapy D-Pe Nishiramin (CUPRIMINE®, Valeant Pharmaceuticals, DEPEN®, Meda Pharmaceuticals) and trientine (SYPRINE®, Aton Pharma, Inc.) nonspecifically chelate Cu and promote urinary Cu excretion. In addition, zinc (Zn), which blocks food-based uptake of Cu, is mainly used in maintenance therapy. Zinc impairs Cu absorption by inducing methylmethyltransferase (MT) in the gastrointestinal (GI) tract.

[0007] Disease control in patients with neurological symptoms at the time of WD diagnosis is a particularly concerning area. More than one-third of patients with neurological symptoms do not show improvement after four years of treatment with chelating agents. This failure to respond to chelation therapy in patients with neurological symptoms may reflect irreversible damage to the nervous system. Furthermore, recent studies have shown that approximately 50% of patients retained neurological symptoms despite years of treatment with Cu modifiers. Worsening of neurological symptoms at the start 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 worsening is thought to be the mobilization of Cu from the liver, leading to elevated Cu levels in the blood and central nervous system activity causing neurological deterioration. This theory is supported by nonclinical data.

[0008] The drugs currently available to treat WD have high rates of discontinuation due to adverse events and treatment failure. Their adverse event profiles and complex drug 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 ammonium salt form has been shown to control Cu and improve liver function even after a single dose. The majority of clinical and nonclinical safety and toxicity studies of tetrathiomolybdate-based therapies have been conducted using ammonium as the cationic counterion.

[0010] The drug absorption of orally administered activators can be affected by food consumed before or after administration. Food can influence drug absorption through several mechanisms: by interacting with the activator or pharmaceutical formulation in the gastrointestinal tract, by stimulating bile flow, by altering gastrointestinal pH, by increasing visceral blood flow, or by delaying gastric emptying. Therefore, the bioavailability of an activator can be affected by food intake approximately two hours before or within one hour of administration.

[0011] Nevertheless, it is difficult to predict whether a particular activator or pharmaceutical formulation will exhibit a food effect. Furthermore, even if one does, the food effect on an activator or pharmaceutical formulation may result in an increase or decrease in bioavailability under feeding 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 certain dose causes a substantial increase or decrease in drug absorption compared to administration under fasting conditions), a pharmaceutical formulation administered under feeding conditions is not bioequivalent to the same pharmaceutical formulation administered under fasting conditions.

[0012] This lack of bioequivalence can lead to serious clinical consequences. For example, administering a pharmaceutical composition with food may provide dangerously high drug plasma levels of the activator, leading to clinical side effects. Alternatively, administering a pharmaceutical composition under fasting conditions may provide an effective dose, while administering the composition with food may provide drug plasma levels below therapeutic levels, rendering the supplied dose ineffective.

[0013] Therefore, to improve Cu metabolism without the side effects associated with currently available treatments, There is a need to develop effective treatments for Wilson's disease that reduce toxic free copper and maintain normal copper levels to improve patients' symptoms. [Overview of the project]

[0014] This disclosure relates to a method for treating Wilson's disease with biscolinetetrathiomolybdate therapy. In some embodiments, biscolinetetrathiomolybdate has the following structure: [ka]

[0015] In some embodiments, the disclosure relates to a method for treating Wilson's disease in a patient by administering 15 mg of biscolinetetrathiomolybdate once daily or once every day. In some embodiments, the disclosure relates to a method for treating Wilson's disease in a patient by administering 30 to 90 mg of biscolinetetrathiomolybdate daily. In further embodiments, the disclosure relates to a method for treating Wilson's disease in a patient by administering 30 to 90 mg of biscolinetetrathiomolybdate daily, wherein the patient has NCC greater than 2.3 μm / L 補正 alanine aminotransferase (ALT) levels less than 80 IU / mL, hemoglobin greater than 8 g / dL, platelets greater than 30,000 / μL, or 1,000 / μL or 1x10⁶ 3 It has one or more neutrophils with a volume greater than / μL.

[0016] In some embodiments, the disclosure relates to methods for modifying biscolinetetrathiomolybdate administration to patients with Wilson's disease receiving biscolinetetrathiomolybdate therapy by decreasing or increasing the daily dose of biscolinetetrathiomolybdate.

[0017] In one embodiment, the disclosure further provides a method for reducing 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 embodiment, the Disclosure provides a pharmaceutical composition comprising bischoline tetrathiomolybdate for the treatment of Wilson's disease in a patient. In another embodiment, the Disclosure provides a kit for the treatment of Wilson's disease comprising at least three sets of pharmaceutical dose units and instructions for use.

[0019] In another embodiment, the disclosure relates to a method for treating Wilson's disease in patients requiring treatment, comprising administering biscolinetetrathiomolybdate in a fasted state. In certain embodiments, biscolinetetrathiomolybdate is administered as an enteric-coated formulation.

[0020] In yet another aspect, the Disclosure relates to a method for treating Wilson's disease in a patient requiring treatment, comprising administering bischolinetetrathiomolybdate for approximately 24 weeks or more, approximately 36 weeks or more, approximately 48 weeks or more, approximately 60 weeks or more, approximately 72 weeks or more, approximately 84 weeks or more, approximately 92 weeks or more, approximately 120 weeks or more, approximately 132 weeks or more, or approximately 144 weeks or more.

[0021] In certain embodiments, this disclosure relates to a pharmaceutical composition comprising 15 mg of biscolinetetrathiomolybdate for use in treating Wilson's disease in patients requiring treatment. In certain embodiments, the pharmaceutical composition comprising 15 mg of biscolinetetrathiomolybdate is suitable for once-daily administration. In further embodiments, the pharmaceutical composition is suitable for once every other day administration. In further embodiments, the pharmaceutical composition is a delayed-release pharmaceutical composition. In further embodiments, the pharmaceutical composition is in the form of a tablet or capsule. In 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 NCC of the patient measured prior to administration, such as 20%, 35%, 50%, or 75% 補正 compared to the NCC measured after 24 weeks of administration 補正 shows a decrease, and the NCC of the patient measured prior to administration 補正 compared to the NCC measured after 24 weeks of administration 補正 shows a decrease.

[0023] In certain embodiments of the present disclosure, the NCC of the patient measured prior to administration, such as 20%, 35%, 50%, or 75% 補正 compared to the NCC measured after 48 weeks of administration 補正 shows a decrease, and the NCC of the patient measured prior to administration 補正 compared to the NCC measured after 48 weeks of administration 補正 shows a decrease.

[0024] In certain embodiments of the present disclosure, the NCC of the patient measured prior to administration, such as 20%, 35%, 50%, or 75% 補正 compared to the NCC measured after 72 weeks of administration 補正 shows a decrease, and the NCC of the patient measured prior to administration 補正 compared to the NCC measured after 72 weeks of administration 補正 shows a decrease.

[0025] In certain embodiments, regarding a pharmaceutical composition comprising bisucolinetetrathiomolybdate for treating Wilson's disease in a patient requiring treatment, 30, 45, 60, 75, or 90 mg of bisucolinetetrathiomolybdate is administered daily, and the patient has one or more of the following: a) NCC greater than 2.3 μm / L 補正 , ​​​​​​e) 10 3 Neutrophils larger than / μL

[0026] In certain embodiments, the Disclosure relates to a biscolinetetrathiomolybdate pharmaceutically active composition for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is reduced when the patient exhibits alanine aminotransferase (ALT) levels at least twice the ALT levels shown when biscolinetetrathiomolybdate therapy is initiated. In certain embodiments, if a patient is receiving a 15 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate every other day; if a patient is receiving a 30 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate once daily; if the patent is for a 45 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 30 mg of biscolinetetrathiomolybdate once daily; if the patent is for a 60 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 45 mg of biscolinetetrathiomolybdate once daily; if the patent is for a 75 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 60 mg of biscolinetetrathiomolybdate once daily; or if the patent is for a 90 mg dose once daily If the dosage is mg of biscolinetetrathiomolybdate, the dosage will be reduced to 75 mg of biscolinetetrathiomolybdate once daily.

[0027] In further embodiments, the disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in patients receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is reduced if the patient exhibits alanine aminotransferase (ALT) levels at least twice the upper limit of normal (ULN). In further embodiments, if the patient is on a 15 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate every other day; if the patient is on a 30 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate once daily; and if the patient is on a 45 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 30 mg of biscolinetetrathiomolybdate once daily. If the patent is for a dose of 60 mg of biscolinetetrathiomolybdate once daily, the dose is reduced to 45 mg of biscolinetetrathiomolybdate once daily; if the patent is for a dose of 75 mg of biscolinetetrathiomolybdate once daily, the dose is reduced to 60 mg of biscolinetetrathiomolybdate once daily; or if the patent is for a dose of 90 mg of biscolinetetrathiomolybdate once daily, the dose is reduced to 75 mg of biscolinetetrathiomolybdate once daily. In further embodiments, the ULN is 30-45 IU / mL. In more specific embodiments, the ULN is 34 IU / mL. In even more specific embodiments, the ULN is 40 IU / mL.

[0028] In certain embodiments, this disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is reduced if the patient's hemoglobin level is 70% or less of the hemoglobin level shown at the start of biscolinetetrathiomolybdate therapy. In certain embodiments, if the patient was on a 15 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate every other day; if the patient was on a 30 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate once daily; and if the patient was on a 45 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 30 mg of biscolinetetrathiomolybdate once daily. If the patent is for a dose of 60 mg of biscolinetetrathiomolybdate once daily, the dose will be reduced to 45 mg of biscolinetetrathiomolybdate once daily; if the patent is for a dose of 75 mg of biscolinetetrathiomolybdate once daily, the dose will be reduced to 60 mg of biscolinetetrathiomolybdate once daily; or if the patent is for a dose of 90 mg of biscolinetetrathiomolybdate once daily, the dose will be reduced to 75 mg of biscolinetetrathiomolybdate once daily.

[0029] In certain embodiments, this disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is reduced if the patient's platelet levels are 70% or less of the platelet levels indicated at the start of biscolinetetrathiomolybdate therapy. In certain embodiments, if the patient was on a 15 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate every other day; if the patient was on a 30 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate once daily; and the patent relates to a 45 mg dose of biscolinetetrathiomolybdate once daily. If the patent is for cholinetetrathiomolybdate, the dose is reduced to 30 mg of bischolinetetrathiomolybdate once daily; if the patent is for 60 mg of bischolinetetrathiomolybdate once daily, the dose is reduced to 45 mg of bischolinetetrathiomolybdate once daily; if the patent is for 75 mg of bischolinetetrathiomolybdate once daily, the dose is reduced to 60 mg of bischolinetetrathiomolybdate once daily; or if the patent is for 90 mg of bischolinetetrathiomolybdate once daily, the dose is reduced to 75 mg of bischolinetetrathiomolybdate once daily.

[0030] In certain embodiments, this disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is reduced if the patient's neutrophil levels are 70% or less of the neutrophil levels shown at the initiation of biscolinetetrathiomolybdate therapy. In certain embodiments, if the patient was on a 15 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate every other day; if the patient was on a 30 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 15 mg of biscolinetetrathiomolybdate once daily; and if the patient was on a 45 mg dose of biscolinetetrathiomolybdate once daily, the dose is reduced to 30 mg of biscolinetetrathiomolybdate once daily. If the patent is for a dose of 60 mg of biscolinetetrathiomolybdate once daily, the dose will be reduced to 45 mg of biscolinetetrathiomolybdate once daily; if the patent is for a dose of 75 mg of biscolinetetrathiomolybdate once daily, the dose will be reduced to 60 mg of biscolinetetrathiomolybdate once daily; or if the patent is for a dose of 90 mg of biscolinetetrathiomolybdate once daily, the dose will be reduced to 75 mg of biscolinetetrathiomolybdate once daily.

[0031] In certain embodiments, the Disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is interrupted if the patient shows an alanine aminotransferase (ALT) level greater than five times the ALT level shown at the start of biscolinetetrathiomolybdate therapy, and the patient shows an ALT level less than twice the level shown at the start of biscolinetetrathiomolybdate therapy, and the therapy is restarted with 15 mg of biscolinetetrathiomolybdate every other day if the patient was on 15 mg of biscolinetetrathiomolybdate every other day before the interruption of biscolinetetrathiomolybdate, or with 15 mg of biscolinetetrathiomolybdate daily if the patient was on 15-90 mg of biscolinetetrathiomolybdate once daily before the interruption of biscolinetetrathiomolybdate.

[0032] In certain embodiments, the Disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is discontinued if the patient has an alanine aminotransferase (ALT) level greater than 200 IU / mL and the patient has an ALT level less than twice the level shown when biscolinetetrathiomolybdate therapy is initiated, and the treatment is discontinued if, prior to discontinuing biscolinetetrathiomolybdate the patient was receiving 15 mg of biscolinetetrathiomolybdate every other day, or if, prior to discontinuing biscolinetetrathiomolybdate the patient was receiving 15-90 mg of biscolinetetrathiomolybdate once daily, the daily dose of biscolinetetrathiomolybdate is discontinued. The treatment will be resumed with tratiomolybdate.

[0033] In certain embodiments, the Disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is interrupted when the patient shows a hemoglobin level less than 8 g / dL and the patient shows a hemoglobin level equivalent to that shown when biscolinetetrathiomolybdate therapy was initiated, and the therapy is restarted with 15 mg of biscolinetetrathiomolybdate every other day if the patient was on 15 mg of biscolinetetrathiomolybdate every other day before the interruption of biscolinetetrathiomolybdate, or with 15 mg of biscolinetetrathiomolybdate daily if the patient was on 15-90 mg of biscolinetetrathiomolybdate once daily before the interruption of biscolinetetrathiomolybdate.

[0034] In certain embodiments, the Disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is discontinued when the patient exhibits platelet levels less than 30,000 μL and the patient exhibits platelet levels equivalent to those exhibited at the initiation of biscolinetetrathiomolybdate therapy, and the therapy is resumed with 15 mg of biscolinetetrathiomolybdate every other day if the patient was on 15 mg of biscolinetetrathiomolybdate every other day prior to discontinuing biscolinetetrathiomolybdate, or with 15 mg of biscolinetetrathiomolybdate daily if the patient was on 15-90 mg of biscolinetetrathiomolybdate once daily prior to discontinuing biscolinetetrathiomolybdate.

[0035] In certain embodiments, this disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is such that the patient's neutrophil levels are reduced to 1.0 × 10⁶ 3 If the neutrophil level is less than / μL and the patient's neutrophil level is equivalent to that shown when biscolinetetrathiomolybdate treatment is initiated, treatment is discontinued and restarted with 15 mg of biscolinetetrathiomolybdate every other day if the patient was on 15 mg of biscolinetetrathiomolybdate every other day prior to discontinuing biscolinetetrathiomolybdate, or with 15 mg of biscolinetetrathiomolybdate once daily if the patient was on 15-90 mg of biscolinetetrathiomolybdate once daily prior to discontinuing biscolinetetrathiomolybdate.

[0036] In certain embodiments, the Disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is interrupted if the patient shows bilirubin levels greater than 2.4 mg / dL and alanine aminotransferase (ALT) levels greater than 120 IU / mL, and the patient shows bilirubin levels below the upper limit of normal, and treatment is restarted with 15 mg of biscolinetetrathiomolybdate every other day if the patient was on 15 mg of biscolinetetrathiomolybdate every other day before interrupting biscolinetetrathiomolybdate, or with 15 mg of biscolinetetrathiomolybdate once daily if the patient was on 15-90 mg of biscolinetetrathiomolybdate once daily before interrupting biscolinetetrathiomolybdate.

[0037] In certain embodiments, the Disclosure relates to a pharmaceutically acceptable composition of biscolinetetrathiomolybdate for use in treating Wilson's disease in a patient receiving biscolinetetrathiomolybdate therapy, wherein the daily dose of biscolinetetrathiomolybdate is such that the patient receives biscolinetetrathiomolybdate. If a patient exhibits bilirubin levels greater than twice the upper limit of normal for lirubin and alanine aminotransferase (ALT) levels greater than three times the ULN for ALT, and the patient exhibits bilirubin levels below the upper limit of normal, treatment is discontinued and restarted with 15 mg of biscolinetetrathiomolybdate every other day if the patient was on 15 mg of biscolinetetrathiomolybdate every other day prior to discontinuing biscolinetetrathiomolybdate, or with 15 mg of biscolinetetrathiomolybdate once daily if the patient was on 15-90 mg of biscolinetetrathiomolybdate once daily prior to discontinuing biscolinetetrathiomolybdate.

[0038] In certain embodiments, this disclosure provides compositions comprising biscoline tetrathiomolybdate for use in a method of 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 intended for use in any of the methods disclosed herein. In some embodiments, the patient is defined as disclosed herein.

[0039] In certain embodiments, this disclosure relates to a pharmaceutical composition of biscoline tetrathiomolybdate for use in the treatment of Wilson's disease, wherein the composition is administered under fasting conditions. In further embodiments, the pharmaceutical composition comprises 15 mg of biscoline tetrathiomolybdate. In even further embodiments, the pharmaceutical composition is an enteric-coated tablet.

[0040] In certain embodiments, the present disclosure relates to the above method for treating Wilson's disease, comprising administering biscolinetetrathiomolybdate to a patient having Wilson's disease, and modifying biscolinetetrathiomolybdate 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 method for treating Wilson's disease, comprising administering biscolinetetrathiomolybdate to a patient having Wilson's disease and modifying biscolinetetrathiomolybdate to a patient having Wilson's disease, wherein the patient does not have cirrhosis.

[0042] In certain embodiments, the present disclosure relates to the above method for treating Wilson's disease, comprising administering biscolinetetrathiomolybdate to a patient having Wilson's disease and modifying biscolinetetrathiomolybdate to a patient having 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 further embodiments, a) the total tremor phenotype includes one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III, selected from resting tremor, head tremor, arm-postural tremor and flapping tremor, postural-leg tremor, and jaw tremor; b) the total gait phenotype includes one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III, selected from getting up from a chair, postural-trunk dystonia, ataxia of stance, and parkinsonism; and c) the dystonia phenotype includes palatal-mandibular dystonia, cervical dystonia d) having one or more neurological symptoms of Wilson's disease, selected from stonia, arm and hand dystonia, trunk dystonia, and gait-leg dystonia, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III; e) having one or more neurological symptoms of Wilson's disease, selected from finger tapping, rapid alternating hand movements, handwriting, finger-to-nose test, and leg agility, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III; and e) having one or more neurological symptoms of Wilson's disease, selected from arms, legs, and neck.

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

[0044] In certain embodiments, the present disclosure relates to the above method for treating Wilson's disease, comprising administering bischolinetetrathiomolybdate to a patient having Wilson's disease and modifying bischolinetetrathiomolybdate to a patient having Wilson's disease, 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 agility, and combinations thereof. In further embodiments, the patient exhibits a handwriting score of 2–4 according to UWDRS Part III, a leg agility score of 2–8 according to UWDRS Part III, or a handwriting and leg agility score of 4–12 according to UWDRS Part III. In further embodiments, the patient exhibits improvement in one or more neurological symptoms of Wilson's disease according to UWDRS Part III after administration of the composition. In further embodiments, the patient shows a reduction in one or more UWDRS Part III scores from a) total tremor phenotype 5–25, b) total gait phenotype 5–20, c) dystonia phenotype 5–15, d) limb agility and coordination phenotype 5–20, and e) rigidity phenotype 5–15.

[0045] In yet another embodiment, the patient exhibits one or more of the following: a decrease in UWDRS Part III scores for handwriting 1–3, a decrease in UWDRS Part III scores for leg agility 1–6, and a decrease in UWDRS Part III scores for handwriting and leg agility 2–9.

[0046] In certain embodiments, the Disclosure provides compositions 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 further embodiments, a) the total tremor phenotype includes one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III, selected from resting tremor, head tremor, arm-postural tremor and flapping tremor, postural-leg tremor, and jaw tremor; b) the total gait phenotype includes one or more neurological symptoms of Wilson's disease according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III, selected from getting up from a chair, postural-trunk dystonia, ataxia of stance, and parkinsonism; and c) the dystonia phenotype includes palatal-mandibular dystonia, cervical dystonia d) having one or more neurological symptoms of Wilson's disease, selected from stonia, arm and hand dystonia, trunk dystonia, and gait-leg dystonia, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III; e) having one or more neurological symptoms of Wilson's disease, selected from finger tapping, rapid alternating hand movements, handwriting, finger-to-nose test, and leg agility, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III; and e) having one or more neurological symptoms of Wilson's disease, selected from arms, legs, and neck.

[0047] In 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, and c) the dystonia phenotype is characterized by a UWDRS Part III score of 15-28. Characterized by the III score, d) limb agility and coordination phenotypes are characterized by a UWDRS Part III score of 20–36, and e) rigidity phenotypes are characterized by a UWDRS Part III score of 10–20.

[0048] In certain embodiments, the Disclosure provides compositions described herein for use in treating Wilson's disease, 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 agility, and combinations thereof. In further embodiments, the patient exhibits a handwriting score of 2–4 according to UWDRS Part III, a leg agility score of 2–8 according to UWDRS Part III, or a handwriting and leg agility score of 4–12 according to UWDRS Part III. In further embodiments, the patient exhibits improvement in one or more neurological symptoms of Wilson's disease according to UWDRS Part III after administration of the composition. In further embodiments, the patient exhibits a reduction in one or more UWDRS Part III scores from a) total tremor phenotype 5–25, b) total gait phenotype 5–20, c) dystonia phenotype 5–15, d) limb agility and coordination phenotype 5–20, and e) rigidity phenotype 5–15.

[0049] In yet another embodiment, the patient exhibits one or more of the following: a decrease in UWDRS Part III scores for handwriting 1–3, a decrease in UWDRS Part III scores for leg agility 1–6, and a decrease in UWDRS Part III scores for handwriting and leg agility 2–9.

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

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

[0052] Additional aspects and embodiments will become apparent from the detailed description below. [Brief explanation of the drawing]

[0053] [Figure 1] The clinical trial profile is shown. [Figure 2] This shows the changes in NCC-corrected concentrations over time. Changes from baseline are the least squares mean (SE) values ​​for 19–25 patients at each time point. One patient discontinued treatment at week 23, but this is within the specified window for including the NCC-corrected measurement as the week 24 value. The p-value is relative to baseline. [Figure 3] This shows changes in disability and neurological status over time. 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 mean (SE) values ​​for 21–28 patients. [Figure 4] This shows the NCC correction level after once-daily WTX101 treatment. [Figure 5] This shows the changes in liver stability measurements after once-daily WTX101 treatment. [Figure 6] This shows changes in impairment and neurological signs resulting from once-daily WTX101 treatment. [Figure 7] This shows the number of adverse events (AEs) reported during the core and extension periods. [Figure 8] Figures 8A and 8B show the mean ± standard error plasma concentrations of total Mo after a single 60 mg (2 × 30 mg) dose of WTX101 EC tablets under fasting conditions (treatment A) and feeding conditions (treatment B), as well as after administration of UC + PPI (treatment C) under fasting conditions. The data are plotted on a linear axis (Figure 8A) and a semi-logarithmic scale (Figure 8B). [Figure 9] This shows the symptoms of UWDRS neurological conditions (Part III) experienced by at least 50% of patients at baseline. Data are expressed as the proportion of patients in the enrolled population (N=28). [Figure 10A]The UWDRS neurological status (Part III) item scores for the study group are shown. Figure 10A shows the items with a maximum score of 4. Figure 10A shows the items with a maximum score of 8. [Figure 10B] The UWDRS neurological status (Part III) item scores for the study group are shown. Figure 10A shows the items with a maximum score of 4. Figure 10A shows the items with a maximum score of 8. [Figure 11A] This shows the number of patients with changes in UWDRS neurological status (Part III) item scores between baseline and week 24. Data are from all patients with data for a given item, including patients with a baseline score of zero (n=22 in each case). Figure 11A shows items with a maximum score of 4. Figure 11A shows items with a maximum score of 8. [Figure 11B] This shows the number of patients with changes in UWDRS neurological status (Part III) item scores between baseline and week 24. Data are from all patients with data for a given item, including patients with a baseline score of zero (n=22 in each case). Figure 11A shows items with a maximum score of 4. Figure 11A shows items with a maximum score of 8. [Figure 12] This outlines the patient flow for the extended study. [Figure 13] This shows NCC-corrected levels in patients with and without cirrhosis. NCC levels are not corrected at baseline because patients 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 the tetrathiomolybdate-copper-albumin complex; SEM, standard error of the mean. [Figure 14] This shows ALT levels in patients with and without cirrhosis. ALT: Alanine aminotransferase; BL: Baseline; SEM: Standard error of mean. [Figure 15]This shows the MELD score (severity of liver disease; score range 6-40) for patients with and without cirrhosis. BL: Baseline; MELD: Model of end-stage liver disease; SEM: Standard error of the mean. [Figure 16] The modified Nazer score (prognostic index, score range, 0-20) is shown for patients with and without cirrhosis. [Figure 17A] This shows albumin levels in patients with and without cirrhosis. [Figure 17B] This table shows the international normalized ratios for patients with and without cirrhosis. BL: Baseline; INR: International normalized ratio; SEM: Standard error of the mean. [Figure 18] This shows blood clotting times in patients with and without cirrhosis. BL: baseline; INR: international normalized ratio; SEM: standard error of the mean. [Figure 19A] The UWDRS is shown for Part II (measures impairment based on patient-reported activities of daily living; score range, 0-40) (Figure 19A) and Part III (measures neurological condition as assessed by clinicians (score range; 0-143)) (Figure 19B). A higher score indicates a worse condition. [Figure 19B] The UWDRS is shown for Part II (measures impairment based on patient-reported activities of daily living; score range, 0-40) (Figure 19A) and Part III (measures neurological condition as assessed by clinicians (score range; 0-143)) (Figure 19B). A higher score indicates a worse condition. [Modes for carrying out the invention]

[0054] Certain aspects of this disclosure are based on the remarkable finding that adverse events associated with the treatment of Wilson's disease can be reduced by administering biscoline tetrathiomolybdate in a 15 mg dosage form, or by modifying the daily dose of biscoline tetrathiomolybdate, to control abnormal liver function in patients. The ammonium salt of tetrathiomolybdate is generally In addition, a higher dose is administered, for example, 90-220 mg per day. Brewer et al. Initial Therapy of Patients with Wilson's Disease with Tetrathiomolybdate. Arch. Neurol. 48:42-47 (1991). According to this disclosure, administration of biscoline tetrathiomolybdate at the same or similar doses as commonly known doses of ammonium tetrathiomolybdate in the art is associated with the adverse events reduced by the method of this disclosure.

[0055] This disclosure provides a method for administering a therapeutically effective dose of biscolinetetrathiomolybdate to patients who have shown abnormal test results after being treated with biscolinetetrathiomolybdate. Abnormal liver function can indicate drug-induced liver injury (hepatotoxicity), so it is important to determine whether the abnormality reflects liver injury or indicates limited toxicity that will be broken down over time if the drug is continued to be taken. According to this disclosure, even in patients with abnormal liver function, it is optional to discontinue biscolinetetrathiomolybdate for a period of time and then continue taking the same dose of biscolinetetrathiomolybdate, or to continue taking a reduced dose of biscolinetetrathiomolybdate. This dosing regimen has the advantage of maximizing the time at the full target dose of the drug and therefore has the potential for beneficial therapeutic effects.

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

[0057] The methods of this disclosure optionally include measuring copper levels in the body. Various means of measuring copper levels 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 assist 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 in 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 unbound copper by ceruloplasmin. It should be understood that this is copper that can be freely stored in the liver and other organs. In a preferred embodiment, unceruloplasmin-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 補正 For example, it can rise significantly above 2.3 μm / L.

[0058] The test results and level ranges in healthy individuals described above can vary depending on the testing conditions and methods, but generally, healthy individuals have ALT levels in the range of 6-34 U / L, 9-34 U / L, or 6-41 U / L, hemoglobin in the range of 11.6-16.4 g / dL, 13.6-18.0 g / dL, or 12.0-16.0 g / dL, and 140-400 × 10⁻¹⁰ 3 Platelets within the range of / μL, 1.96~7.23 × 10⁴ 3 It is known to show neutrophils in the range of / μL and bilirubin in the range of 0.2–1.2 mg / dL or 0.10–1.10 mg / dL. Further information on clinical testing methods for the diagnosis and treatment of Wilson's disease can be found at the European Association. This information is provided in the Study of the Liver (EASL) Clinical Practice Guidelines: Wilson's Disease; J. Hepatology 56:671-685 (2012). The entirety of this is incorporated into this disclosure.

[0059] In some embodiments, the present disclosure relates to a method for treating Wilson's disease in a patient by administering 15 mg of bischolinetetrathiomolybdate once daily or once daily. The once-daily dose may be given in the form of a single dose, or two doses, optionally divided into two doses, or three, four, or five doses. The dose may be delivered orally, intravenously, intramuscularly, or by other methods known in the art.

[0060] In some embodiments, the present disclosure relates to a method for treating Wilson's disease in a patient by administering 30 to 90 mg of bischoline tetrathiomolybdate daily, wherein the patient has NCC greater than 2.3 μm / L. 補正 alanine aminotransferase (ALT) levels less than 80 IU / mL, hemoglobin greater than 8 g / dL, platelets greater than 30,000 / μL, or 1,000 / μL or 1x10⁶ 3 The patient has one or more neutrophils greater than / μL. The patient has NCC greater than 2.3 μm / L. 補正 and alanine aminotransferase (ALT) levels less than 80 IU / mL, or NCC levels 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 In another embodiment, two or more of the parameters are measured. In yet another embodiment, all parameters are measured.

[0061] In some embodiments, this disclosure relates to a method for treating Wilson's disease in a patient by administering 30 to 90 mg of bischoline tetrathiomolybdate daily, wherein the patient has NCC greater than 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 μm / L. 補正 , or NCC 補正Alanine aminotransferase (ALT) levels less than twice the upper limit of normal (ULN), 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 IU / mL, or hemoglobin greater than twice the upper limit of normal (ULN) of ALT, 6, 7, 8, 9, or 10 g / dL, or platelet counts 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 Having one or more neutrophils greater than / μL. In certain embodiments, the patient may be a combination of two or more of these parameters. In some embodiments, one or more parameters will be measured. In another embodiment, NCC 補正 In further embodiments, two or more of the parameters are measured. In even further embodiments, all of them are measured.

[0062] In some embodiments, the Disclosure relates to a method for modifying biscolinetetrathiomolybdate administration to patients with Wilson's disease who are receiving biscolinetetrathiomolybdate therapy by increasing the daily dose of biscolinetetrathiomolybdate. In some embodiments of the Disclosure, the dose of biscolinetetrathiomolybdate is increased in patients showing specific test results. In some embodiments, the daily dose of biscolinetetrathiomolybdate is increased in increments of 15 mg. In some embodiments, the Disclosure relates to a method for modifying biscolinetetrathiomolybdate administration to patients with Wilson's disease who have NCC greater than 2.3 μm / L. 補正 alanine aminotransferase (ALT) levels less than 80 IU / mL, hemoglobin greater than 8 g / dL, platelets greater than 30,000 / μL, or 1,000 / μL or 1x10⁶ 3 The daily dose is increased if the patient has one or more neutrophils greater than 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 μm / L. In further embodiments, the disclosure relates to patients with NCCs greater than 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 μm / L. 補正 , or NCC補正 Alanine aminotransferase (ALT) levels less than twice the upper limit of normal (ULN), 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 IU / mL, or above the normal ALT level (ULN). Hemoglobin greater than twice the 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 0.5 x 10 3 , 1x10 3 , 1.5x10 3 , 2x10 3 , or 2.5x10 3 The daily dose is increased if the patient has one or more neutrophils greater than 2.3 μm / L. 補正 and alanine aminotransferase (ALT) levels less than 80 IU / mL, or NCC levels 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 In another embodiment, two or more of the parameters are measured. In yet another embodiment, all parameters are measured. In a particular embodiment, the daily dose is increased in increments of 15 mg of biscolinetetrathiomolybdate. In a particular embodiment, the daily dose is increased during the initiation of treatment, typically during the first three, four, five, or six months of treatment with biscolinetetrathiomolybdate. In a particular aspect of this disclosure, the patient's dose is increased once. In a further aspect of this disclosure, the patient's dose is increased twice. In a further aspect of this disclosure, the patient's dose is increased three or more times.

[0063] In some embodiments, this disclosure relates to methods for modifying biscolinetetrathiomolybdate administration to patients with Wilson's disease receiving biscolinetetrathiomolybdate therapy by reducing the daily dose of biscolinetetrathiomolybdate. In some embodiments, the daily dose of biscolinetetrathiomolybdate is reduced in increments of 15 mg. In one embodiment, the daily dose is reduced by administering the dose every other day. In another embodiment, the daily dose is reduced by administering 15 mg every other day so that the patient receives an average of 7.5 mg of biscolinetetrathiomolybdate per day.

[0064] In one embodiment, the disclosure further provides a method for reducing the daily dose of biscolinetetrathiomolybdate in patients exhibiting abnormal test results. In certain embodiments of the disclosure, if a patient exhibits certain abnormal test results, administration of biscolinetetrathiomolybdate is temporarily discontinued and optionally resumed at a lower dose if the patient exhibits improved test results. In one embodiment, the test is a liver function test. Any liver function test known in the art may be used. In one embodiment, alanine aminotransferase (ALT) or bilirubin levels are used. In one embodiment, the test is a test for myelosuppression caused by prolonged excessive copper loss leading to cytopenia. In one embodiment, hemoglobin levels, platelet levels, or neutrophil levels may 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 biscolinetetrathiomolybdate in patients showing abnormal test results is reduced by 15 mg so that the dose for patients taking 15 mg of biscolinetetrathiomolybdate daily prior to the abnormal test result is reduced to 15 mg of biscolinetetrathiomolybdate every other day, the dose for patients taking 30 mg of biscolinetetrathiomolybdate daily prior to the abnormal test result is reduced to 15 mg per day, the dose for patients taking 45 mg of biscolinetetrathiomolybdate daily prior to the abnormal test result is reduced to 30 mg per day, the dose for patients taking 60 mg of biscolinetetrathiomolybdate daily prior to the abnormal test result is reduced to 45 mg per day, the dose for patients taking 75 mg of biscolinetetrathiomolybdate daily prior to the abnormal test result is reduced to 60 mg per day, and the dose for patients taking 90 mg of biscolinetetrathiomolybdate daily prior to the abnormal test result is reduced to 75 mg per day. In other embodiments, the daily dose of biscolinetetrathiomolybdate in patients showing abnormal test results is reduced by 15 mg so that the dose for patients taking 15 mg of biscolinetetrathiomolybdate daily prior to the abnormal test result is reduced to 75 mg per day. The daily dose of ribdate is reduced by half. In other embodiments, in patients showing abnormal test results who were taking 30-90 mg of biscolinetetrathiomolybdate daily prior to the abnormal test results, the dose of biscolinetetrathiomolybdate is reduced to 15 mg of biscolinetetrathiomolybdate daily, and in patients showing abnormal test results who were taking 15 mg of biscolinetetrathiomolybdate daily prior to the abnormal test results, the dose of biscolinetetrathiomolybdate is reduced to 15 mg of biscolinetetrathiomolybdate every other day.

[0066] In certain embodiments, if a patient exhibits certain abnormal test results, administration of biscolinetetrathiomolybdate is temporarily interrupted and resumed when the test results meet a certain threshold. In certain embodiments, administration is interrupted when two consecutive test results are abnormal. In further embodiments, administration is resumed when two consecutive test results meet a certain threshold. In certain embodiments, the daily dose of biscolinetetrathiomolybdate is resumed at the level before the interruption. In further embodiments, the daily dose of biscolinetetrathiomolybdate is resumed at a reduced dose level as described above. In even further embodiments of this disclosure, the daily dose is resumed at 15 mg of biscolinetetrathiomolybdate. In even further embodiments of this disclosure, if a patient was taking 30-90 mg of biscolinetetrathiomolybdate daily prior to the abnormal test results, the daily dose is resumed at 15 mg of biscolinetetrathiomolybdate. In further embodiments of this disclosure, if a patient was taking 15 mg of biscolinetetrathiomolybdate daily prior to the abnormal test result, the dose is restarted with 15 mg of biscolinetetrathiomolybdate every other day.

[0067] Abnormal test results may be defined as being above or below a set threshold, while liver function or bone marrow function is said to be normal. In any embodiment, an upper limit of normal (ULN) is defined relative to the test results. In any embodiment, medication is modified if the patient shows two consecutive abnormal test results. Dosage of biscolinetetrathiomolybdate may be modified by test results greater than the ULN, or twice the ULN, or three times the ULN, or four times the ULN, or five times the ULN, or any multiple of the ULN, or by liver function tests greater than a small multiple of the ULN between one, two, three, four, or five times the ULN. In one embodiment, if the test result is between two and five times the ULN, the daily dose of biscolinetetrathiomolybdate is reduced. In one embodiment, if the test result is greater than five times the ULN, the daily dose of biscolinetetrathiomolybdate is discontinued. In another embodiment, the liver function test is ALT. Optionally, if ALT is less than twice the ULN, administration of biscolinetetrathiomolybdate is resumed. Optionally, if ALT is less than twice the ULN, the daily dose of biscolinetetrathiomolybdate is resumed at a lower dose. In one embodiment, the lower limit of normal (LLN) for ULN and ALT depends on the specific assay used. In one embodiment, the ULN for 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 for ALT is 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 IU / mL, or any fraction in between. In another embodiment, the ULN of ALT is 34 IU / mL. In yet another embodiment, the ULN of ALT is 40 IU / mL.

[0068] In another optional aspect, the daily dose of biscolinetetrathiomolybdate is adjusted if liver results fall below baseline measurements from a trial conducted prior to the initiation of biscolinetetrathiomolybdate administration. Optionally, this baseline is patient-specific. Optionally, this baseline is determined by medical judgment. Optionally, this baseline is determined by clinical trial results. Optionally, the medication is adjusted if the patient has two consecutive abnormal trials. The dosage is modified when presenting the results of the trial. In one embodiment, the threshold for modifying the dose of biscolinetetrathiomolybdate is 50%, 60%, 70%, 80%, 90%, or any percentage in between from baseline. In another embodiment, the threshold is 65%, 70%, or 75% from baseline. In one embodiment, the threshold is 70% from baseline. In any embodiment, the dose of biscolinetetrathiomolybdate is modified if the patient's hemoglobin level is less than 70% of the patient's baseline hemoglobin. In any other embodiment, the threshold is 70% of baseline platelets or 70% of baseline neutrophils.

[0069] In a further embodiment, if the patient's hemoglobin level is less than 6, 7, 8, 9, or 10 g / dL, the dose of biscolinetetrathiomolybdate is reduced or temporarily discontinued. In yet another embodiment, if the patient's hemoglobin level is less than 8 g / dL, the dose of biscolinetetrathiomolybdate is reduced or temporarily discontinued. In yet another embodiment, if the platelet count is less than 20,000, 25,000, 30,000, 35,000, or 40,000 / μL, the dose of biscolinetetrathiomolybdate is reduced or temporarily discontinued. In yet another embodiment, if the platelet count is less than 30,000 / μL, the dose of biscolinetetrathiomolybdate is reduced or temporarily discontinued. In yet another embodiment, if the neutrophil count is 0.5 × 10⁶ 3 , 1 x 10 3 , 1.5×10 3 , 2×10 3 , or 2.5 × 10 3If the dose is less than 1 / μL, the dose of biscolinetetrathiomolybdate is reduced or temporarily discontinued. In yet another embodiment, neutrophils are 1 × 10⁶ 3 If the value is less than / μL, the dose of bischolinetetrathiomolybdate is reduced or temporarily discontinued. Optionally, the medication is modified if the patient exhibits two consecutive abnormal test results.

[0070] In certain embodiments, if the dose of bischoline tetrathiomolybdate is temporarily interrupted, the patient may have hemoglobin levels of 6, 7, 8, 9, or 10 g / dL or higher, platelet counts of 20,000, 25,000, 30,000, 35,000, or 40,000 / μL or higher, and / or 0.5 x 10 3 , 1x10 3 , 1.5x10 3 , 2x10 3 , or 2.5x10 3 Drug administration is resumed if the patient shows one or more neutrophils of 8 g / dL or higher, 30,000 / μL or higher, and / or 1x10⁶ 3 Medication is resumed if the patient shows one or more neutrophils at or above / μL. In a further embodiment, if the dose of biscoline tetrathiomolybdate is temporarily interrupted, medication is resumed if the patient shows one or more baseline levels of hemoglobin, platelets, or neutrophils.

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

[0072] In another embodiment, the disclosure further provides a method for reducing the daily dose of bischolinetetrathiomolybdate in patients exhibiting neurological exacerbation. In one embodiment, neurological exacerbation is assessed using the UWDRS Part III score. In one embodiment, the baseline UWDRS Part III is determined before administration of bischolinetetrathiomolybdate. In one embodiment, neurological exacerbation is defined as an increase in the UWDRS Part III score above baseline by 1, 2, 3, 4, 5, 6, 7, or 8 points. In another embodiment, neurological exacerbation is defined as an increase in the UWDRS Part III score above baseline by 4, 5, or 6 points. In another embodiment, neurological exacerbation is defined as an increase in the UWDRS Part III score above baseline by 4 points when the baseline UWDRS Part III is less than 20. It is defined as an increase in the Part III score. In another embodiment, neurological deterioration is defined as an increase in the UWDRS Part III score above baseline of 6 if the baseline UWDRS Part III was 20 or greater. In any embodiment, the modification includes discontinuing bischolinetetrathiomolybdate. In any embodiment, the modification includes administering a modified dose of bischolinetetrathiomolybdate after the patient has stopped showing neurological deterioration. In certain embodiments, if the patient's UWDRS Part III score is determined to be stable, the patient does not show neurological deterioration. 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 showed neurological deterioration. In other embodiments, the modified dose is less than the daily dose administered before the patient showed neurological deterioration, for example, 15 mg less than the daily dose administered before the patient showed neurological deterioration. In some embodiments, if the patient is receiving a 15 mg dose of biscolinetetrathiomolybdate once daily, the patient may receive 15 mg of biscolinetetrathiomolybdate every other day; if the patient is receiving a 30 mg dose of biscolinetetrathiomolybdate once daily, the patient may receive 15 mg of biscolinetetrathiomolybdate once daily; if the patent is for a 45 mg dose of biscolinetetrathiomolybdate once daily, the patient may receive 15-30 mg of biscolinetetrathiomolybdate once daily. If the patent is for a 60 mg dose of biscolinetetrathiomolybdate once daily, the dosage will be 30 mg of biscolinetetrathiomolybdate once daily. If the patent is for a 75 mg dose of biscolinetetrathiomolybdate once daily, the dosage will be 30-45 mg of biscolinetetrathiomolybdate once daily. If the patent is for a 90 mg dose of biscolinetetrathiomolybdate once daily, the dosage will be 45 mg of biscolinetetrathiomolybdate once daily.

[0073] In some embodiments, the disclosure relates to increasing or decreasing the dose of biscolinetetrathiomolybdate in constant increments. In one embodiment, the method includes administering to a patient a first dose level containing about 15 to about 90 mg of biscolinetetrathiomolybdate per day for a certain period, and then administering a second dose level containing at least about 15 mg less of biscolinetetrathiomolybdate per day than the amount of biscolinetetrathiomolybdate in the first dose level for a second period. In one embodiment, the second dose level is 15 mg every other day. The dose levels and daily doses may be used interchangeably. The dose levels may include 1, 2, 3, 4, 5, or more doses given at different times of day or at the same time. The dose may optionally be one tablet or two tablets. Optionally, the dose may be provided in tablet, capsule, or other pill form. Optionally, the 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 embodiment, the first dose level may exceed 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 embodiment, the second dose level may exceed 90 mg. Those skilled in the art will understand that this enumeration of dose levels is non-limiting. Optionally, the dose may be adjusted based on the subject's body weight. Optionally, the dose may 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 may be adjusted by measuring the copper content in the patient's serum. Optionally, the dose may be adjusted by NCC 補正 It can be adjusted by measuring it.

[0075] In one embodiment, the first dose level is 90 mg and the second dose level is 15 mg. In another embodiment, the first dose level is 90 mg and the second dose level is 75 mg. In yet another embodiment, the first dose level is 90 mg, or 75 mg, or 6 The second dose level is 0 mg or 45 mg, with the second dose level being 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 yet another embodiment, treatment with biscoline tetrathiomolybdate is interrupted between the first and second dose levels. In one embodiment, treatment is interrupted after an abnormal test result. In one embodiment, treatment with the second dose level is performed after the patient does not show an abnormal test result.

[0076] In another aspect, the disclosure provides a pharmaceutical composition comprising biscolinetetrathiomolybdate for the treatment of Wilson's disease in a patient. Specific pharmaceutical compositions of biscolinetetrathiomolybdate are provided by U.S. Patent No. 7,189,865, which is incorporated in whole by reference. 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 pharmaceutically active ingredient. In one embodiment, the second pharmaceutically active ingredient is zinc. Zinc may be provided as zinc acetate or zinc sulfite. In one embodiment, the second pharmaceutically active ingredient is a tetrathiomolybdate salt other than a bischoline salt. Optionally, the second pharmaceutically active ingredient is tetrathiomolybdate ammonium. In another embodiment, the second pharmaceutically active ingredient is a copper chelating agent. In any embodiment, the second pharmaceutically active ingredient is 2,3,2-tetramine or D-penicillamine.

[0078] In some embodiments, the compositions and methods of the present disclosure relate to salts of tetrathiomolybdate other than bischoline salts of tetrathiomolybdate. In some embodiments, the tetrathiomolybdate salt is a salt of tetrathiomolybdate and any pharmaceutically acceptable counterion. Exemplary counterions include, but are not limited to, ammonium, choline, and acetylcholine. The counterion may be, for example, a positively charged organic acid. Dosage is adjusted according to the molecular weight of the salt.

[0079] In another embodiment, the Disclosure provides a kit for treating Wilson's disease, comprising at least three sets of pharmaceutical dose units and instructions for use. In one embodiment, the kit, along with instructions for use, comprises enough tablets for a 7-day, 30-day, or 90-day course of treatment. In one embodiment, the instructions for use indicate liver function and threshold tests for increasing or decreasing the number of pharmaceutical dose units or subunits of pharmaceutical dosing units administered each day. In one embodiment, the kit further comprises zinc tablets. In one embodiment, the kit further comprises a copper chelating agent other than bischolinetetrathiomolybdate. In another embodiment, the Disclosure provides a composition for use in any of the methods of the Disclosure. In another embodiment, the Disclosure provides a composition for use in the manufacture of a pharmaceutical product for use in any of the methods of the Disclosure.

[0080] For oral administration, the pharmaceutical compositions of this disclosure may take the form of solid dosage forms, such as tablets (both swallowable and chewable forms), capsules, or gel caps, prepared by conventional means using pharmaceutically acceptable excipients and carriers, such as binders (e.g., pregelatinized corn 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.), and wetting agents (e.g., sodium lauryl sulfate). Such tablets may also be coated by methods well known in the art.

[0081] The dose administered depends on the patient's age, weight, and condition, as well as the route of administration, dosage form, and The regimen can be adjusted according to the desired outcome. In some embodiments, the dose administered to the subject is titrated until the desired endpoint is reached.

[0082] The compositions described above may be administered in the dosage forms described above, either as a single dose or in divided doses, once to four times a day.

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

[0084] In some embodiments, biscoline tetrathiomolybdate is provided in the form of divisible dose units. For example, in some embodiments, scored tablets may provide the dose units. Under the direction of a physician or other healthcare professional, a subject may be instructed to take one portion of a dose unit, one portion providing a desired dose level at a predetermined interval. At intervals below, the patient may be instructed to take two or more portions of a dose unit, two or more portions providing a desired dose level at that interval.

[0085] Liquid formulations can also be prepared by dissolving or suspending one or a combination of active substances in a conventional liquid vehicle that is pharmaceutically acceptable to provide the desired dose in 1 to 4 teaspoons.

[0086] These dosage forms can be administered to patients in regimens of 1 to 4 times per day.

[0087] Certain embodiments of this disclosure are based on the remarkable finding that when biscolinetetrathiomolybdate is administered in a fed state, its absorption is reduced by 60% to 75% compared to when it is administered under fasting conditions. In one embodiment of this disclosure, biscolinetetrathiomolybdate is administered in a fasted state to a patient suffering from Wilson's disease. In another embodiment, biscolinetetrathiomolybdate is administered after an overnight fast. In yet another embodiment, biscolinetetrathiomolybdate is administered on an empty stomach after fasting for about 1, 2, 3, 4, 5, 6, 7, or 8 hours. In certain embodiments, biscolinetetrathiomolybdate is administered as an enteric-coated formulation.

[0088] All features described herein (including any appended claims, abstracts, and drawings), and / or all steps of any method disclosed herein, can be combined in any combination with any of the embodiments described herein, except for at least some combinations in which such features and / or steps are mutually exclusive. In particular, any of the activators and compositions described herein can be used in any of the therapeutic methods described herein. Any and all combinations are expressly assumed to form part of the present invention.

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

[0090] "Biscolintetrathiomolybdate" refers to the bischoline salt of tetrathiomolybdate or its pharmaceutically acceptable composition. Biscolintetrathiomolybdate is also known as cholinetetrathiomolybdate, or ATN-224, or WTX101, or WTX-101, or DECUPRATE®. "WD" refers to Wilson's disease.

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

[0092] "Continuous test results" or "continuous abnormal test results" refers to two or more measurements of the same parameter taken at two different time points. In certain embodiments, the measurements are taken at one-week intervals. In other embodiments, the measurements are taken at two-week intervals.

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

[0094] NCC 補正 " or "NCC corr"NCC" refers to the NCC corrected for copper in the tetrathiomolybdate-copper-albumin complex. corr An exemplary method for determining is provided in Weiss et al. Lancet Gastroenterol Hepatol. 2:869-876 (2017), which is incorporated throughout this disclosure. The mechanism of copper uptake into ceruloplasmin is described in Hellman et al. J. Bio. Chem. 48:46632-38 (2002).

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

[0096] The "Modified Nazer Score" refers to an assessment of liver health 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, with lower values ​​indicating improvement.

[0097] The "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 sonograms to measure the speed of sound waves passing through the liver, thereby evaluating the degree of hepatic fibrosis or fatty deposition in the liver. To point.

[0099] "Ceruloplasmin" refers to the feroxidase enzyme encoded by the CP gene in humans. Ceruloplasmin is the main copper transporter 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 concentration of copper and total concentration of molybdenum (Mo) in a patient's serum.

[0101] Speciation profiling refers to profiling of Mo, Cu, and protein complexes using size exclusion chromatography.

[0102] The Unified Wilson's Disease Assessment Scale, or UWDRS, refers to a clinical assessment scale designed to evaluate the neurological symptoms of Wilson's disease (WD), which can generally be classified into three movement disorder syndromes: a. dystonia, b. ataxia, and c. Parkinsonian syndrome. The UWDRS consists of three parts: UWDRS Part I (Consciousness, item 1), UWDRS Part II (History review of daily activity items [impairment], items 2-11), and UWDRS Part III (Neurological examination, items 12-34). UWDRS Parts I and III are typically assessed by a neurologist. UWDRS Part II is typically reported by the subject or family. The UWDRS is described in Czlonkowska A et al. Neurol Neurochir Pol 41:1-12 (2007), and the entire text is incorporated into this disclosure.

[0103] The Comprehensive Clinical Findings-Severity Scale, or CGI-S, refers to a 7-point scale in which a clinician must assess the severity of a patient's illness at the time of assessment, comparing it to past experience with patients having the same diagnosis. Taking into account total clinical experience, patients are assessed at the time of assessment for the severity of their illness as follows: 1, normal, not ill at all; 2, borderline illness; 3, mild illness; 4, moderate illness; 5, marked illness; 6, severe illness; or 7, extreme illness.

[0104] The Clinical Comprehensive Findings-Improvement Scale, or CGI-I, is a 7-point scale that requires clinicians to assess how much the disease in question has improved or worsened compared to the baseline state at the start of the intervention, and is evaluated as follows: 1, greatly improved, 2, significantly improved, 3, minimally improved, 4, no change, 5, minimally worsened, 6, significantly worsened, or 7, very worsened.

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

[0106] "EuroQoL 5D" or "EQ-5D" refers to an assessment consisting of the EQ-5D-5L Descriptive System and the EQ Visual Analog Scale. The descriptive system comprises five dimensions (mobility, self-care, usual activity, pain / discomfort, anxiety / depression), each with five levels of severity (no problem / mild problem / moderate problem / severe problem / extreme problem). For the EQ-5D-5L Descriptive System, respondents are asked to indicate their health status by checking (or crossing) the most appropriate description for each of the five dimensions. This decision yields a single-digit number representing the selected level for that dimension. The five-dimensional digits are combined into a five-digit number that describes the respondent's health status. It can be done.

[0107] The "Therapeutic Satisfaction Questionnaire" or "TSQM-9" refers to a score used to assess the overall level of satisfaction or dissatisfaction of individuals receiving pharmacotherapy. This composite scale consists of two items in the TSQM-9 survey: To what extent are you satisfied with the positive aspects of this pharmacotherapy outweighing the negative aspects? And, taking everything into account, to what extent are you satisfied or dissatisfied with this pharmacotherapy?

[0108] The "three most troublesome symptoms" refer to the three most troublesome symptoms of the subject. Each subject, or the subject and their caregiver, will identify three most troublesome symptoms, and these will also be documented in writing, along with their impact on daily living activities. The three most troublesome symptoms will be recorded via videotape from the consenting subject, where feasible and appropriate.

[0109] The "Timed 25-Foot Walk Test" refers to a quantitative mobility and leg function performance test based on a timed 25-foot walk. Participants are instructed to walk 25 feet as quickly and safely as possible to one end of a clearly marked 25-foot course. Time is calculated from the start of the instruction and ends when the participant reaches the 25-foot mark. The task is then immediately repeated, with the participant walking the same distance back. The score for the Timed 25-Foot Walk Test is the average of the two trials. Participants may use assistive devices while performing this task.

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

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

[0112] A "countable span trial" refers to a trial measured for the forward and reverse forward (backward) recall of countable sequences and countable span sequence determinations. Countable sequences are displayed starting with a length of two digits, and each trial is displayed with an increasing enumeration length. The trial is terminated if the subject cannot accurately report the trial with one sequence length, or if the maximum enumeration length (9 digits, 8 backwards) is reached.

[0113] An "adverse event" refers to an unfavorable medical occurrence in a clinical study subject receiving a drug, which is not necessarily causally related to the treatment. Therefore, an adverse event may be any undesirable and / or unintended sign (including abnormal laboratory findings), symptom, or illness that is temporarily related to the use of the investigational drug, whether or not it is related to the investigational drug. Clinically significant abnormal laboratory findings or other laboratory findings, including neurological findings, are reported as adverse events. A person skilled in the art will exercise their medical and scientific judgment in determining whether an abnormal laboratory finding or other abnormal assessment is clinically significant. Abnormal tests determined to be errors do not need to be reported as adverse events.

[0114] The severity of all adverse events is 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 is used: Mild (CTCAE Grade 1): Transient symptoms, signs / symptoms recognized but easily tolerable, and not interfering 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 significant and unacceptable interference with the subject's daily activities, making it impossible to live normally. Life-threatening (CTCAE Grade 4): Life-threatening or incapacitating adverse events. Death (CTCAE Grade 5): Death-related adverse events.

[0115] An "adverse (drug) response" refers to any adverse and unintended reaction to a drug associated with any given dose, and is considered an adverse drug reaction. A "response" to a drug means that there is at least a reasonable possibility of a causal relationship between the drug and the adverse event, that is, the relationship cannot be ruled out.

[0116] "Unexpected adverse drug response" refers to an adverse response whose nature or severity does not match the applicable product information.

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

[0118] A “Special Interest Adverse Event” refers to any new neurological symptom or clinically significant worsening of an ongoing neurological symptom after the initiation of a research-based drug therapy, whether severe or not, that is designated as an AESI.

[0119] A "serious adverse event" refers to an adverse event or adverse response resulting from any of the following: death or life-threatening adverse event, hospitalization or prolonged current hospitalization, permanent or significant disability / loss of legal capacity or substantial impairment of the ability to perform normal life functions, birth defects / absences, or significant medical events.

[0120] An adverse event or side effect is considered "life-threatening" if, from the perspective of either the principal investigator or the sponsor, its occurrence poses an immediate risk of death to the subject. This does not include events that may lead to death in a more severe form.

[0121] A hospital stay of at least one night is considered an admission for an inpatient. Visits to the emergency room without hospitalization are not recorded as SAEs under this criterion, nor are scheduled or planned hospitalizations made prior to signing informed consent. However, unexpected complications and / or extensions of hospital stay occurring during elective surgery are recorded as adverse events and their severity must be assessed. Hospitalization due to social or situational reasons (i.e., having no place to stay, living too far away to visit) is not considered an admission for an inpatient.

[0122] Based on appropriate medical judgment, any significant medical event that is not fatal, life-threatening, or requires hospitalization may be considered a SAE if it could endanger the subject and medical or surgical intervention may be required to prevent one of the consequences listed above. Examples of such medical events include allergic bronchospasm requiring intensive care in the emergency room or at home, poor circulation in hospitalized patients that does not result in hospitalization, seizures, and the onset of drug addiction.

[0123] "Medical history" refers to information regarding past and current drug therapies, past and current diagnoses, conditions, and surgeries considered to involve significant tobacco, alcohol, or drug use.

[0124] "Clinical laboratory evaluation" or "clinical laboratory measurement" includes chemistry, hematology, coagulation, and urinalysis (microscopic).

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

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

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

[0128] As used herein, the term “score” refers to a relative value, level, intensity, or degree of an assay result. It can be artificially generated by a person skilled in the art, or by using an algorithm, possibly using a sample containing a known analyte, or optionally using a sample with a known concentration or titer of a known analyte. It can be a number manually assigned by a person skilled in the art, or a number generated by a formula or algorithm. Symbols such as “-”, “+”, and “++” may also be used. Scores can be generated from calculations using formulas or algorithms, or assigned by visual inspection, measurement, or estimation of assay results. When using a sample with a known concentration or titer of a known analyte, such a sample can be assayed under diluted and undiluted conditions to generate a range of scores or a standard curve of scores, which can be used in some embodiments used in the same analysis to assign or estimate scores to unknown samples analyzed for the same analyte. [Examples]

[0129] Example 1: Bischoline tetrathiomolybdate in patients with Wilson's disease: Open-label, multicenter, Phase 2 clinical trial. background Wilson's disease is a genetic disorder in which copper accumulates in the liver, brain, and other tissues. Treatment has been limited by efficacy, safety concerns, and the need for multiple daily doses. Bischoline tetrathiomolybdate (WTX101) is an orally administered, first-in-class copper protein aggregation molecule that targets hepatic intracellular copper and reduces plasma nonceruloplasmin-bound copper (NCC) by forming a triple complex with albumin and increasing copper excretion into the bile. The efficacy and safety of WTX101 were evaluated in first-line or initial treatment for patients with Wilson's disease.

[0130] method This open-label phase 2 trial was conducted at 11 hospitals in the United States and Europe. Patients with Wilson's disease (≥18 years of age) who were treatment-naïve or had not received chelating or zinc therapy for more than 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). Eligible patients received WTX101 monotherapy at an initial dose of 15–60 mg / day based on baseline NCC concentrations during the first 4–8 weeks, followed by individualized response induction dosing for the remaining weeks up to a maximum of 24 weeks. The investigators, other hospital personnel, and patients were aware of the nature of the treatment. The primary endpoint was tetrathiomolybdate-copper-albumin complex (NCC) at 24 weeks. 補正 ) is the change in baseline NCC concentration corrected for copper, and treatment success is normalized NCC 補正 Achieving or maintaining (≤2·3 μmol / L [upper limit of normal]), or NCC from baseline at 24 weeks. 補正 This was defined as achieving a reduction of at least 25%. This study is registered on ClinicalTrials.gov, NCT02273596.

[0131] findings Twenty-eight patients were enrolled and received WTX101, with 22 patients (79%) completing the study up to week 24. At 24 weeks, 20 of the 28 patients (71%, 95% CI 51.3–86.8; p < 0.0001) met the criteria for treatment success, 16 patients (57%) treated with WTX101 achieved or maintained normalized NCC-corrected concentrations, and 4 patients (14%) experienced at least a 25% reduction from baseline NCC-corrected. The mean NCC-corrected concentration decreased by 72% from baseline to week 24 (least squares mean difference -2.4 μmol / L [SE 0.4], 95% CI -3.2–-1.6; p < 0.0001). Surprisingly, no cases of paradoxical drug-related neurological exacerbations were recorded. Liver function was stable in all patients, but asymptomatic alanine, or aspartate aminotransferase, or γ-glutamyltransferase levels reversibly increased, while bilirubin did not increase, in 11 of 28 patients (39%) who received at least 30 mg / day of WTX101. Eleven serious adverse events were reported in 7 patients (25%), including psychiatric disorders (six events in 4 patients), gait disturbance (one event), elevated liver aminotransferases (two events in 2 patients, one of which was agranulocytosis), and impaired neurological function (one event, causality could not be ruled out, but was likely due to the progression of a spontaneous disease). Seven serious adverse events classified as psychiatric disorders and gait disturbances were assessed as unlikely to be related to the investigational drug, while the remaining four events were possibly related or likely 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. Considering its once-daily administration and favorable safety profile, WTX101 could improve the treatment of patients with this debilitating condition.

[0133] introduction Wilson's disease is an autosomal recessive disorder of impaired copper transport, leading to the accumulation of copper in the liver, brain, and other tissues. The disease is caused by mutations in the ATP7B gene, which encodes a copper transport ATPase. When ATP7B function is impaired, copper uptake into ceruloplasmin decreases, and copper excretion in the bile is impaired. Wilson's disease affects approximately 1 in 30,000 people, but the prevalence varies across populations and diagnosis can be significantly understated. Clinical manifestations vary widely and include forms of hepatic disease, neurological and psychiatric symptoms, and the Kaiser-Fleischer ring. 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) that increase urinary excretion of copper or zinc and inhibit copper absorption in the gastrointestinal tract.

[0135] There have been few forward-looking studies using these therapies, and there is a considerable unmet need regarding the efficacy, safety, and simplicity of the drug regimens. Furthermore, patients with neurological symptoms who initiate treatment with penicillamine or trientine have a neurological disorder. Paradoxical early exacerbations can occur, with the rapid emergence of new neurological signs or a worsening of existing neurological signs leading to significant impairment. In clinical studies, the proportion of patients with neurological Wilson's disease affected by early exacerbation after chelating therapy ranges from 19% to 35%. Early neurological exacerbations may be irreversible and may be due to the rapid mobilization of free copper.

[0136] Biscoline tetrathiomolybdate (WTX101) is an orally administered, first-in-class copper protein-binding molecule being investigated as a once-daily monotherapy for Wilson's disease. The previous form of the drug, tetrathiomolybdate ammonium, rapidly controlled copper levels in clinical studies but was too unstable for routine use. The biscoline portion represents a significant improvement due to its increased stability, and unlike other available therapies, WTX101 appears to have direct intracellular activity in hepatocytes, binding to excess copper and promoting copper excretion into the bile. WTX101 also rapidly binds to free plasma copper, forming a stable triple complex with tetrathiomolybdate, copper, and albumin.

[0137] method An open-label phase 2 trial was conducted at 11 hospitals. Eligible patients were 18 years of age or older and diagnosed with Wilson's disease by a Leipzig score of 4 or greater. At enrollment, patients had either no prior treatment for Wilson's disease or had been treated with a chelating agent or zinc within the past 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 greater than 11, or a modified Nazer score greater than 6 (revised King's score) were excluded.

[0138] The protocol and all amendments were approved by the local institutional review board and ethics committee. The implementation of the study was monitored by an independent data and safety monitoring committee. All participants provided written informed consent in accordance with the Declaration of Helsinki.

[0139] The principal investigator, other hospital staff, patients, and the sponsor were aware of the nature of the treatment. Patients who had previously received treatment had a 48-hour washout period before starting WTX101. Patients received an initial dose of WTX101 of 15–60 mg / day based on their baseline NCC concentration for the first 4–8 weeks, followed by individualized response induction dosing for the remainder of the 24 weeks. WTX101 was initially administered twice daily, but early protocol modifications resulted in once-daily administration (where deemed appropriate by the principal investigator).

[0140] Following elevated alanine aminotransferase (ALT) levels in patients 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 discretion of the principal investigator, the dose of WTX101 may be adjusted in predefined increments based on various factors including clinical chemistry and hematology, clinical evaluation, safety, and NCC concentration. Dose increases were gradual, with each increase limited to double the previous dose and not permitted 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) levels at least 2–5 times above the normal range, a decrease of 30% or more in baseline hemoglobin, or an increase of 4 points or more in neurological signs based on the Unified Wilson's Disease Rating Scale (UWDRS) Part III (an approved and validated quantitative neurological scoring system specifically developed for Wilson's disease).

[0142] Using the values ​​of total plasma copper concentration and ceruloplasmin concentration, NCC is calculated from total copper concentration to cell The amount of copper bound to loplasmin was subtracted (determined by inductively coupled plasma mass spectrometry). Since this is not part of the reactive toxic copper pool, the NCC measurement was corrected by subtracting the amount of copper bound to the tetrathiomolybdate-copper-albumin complex after WTX101 treatment. The correction method was determined using the relationship between NCC and plasma molybdenum concentration and the mean molar ratio of molybdenum to copper in the triple complex, confirmed by two independent methods. The NCC correction method was validated using random selection of test and validation samples.

[0143] The primary endpoint is NCC from baseline to 24 weeks. 補正 This is a change in the tetrathiomolybdate-copper-albumin complex (NCC 補正 The NCC concentration was measured as a corrected value for copper contained in ). Treatment success was measured as NCC 補正 Achieving or maintaining a normalized concentration of (≤2·3 μmol / L [upper limit of normal]), or NCC from baseline over 24 weeks. 補正 This was defined as achieving a reduction of at least 25%.

[0144] The secondary endpoint is NCC 補正The metrics included level clinical neurological disorder, liver function, clinical symptoms, health-related quality of life (HRQoL), mental state, pharmacokinetics and exchangeable copper, speciation profiling, safety and tolerability of normalization of urinary copper, change and time. Mental state, pharmacokinetic data, and copper endpoints were also measured. Neurological disorder was assessed as patient-reported impairment as measured by UWDRS Part II and as neurological state of trained evaluators as measured by UWDRS Part III. Hepatic synthetic function was assessed by monitoring of international normalized ratio (INR) and albumin concentration. Furthermore, changes in liver function were assessed by the modified Nazer score (based on bilirubin, INR, AST, albumin, and white blood cell count) and, in a post-hoc analysis, by the MELD score (based on bilirubin, creatinine, INR, and cause of liver disease). HRQoL was measured using the EuroQoL 5 Dimensions Visual Analogue Scale (EQ VAS).

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

[0146] The planned enrollment was 30 patients, and it was estimated that at least 15 patients had received limited (≤90 days) prior treatment with chelating agents or zinc. Formal power calculations were not performed as the study's primary objective was to present descriptive statistics. Changes in copper concentration and score were summarized over time with descriptive statistics. A mixed model repeated measures analysis with fixed effects terms was applied at clinic visits, and a spatial force covariance structure was applied to model within-participant error. The spatial force covariance structure was chosen because it was assumed that within-participant correlations would attenuate as the time distance between repeated measures increased. SAS (version 9.3) was used to provide the least squares mean over time, as well as the relevant 95% CI, SE, and two-tailed p-values.

[0147] Twenty-eight patients were enrolled and treated with WTX101, and 22 patients (79%) completed the study by up to week 24 (Figure 1). At baseline, 15 patients (54%) were female, with a mean age of 34.1 years (SD 11.86), ranging from 18 to 64 years. Nine patients (32%) had not received prior treatment for Wilson's disease. Nine patients (32%) had received treatment for less than 28 days, and 10 patients (36%) had received treatment for 28 days to 2 years (median 100 days [range 7–714]). Most patients had varying degrees of neurological signs at enrollment, with dysarthria (19 [68%]), postural tremor (18 [64%]), alternating hand movements (18 [64%]), and abnormal gait (17 [61%]), and abnormal gait mainly caused by ataxia (12 [43%]). Mean UWDRS Part III score at baseline. The score for A was 22.8 (SD 21.0; range 0-83), and only 3 patients (11%) had a score of 0 (no neurological abnormalities). At baseline, 13 patients (46%) had cirrhosis, based on estimated medical history (7 patients) or AST-to-platelet ratio index (6 patients). 14 patients (50%) had 26 abnormal liver tests at study participation (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 at the final dose for patients who discontinued treatment early, the daily dose was 15 mg for 6 patients (21%), 30 mg for 13 patients (46%), and 60 mg for 9 patients (32%). More than 80% of the total WTX101 doses in the study were once daily.

[0149] Treatment with WTX101 is administered by NCC 補正 This is related to the rapid improvement in average NCC 補正Concentrations fell below the upper limit of normal by week 12 (Figure 2). After 24 weeks, 20 out of 28 patients (71%, 95% CI 51.3–86.8; p < 0.0001) achieved treatment success, and 16 (57%) achieved normalized NCC. 補正 Achieved or maintained the concentration, and 4 people (14%) were NCC from baseline. 補正 It decreased by at least 25%. Overall, the average NCC 補正 The level 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; Table 1, Figure 2). [Table 1] [Table 2]

[0150] Disease-related impairments significantly improved after treatment with WTX101 (Table 1, Figure 3). The 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). The UWDRS Part II score improved by at least 1 point in 12 patients (57%), remained unchanged in 9 patients (43%), and no patients reported worsening except for one patient who discontinued treatment at 21 weeks due to further exacerbation of pre-existing neurological conditions.

[0151] The mean UWDRS Part III score significantly improved from 22.8 (21.0) at baseline to 16.6 (17.7) at week 24 (Table 1, Figure 3B). At week 24, UWDRS Part III scores improved by 4 points or more in 14 patients (67%) and stabilized (within 3 points of baseline) in 5 patients (24%). Two patients (10%) experienced a 5-point deterioration; one patient scored 19 at baseline with fluctuations of 16–27 during the study, and the second patient scored 3 at baseline and 8 between weeks 18–24. These patients' impairments were rated as 0 throughout the study. Remarkable. Furthermore, no cases of paradoxical neurological deterioration attributable to the investigational drug were recorded within 12 weeks of the start of treatment.

[0152] While improvements in INR and albumin from baseline to week 24 were statistically significant, they were numerically small and indicated stable liver function (Table 1). Liver status remained largely unchanged throughout the study, as estimated by MELD and modified Nazer scores (Table 1).

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

[0154] Treatment with WTX101 generally demonstrated good tolerance, and most adverse events were mild or moderate in severity (summarized in Table 2). Increased enzyme concentrations, primarily ALT, AST, or γ-glutamyltransferase, were recorded in 11 of 28 patients (39%) receiving WTX101 at 30 mg / day or higher, without increased bilirubin. These increases typically occurred 4–10 weeks later, were mostly mild or moderate, all asymptomatic, and normalized within 1–2 weeks after dose adjustment or treatment discontinuation of 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%) discontinued treatment with ALT increases of 14.3–29.3 times from baseline. Secondly, a high ALT signal (615 U / L) occurred in one of the first enrolled patients who received WTX101 at 120 mg / day. Subsequently, the protocol-specific dose regimen was revised, reducing the maximum dose to 60 mg / day. The patient with the most pronounced ALT signal (1341 U / L) received WTX101 at 30 mg / day and had elevated ALT (peak 400 U / L) from previous penicillamine treatment prior to enrollment. In the three patients who discontinued the drug due to elevated ALT levels, the abnormal results on liver tests were reversible and not associated with a significant increase in bilirubin. [Table 3]

[0155] Adverse events that occurred with treatment, and serious adverse events that occurred with all treatments, were listed as reported by the principal investigator in at least two patients. Patients may have had multiple adverse events or serious adverse events. Seven serious adverse events, classified as psychiatric and gait disturbances, were assessed as unlikely to be related to the investigational drug, while the remaining four events were possibly related or likely related. One patient reported adjustment disorder and recorded exacerbation of acute condition disorder at 6 weeks (listed here as one serious adverse event). In another patient, mania was reported in two separate instances 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 patients (7%) reported leukopenia and one patient (4%) reported thrombocytopenia, which were likely, or clearly, associated with the investigational drug, but all recovered after dose adjustment. Few patients reported gastrointestinal or skin adverse events associated with the study treatment. There were hardly any (Table 2).

[0157] Eleven serious adverse events were reported in seven patients (25%), including psychiatric disorders (six events in four patients), elevated hepatic aminotransferases (two events in two patients, one of which was agranulocytosis), gait disturbance (one event), and impaired neurological function (one event; Table 2). While the psychiatric serious adverse events and gait disturbance were assessed as remote or unlikely to be related to the investigational drug due to symptoms of pre-existing neurological or psychiatric disorders, the other four serious adverse events were considered to be potentially or highly likely to be related to the treatment.

[0158] One previously treated patient who presented with neurological deterioration prior to enrollment showed further neurological decline after 12 weeks despite study treatment, discontinued at 21 weeks, and had a 3-point increase in UWDRS Part II and an 11-point increase in UWDRS Part III from baseline. While causality could not be ruled out, the neurological decline was assessed as likely due to the progression of a natural disease. The principal investigator discontinued treatment for two patients (7%) due to psychiatric or behavioral symptoms that prevented adherence to the protocol. These patients did not improve or change their UWDRS Part III scores.

[0159] Discussion The results showed that WTX101 showed significant NCC after approximately 3 months. 補正 This study demonstrates rapid copper control accompanied by a reduction in [specific factor], and shows significant early improvement in neurological symptoms and function in most patients. This study is the first multinational prospective clinical trial conducted in patients with Wilson's disease, aiming to evaluate treatment with the novel oral drug WTX101 and its significant advantages in administration and dosing.

[0160] Previous 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 the previous treatment regimen in most patients with liver disease or compensated cirrhosis, symptom improvement in those with neurological disorders may be slower and not improve or resolve as much as liver function. Without being bound by any particular theory, the rapid biochemical and clinical improvements observed with WTX101 may be related to its novel copper-specific and direct hepatic mechanism of action, which reduces the concentration of toxic free copper in the plasma. Treatment of patients presenting with neurological symptoms has been particularly challenging, as approximately half of patients with neurological disorders at symptomatic stage still have residual signs even after years of chelation therapy. Furthermore, paradoxical early neurological deterioration may be observed in patients with neurological Wilson's disease even after initiation of standard chelating therapy, and neurological deficits may be irreversible in one-third to one-half of patients. In a study by Litwin and colleagues, early neurological worsening was observed in 12 out of 42 patients (29%) with neurological Wilson's disease treated with penicillamine, with a mean duration of 2-3 months from the start of treatment. (Litwin et al. Early neurological worsening in patients with Wilson's disease. J. Neurol Sci 355:162-67 (2015)). Potentially, the binding of WTX101 to copper in an inactive, large protein complex that cannot be redistributed to the CNS may be the cause of the apparent absence of early neurological worsening within the first 12 weeks of treatment. One possibility is that previously treated patients received chelation therapy for a sufficiently long period, as they did not observe neurological worsening with subsequent WTX101 treatment; however, no cases of early neurological worsening have been recorded in treatment-naive patients. One previously treated patient (<28 days of zinc) with neurological deterioration prior to enrollment had an inadequate clinical response to WTX101 and, despite increased doses, experienced further neurological decline, leading to the discontinuation of study treatment at week 21. The neurological decline was assessed as likely due to the progression of a natural disease, but a causal relationship could not be ruled out.In addition to the patient who discontinued at week 21, two other participants also discontinued due to neurological or psychiatric reasons. Treatment with TX101 was discontinued. Neurological, psychiatric, or both neurological and psychiatric symptoms frequently occurred in patients with Wilson's disease, causing these two participants to be unable to follow the study procedures. In addition, pre-existing psychiatric disorders required hospitalization at several hospitals during the study, which was documented as a serious adverse event by definition. In fact, eight of the eleven reported serious adverse events were essentially neurological or psychiatric and occurred in five patients.

[0161] As indicated by the INR and albumin concentration results, synthetic liver function appeared stable with WTX101 over the 24-week study. This finding was observed in all patients, regardless of evidence of cirrhosis. Notably, reversible increases in liver function tests were observed in 39% of patients in this study, regardless of stage of liver disease. The increases occurred at doses of 30 mg / day or higher within 4–10 weeks after initiation and were mostly mild or moderate. All patients with increases were asymptomatic with respect to liver disease. Results from liver function tests were normalized within 1–2 weeks after dose adjustment or treatment discontinuation. Patients with increased liver function test results, including those who discontinued the drug, did not show significant increases in bilirubin, indicating the absence of serious drug-induced liver injury. Similar dose-dependent, early reversible increases in aminotransferase occurred in patients with Wilson's disease treated with tetrathiomolybdate ammonium, which also responded to dose reduction or treatment discontinuation. However, no similar liver test abnormalities have been reported with tetrathiomolybdate in patients without liver disease or primary biliary cirrhosis, suggesting that the observed effects are specific to Wilson's disease. One mechanism by which liver enzyme levels rise in response to WTX101 treatment may be related to its copper-modulating activity, such as by removing copper from the liver pool containing metallothionein, leading to a subsequent transient increase in liver aminotransferases. However, the exact mechanism remains unclear.

[0162] Previous available treatments for Wilson's disease were subject to other potentially serious adverse events that frequently led to treatment interruption and modification. In a retrospective study, 32% of patients using chelating agents and 11% of patients using zinc discontinued treatment due to adverse events. Penicillamine is associated with early susceptibility reactions such as fever, rash, and various skin reactions, as well as later reactions such as lupus-like syndrome and nephrotoxicity. Gastrointestinal adverse events were frequently reported with zinc treatment, with 40% of children treated with zinc experiencing 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 to be related to the study treatment, but these were generally mild to moderate and did not lead to discontinuation. Six patients discontinued the study treatment. These interruptions reflect the chronic, life-limiting nature of symptomatic patients with Wilson's disease, with most registered patients exhibiting varying degrees of neurological or psychiatric symptoms, and an exploratory approach requiring modifications to initial medication regimens.

[0163] Previously available treatments for Wilson's disease were prescribed in multiple daily doses, up to four times a day, and had to be taken without food. Studies suggest that up to 45% of patients treated with current therapies have poor or problematic long-term adherence. Failure to adhere to lifelong treatment can lead to symptom relapse and progression of liver disease, or neurological or psychiatric symptoms, although the timeframe varies from person to person. WTX101 allows for once-daily oral administration, which may lead to improved treatment adherence and better patient outcomes.

[0164] The sample size was sufficient for a Phase 2 trial in a rare disease, but relatively small when evaluating outcomes in clinically heterogeneous diseases. 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 rapidly after diagnosis, a mixed population of untreated and previously treated patients was necessary. Including 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. Internal controls are desirable, but this is not always feasible in early drug development for rare diseases. However, there were improvements in bias-less outcomes, including copper control and liver function. The trial duration was relatively short, but an extension study is underway to further investigate the long-term safety and efficacy of WTX101.

[0165] In conclusion, WTX101 treatment rapidly reduced free copper levels in patients with Wilson's disease, and this copper control was associated with reduced impairment, improved neurological status, and stable liver function over 24 weeks. With dose adjustments, WTX101 demonstrated a favorable safety profile with a simple once-daily oral administration regimen without food effects. Therefore, 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 continued extension of a Phase 2 trial. In Example 1, oral WTX101 monotherapy once daily rapidly reduced and controlled NCC, and improved impairment and neurological status, but there was no early drug-induced neurological deterioration or stabilization of liver function in patients with WD at 24 weeks. The 72-week efficacy and safety data from the continued extension period of the Phase 2 trial represent the first prospective report on long-term disease management with WTX101 in WD.

[0167] Example 1 was an open-label, multicenter, single-arm phase 2 trial conducted in 28 adults with a WD diagnosis established by a Leipzig score of ≥4. If present, NCC levels had to exceed the lower limit of the usual reference range (≥0.8 μM). Participants had either no prior treatment for WD (n=9) or prior treatment with chelated or zinc for ≤24 months (<28 days, n=9; 28 days to 2 years, n=10). Participants received WTX101 for 24 weeks using response-inducing dosing regimens at individualized doses between 15 and 120 mg / day, based on NCC levels, clinical assessments, and safety criteria.

[0168] The data shows (a) corrected NCC levels (NCC) for bound copper in the tetrathiomolybdate-copper-albumin complex. 補正 (b) liver status measured using standard laboratory measurements and the End-Stage Liver Disease Model (MELD) score (based on bilirubin, creatinine, and international normalized ratio [INR]), (c) patient-reported disability using the Unified Wilson's Disease Assessment Scale (UWDRS) Part II and neurological status using the 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 developed cirrhosis based on medical history (n=7) or AST-to-platelet ratio index (n=6). At week 24 or when patients with early discontinuation received their final dose, the daily dose was 15 mg for 6 patients, 30 mg for 13 patients, and 60 mg for 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 wanted to become pregnant, Treatment was discontinued. One patient, despite continuing treatment, was unable to adhere to the study procedures due to the progressive course of their disease. [Table 4]

[0171] Unless otherwise specified, mean ± standard error Free copper levels in plasma Baseline rising mean (SEM) NCC 補正 (3.6[0.4]μM) decreased, was controlled 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, observed in 39% of patients (≥30 mg / day) at week 24 (Example 1), were not observed in the extended period.

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

[0175] WTX101 was generally well tolerated after 72 weeks of treatment. Overall, the number of reported adverse events (AEs) and serious adverse events (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 to or unrelated to treatment.

[0176] At baseline, decreased platelet counts (56%) and neutrophil counts (32%) were common, and similar reports were observed throughout follow-up. Most occurrences were not accompanied by low NCC levels and were unlikely to reflect copper deficiency. Throughout the follow-up period, low hemoglobin was rare, with 5.2% of measurements below the normal range, and seven patients exhibited low hemoglobin at some point, but none of the measurements were below 100 g / L. Two subjects had evidence of neutropenia with mild anemia and low NCC levels, which may have been consistent with copper deficiency between weeks 36 and 72, respectively, and both responded rapidly to dose reduction. [Table 5]

[0177] Initial improvements in free copper levels, as well as hepatic and neurological status, were maintained or further improved from week 24 to week 72 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, along with its simple dosing regimen, suggest This indicates that WTX101 addresses several unmet needs in the treatment of WD.

[0178] Example 3: A phase 3, randomized, evaluator-blinded, multicenter study evaluating the efficacy and safety of WTX 101 administered for 48 weeks in Wilson's disease patients aged 18 years or older with a prolonged period of up to 60 months. Summary of the research design A randomized, evaluator-blinded, multicenter trial was conducted to evaluate the efficacy and safety of individual WTX101 dosing regimens administered for 48 weeks compared to State of Care (SOC) in WD subjects aged 18 years or older.

[0179] Approximately 102 participants will be registered at around 5-10 facilities in North America and 15-25 other facilities worldwide.

[0180] Eligible subjects with diseased dysregulation (WD) who had received >28 days of SoC therapy (i.e., chelation therapy with penicillamine or trientine, Zn therapy, or a combination of both) (Cohort 1), were untreated, or had received ≤28 days of SoC therapy (i.e., chelation therapy with penicillamine or trientine, Zn therapy, or a combination of both) (Cohort 2) were randomized in a 2:1 ratio to receive 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] Participants who met all inclusion and exclusion criteria were enrolled in the study and studied as outpatients. Previously treated subjects randomized to receive WTX101 were required to undergo a washout of their previous SoC therapy for ≥48 hours immediately prior to initiating WTX101 treatment. Eligible subjects randomized to WTX101 received WTX 101 as delayed-release tablets for oral administration at doses ranging from 15 mg to 60 mg every other day (QOD). The maximum QD dose of up to 90 mg should be discussed and agreed upon with the medical monitor only if the following criteria are met: NCC 補正 The upper limit of normal (ULN) is >, alanine aminotransferase (ALT) is <2×ULN, and hematological parameters (hemoglobin, platelets, neutrophils) remain above the threshold requiring dose adjustment according to Table 1. Efficacy and safety will be evaluated at scheduled visits, but adverse events and concomitant medications will be continuously monitored throughout the study.

[0182] The visit scheme consists of screening visits, registration visits, treatment phase visits, and end-of-study (EOS) (or early termination [ET]) visits. The visit schedule is summarized below.

[0183] Screening visits were conducted within 28 days of the registration visit (Day 1). Following the Day 1 visit, telephone evaluations were conducted at weeks 1, 2, 30, and 42 (days 8, 15, 211, and 295, respectively), and then study visits were conducted at weeks 4, 6, 8, 12, 18, 24, 36, and 48 (days 29, 43, 57, 85, 127, 169, 253, and 337, respectively).

[0184] Participants who have completed the 48-week treatment period will be offered the opportunity to participate in an extended study to evaluate the long-term safety and tolerance of WTX101. If a participant chooses not to participate in this extended study, he / she will be assisted in transitioning to a State of Care (SoC) under the guidance of a local physician.

[0185] End-of-Service (EOS) visits will be conducted at week 52 (day 365) only for subjects who do not enter the extension phase. For each subject who does not enter the extension phase, the primary study phase will end approximately 52 weeks (approximately 365 days) from the start of treatment on day 1 (48 weeks of treatment with an EOS visit 4 weeks after the last dose). For each subject who enters the extension phase, the primary study phase will end approximately 48 weeks (day 337) from the start of treatment on day 1.

[0186] Individual dose adjustments Detailed criteria regarding temporary interruption or dose increase restrictions for WTX101 are detailed in Table 5. [Table 6] [Table 7] [Table 8] [Table 9]

[0187] Two consecutive results (i.e., obtained over two consecutive study visits) for a specific laboratory parameter or a pre-specified parameter consistent with toxicity or exacerbation in UWDRS Part III must be obtained to apply dose adjustment criteria. Continue weekly repeated trials until results return to baseline or within the normal range limits. The trial will then be repeated after two weeks. If results remain at baseline or within the normal range limits, the perprotocol scheduled timing will then be resumed.

[0188] Research period For each subject, the primary study period will end approximately 52 weeks (approximately 365 days) after the start of treatment on day 1 of the study (if the subject does not enter the extension period, a 48-week treatment will be administered via an EOS visit 4 weeks after the final dose date). 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 a subject does not choose to participate in this extension period, he / she will be assisted in transitioning to a State of Care (SoC) under the guidance of a local physician.

[0189] Unscheduled visits may occur if the principal investigator determines that additional clinical evaluations are necessary beyond the scheduled visits, or if the subject meets the dose adjustment criteria. Furthermore, if there is clear neurological deterioration, such as indicated by signs or symptoms of neurological deterioration, additional neurological evaluations will be performed at the discretion of the principal investigator.

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

[0191] treatment group Participants will be treated with WTX101 or SoC therapy at doses ranging from 15 mg QOD to 60 mg QD. Participants will be randomized to one of two cohorts: Cohort 1 - Participants treated with 28 days of chelation therapy or Zn therapy, or a combination of chelation therapy and Zn therapy; or Cohort 2 - Untreated, or previously treated with ≤28 days of chelation therapy or Zn therapy, or a combination of both chelation therapy and Zn therapy. The subject being referred to.

[0192] Evidence for prescribing medication The dosage of WTX101 will be adjusted for individual subjects as needed, based on the guidelines specified in the protocol. Detailed dosing guidelines for WTX101 dosage modifications are 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 provided in accordance with clinical chemistry, hematology, clinical evaluation, safety, and NCC. 補正 Based on various factors, including:

[0194] Dosage increases are possible at the discretion of the principal investigator if the disease is not adequately controlled, with increases of 15 mg at least every 4 weeks. 補正 Taking into account the clinical status of the subjects and their free blood Cu levels as measured by [method / tool], dose adjustment criteria will not be applied. After dose increase, subjects will be monitored for adverse events and laboratory assessments every two weeks for a period of four weeks. If regular study visits are not scheduled during this period, home care nurses may complete these assessments.

[0195] NCC 補正 If the level decreases to within the normal range (<2.3 μmol / L) and the patient's clinical condition is stable or improving in two consecutive assessments, the WTX101 dose may be maintained or reduced at the discretion of the principal investigator. To avoid overtreatment, if the patient's clinical condition indicates a possibility of overtreatment, and / or NCC / NCC 補正If the value falls below the normal range, the principal investigator may reduce the dose at any time as directed. However, the NCC is the standard for dose adjustment. 補正 The use of this is optional and reflects different clinical practices across departments in global research. If any of the dose adjustment criteria are met, the dose should be reduced or discontinued.

[0196] Administration of research drugs WTX101 will be supplied as tablets containing 15 mg of bischolinetetrathiomolybdate for oral administration. WTX101 will be administered in doses ranging from 15 mg QOD to 60 mg QD. The maximum dose of up to 90 mg QD should be discussed and agreed upon 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 the thresholds requiring dose adjustment according to Table 1.

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

[0198] Individualized WTX101 dosing will be used throughout the study based on the following parameters: Clinical criteria: Dosage setting based on hepatic and neurological status, NCC 補正 :Dose setting based on NCC levels adjusted for the amount of Cu bound to WTX101 TPC, and safety monitoring:Dose adjustment criteria based on regularly scheduled assessments of observed hematological effects in Cu reduction, liver tests, and neurological tests.

[0199] If an adverse event requiring dose reduction occurs, the WTX101 dose may also be reduced. Dosage guidance related to specific events is provided in the dose adjustment criteria (Table 5), and dose reductions for other events will be handled as appropriate by the principal investigator (or, if applicable, the associate investigator) at the site in cooperation with the medical monitor.

[0200] In all subjects, WTX101 will be administered at a QD starting dose of 15 mg on day 1 and continued for the first four weeks. After four weeks, if the disease is not adequately controlled, the dose setting may be increased to 30 mg QD 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, without applying dose adjustment criteria. Further dose increases may be made at the discretion of the principal investigator, in increments of 15 mg at least every four weeks, according to the same criteria described above.

[0201] NCC 補正 If the level drops to within the normal range (<2.3 μmol / L) and / or if the patient's clinical condition is stable or improving in two consecutive assessments, the WTX101 dose may be maintained or reduced at the discretion of the principal investigator. To avoid overtreatment, if the patient's clinical condition indicates a possibility of overtreatment and / or NCC / NCC 補正 If the value falls below the normal range, the principal investigator may reduce the dose at any time as directed. However, the NCC is the standard for dose adjustment. 補正 The use of this is optional and reflects different clinical practices across departments in global research. If any of the dose adjustment criteria are met, the dose should be reduced or discontinued.

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

[0203] The following parameters should be followed for accuracy in measurements. Estrogen may interfere with biliary Cu excretion. Vitamin E is used as an adjunctive therapy in WD treatment regimens. Participants should not use vitamins or minerals containing Cu, Zn, or Mo. Gadolinium and iodine-containing contrast agents are known to interfere with tests for Mo. Gadolinium and iodine-containing contrast agents were required not to be used within 96 hours prior to the Mo test. Barium-containing contrast agents are known to interfere with tests for Cu. Barium-containing contrast agents were required not to be used within 96 hours prior to the Cu test. Participants should avoid consuming foods and beverages high in Cu during the study period.

[0204] Following randomization and washout (if applicable), subjects will return for visits and procedures: visits between weeks 1 and 30 and at week 42 will occur within ±3 days of the scheduled time, and visits between weeks 36 and 48 will occur within ±7 days of the scheduled time.

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

[0206] Secondary efficacy assessments include: liver status using the 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] The tertiary efficacy evaluations include: individualized evaluations of the three most troublesome symptoms for each subject, fibrosis of the liver using the FIB-4 index and transient elastography, the modified Na zer score for liver status, psychiatric symptoms using the BPRS-24, and QoL / PRO endpoint measurements using the EQ-5D and TSQM-9. The exploratory efficacy evaluations include:

[0208] Evaluation of Cu control using exploratory measurements of total plasma Cu, free Cu, PUF-Cu, and Cu speciation, evaluation of Mo plasma levels, evaluation of 24-hour urinary Cu and urinary Mo, evaluation of the timed 25F walking test, evaluation of 9-HPT, evaluation of the non-verbal Stroop interference test, and evaluation of the counting span test.

[0209] Statistics All statistical analyses will be performed according to procedures recognized in the art. A general description of the statistical methods used to analyze the efficacy and safety data is outlined below. The statistical analysis will be performed using SAS (registered trademark), version 9.3 and later, SAS Institute, Cary, North Carolina, USA.

[0210] The primary evaluation item is Cu control, which is evaluated as the rate of change from the NCC level baseline up to 48 weeks. For subjects treated with WTX101, the NCC level was corrected by the amount of Cu bound to WTX101 TPC.

[0211] The rate of change from baseline in NCC levels was analyzed using a mixed-model repeated measures (MMRM) analysis stratified by cohort and prior SoC treatment. Changes from baseline are included at weeks 4, 8, 12, 24, 36, and 48. Restricted maximum likelihood estimation will be used. The model was stratified by cohort and prior SoC treatment. NCC may be log-transformed before analysis to better normalize the data. Fixed-effect terms include randomized treatment (WTX101 or SoC), randomized treatment with visits and visit interactions, and baseline NCC levels as a covariate. Treatment with visit interactions will remain in the model regardless of importance. An unstructured covariance matrix is ​​used to model within-subject errors, and the Kenward-Roger approximation is 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: Teplitz with heterogeneity, autoregressive with heterogeneity, Teplitz, and autoregressive. The primary contrast 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 mean percentage change in NCC levels at week 48 are provided. If a low two-sided 95% CI excludes -15% difference, non-inferiority of WTX101 across the SoC-related overall study population is concluded; if a low two-sided 95% CI excludes 0% difference, superiority of WTX101 across the SoC-related overall study population is concluded. Least squares (LS) extracts the change from the baseline and associated standard error (SE) at early point in time (i.e., weeks 4, 8, 12, 24, and 36) and displays it graphically for each arm over time.

[0212] A supportive analysis of the primary endpoint within Cohort 1 reflects what has been described for the overall population analysis, except that the analysis is not stratified by cohort.

[0213] The rate of change from the NCC-level baseline was descriptively analyzed using MMRM analysis, and no formal statistical comparisons were made between randomized treatment groups. The rates of change from baseline at Week 4, Week 8, Week 12, Week 24, Week 36, and Week 48 were estimated using the same model terms as described for the analysis of Cohort 1. The primary outputs of interest were the LS means, SEs, and p-values of the rates of change from the baseline of the NCC levels within each 48-week period. The mean change in LS within the arm and SEs from early baseline time points (i.e., Week 4, Week 8, Week 12, Week 24, and Week 36) were extracted and graphed by arm for each.

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

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

[0216] An NCC response was defined as the proportion of subjects achieving or maintaining a normalized level of NCC or NCC 補正 (from 0.8 μM to 2.3 μM) or achieving at least a 25% decrease in NCC or NCC 補正 over 48 weeks. For subjects treated with WTX101, the NCC level will be corrected by the amount of Cu bound to the 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 level. Again, supportive and relative analyses will be performed for Cohort 1 subjects, and supportive and descriptive analyses within the arm will be performed for Cohort 2 subjects.

[0218] Example 4: Absorption of bischolinetetrathiomolybdate after a single dose of enteric-coated formulations with and without food, and an uncoated formulation administered concurrently with a proton pump inhibitor without food. A single-center, open-label, randomized, 3-period, 3-treatment, 6-sequence crossover study was conducted to evaluate the pharmacokinetics (PK) of a single dose of bischolinetetrathiomolybdate in healthy subjects based on measurements of total plasma molybdenum concentration. As shown in the study diagrams in Figures 8A and 8B, 18 healthy non-smokers, using adult male and female subjects, received treatment A, B, or C over a 3-period course. Subjects received each treatment at one time. Subjects were omissionably assigned to one of six treatment sequences: ABC, ACB, BAC, BCA, CAB, and CBA. All investigational drugs were administered orally with approximately 240 mL of water. Subjects were instructed not to crush, split, or chew the investigational drugs. Treatment A: After an overnight fast, administer 60 mg of biscolinetetrathiomolybdate at time 0 on day 1 (2x biscolinetetrathiomolybdate enteric-coated (EC) tablets, 30 mg; see Table 6). Treatment B: Fast overnight prior to treatment, followed by 60 mg of biscolinetetrathiomolybdate (2x biscolinetetrathiomolybdate 1 EC tablet, 30 mg) 30 minutes after the start of a high-fat breakfast, at time 0 on day 1. Treatment C: 20 mg of omeprazole (1 x 20 mg delayed-release capsule of PPI (proton pump inhibitor)) QD on the morning of days -5 to -1 after an overnight fast, 20 mg of omeprazole delayed-release capsule at time -1 on day 1 after an overnight fast, and 60 mg of bisucolinetetrathiomolybdate at time 0 on day 1 (2 x bisucolinetetrathiomolybdate uncoated (UC) capsules, 30 mg, see Table 7).

Table 10

Table 11

[0219] All 18 enrolled and completed subjects were included in the safety and PK analysis. However, since the measurable pre-dose plasma total Mo concentration was > 40% of the corresponding C max (maximum measured plasma concentration), one subject was excluded from the PK descriptive statistics and statistical analysis of Treatment B. Therefore, the PK analysis population consisted of 18 subjects on fasting EC tablets (Treatment A) and fasting UC + PPI (Treatment C), and 17 subjects on fed EC tablets (Treatment B).

[0220] Pharmacokinetic results The PK parameters of plasma total Mo were calculated as follows: AUC 0-t : Area under the plasma concentration-time curve from time 0 to the last measurable concentration, calculated by the linear trapezoidal method. AUC 0-inf : Area under the plasma concentration-time curve from time 0 to infinity. AUC 0-inf was calculated as the sum of AUC 0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant. C max : Maximum measured plasma concentration over the specified span of time. t max : Time of maximum measured plasma concentration. When the maximum value occurred at multiple time points, t max was defined as the first time point with this value. λz: The apparent first-order terminal elimination rate constant calculated from the semi-logarithmic plot of plasma concentration versus time. The parameter was calculated by linear least-squares regression analysis using the maximum number of points in the terminal logarithmic linear phase (e.g., three or more non-zero plasma concentrations) starting from the last non-zero concentration. t 1 / 2 : The apparent first-order terminal elimination half-life was calculated as 0.693 / λz. T lag Absorption lag 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 concentration of total Mo was slightly lower after administration of EC tablets (Treatment A) in the fasting state compared to uncoated capsules (UC) + PPI (Treatment C) in the fasting state. However, there was variability among the subjects, with 3 out of 18 showing much lower concentrations for EC tablets, 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) mean values were lower for EC tablets (Treatment A) in the fasting state than for UC capsules + PPI (Treatment C) in the fasting state. The GMR was in the range of 75.81% - 87.16%, and the lower limit of the associated 90% CI was <80.00% (Table 9), indicating a reduction in exposure on average. The median of T max was equivalent at 4.54 hours and 4.50 hours for each treatment, respectively, and was in an equivalent range (Table 8).

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

[0224] Administering EC tablets (treatment B) with food resulted in a significant decrease in mean total plasma Mo concentration (Figure 5). This was observed in all but two of the 17 subjects evaluable with this treatment. max AUC 0-t , and AUC inf The GMR decreased after EC tablets were administered 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 delay was similar and within a similar range, with and without food, at 4.55 hours and 4.54 hours, respectively (Table 8). Compared to EC tablets on a fast (Treatment A), more subjects (6 subjects) experienced delayed absorption, with the median (range) increasing to 3.00 hours (2.00–5.00 hours) (Table 8).

[0225] average t 1 / 2 The duration was essentially the same across all three treatments (Table 8), with an overall average of approximately 48 hours or 2 days. CL / F and Vz / F were comparable in the two fasting treatments, but were more expensive in those treatments due to the lower bioavailability after administration of EC tablets during feeding.

[0226] C max AUC 0-t , and AUC inf The lowest between-subject coefficient of variation (BSCV) was observed with UC capsules + PPI (treatment C) during fasting, with values ​​ranging from 15.8% to 19.1% (Table 8). Administration of EC tablets (treatment A) during fasting resulted in a higher BSCV ​​(26.1% to 35.2%; Table 8). When EC tablets were administered after a high-calorie / high-fat meal, the BSCV ​​was much higher, particularly in AUC. 0-t and AUC inf The percentages were 81.5% and 72.6%, respectively (Table 8). Compared to EC tablets administered under fasting conditions, the BSCV ​​for AUC was approximately 2.2 times higher when EC tablets were administered under feeding conditions.

[0227] As shown in Figures 8A and 8B, compared to UC+PPI in a fasted state (treatment C), there was a slight decrease in the mean ± standard error plasma concentration of total Mo after administration of EC tablets in a fasted state (treatment A). max Similar trends were observed for AUC(0-t) and AUC(inf) (Tables 6 and 7). Nevertheless, when examining the data for individual subjects, while similar patterns were observed in some individual subjects, the majority had equivalent total Mo concentration-time profiles for biscolinetetrathiomolybdate EC tablets and biscolinetetrathiomolybdate UC + PPI when both were administered under fasting conditions. However, administration of biscolinetetrathiomolybdate EC tablets (treatment B) during ingestion resulted in a consistent 60%–75% reduction in absorption 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. The data collected during the Phase II study described in Example 1 were further analyzed to characterize specific neurological changes after 24 weeks of treatment with WTX101.

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

[0230] result Of the 28 patients enrolled, 25 exhibited neurological symptoms. The mean baseline UWDRS Part II (Disability) and Part III (Neurological Status) scores were 6.6 (SD 10.0; range 0–35) and 22.8 (SD 21.0; range 0–83), respectively. By week 24, the mean [SD]UWDRS Part II score was 4.1[8.2]; p Both Part II and Part III scores (<0.001) improved. There was a very significant predictive relationship over time between the total scores of Part II and Part III (p<0.0001). The most common UWDRS Part III abnormalities at baseline were postural arm tremors (71%), dysarthria (68%), gait (61%), and limb dexterity and coordination scale items, such as 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 were 2.0 [0.8] and 1.8 [0.9], respectively). The greatest mean improvement (change %) over 24 weeks was observed in handwriting (51.4%), leg agility (40.8%), postural arm tremor (39.5%), and alternating hand movements (35.0%). Similar improvements were observed when total tremor or limb dexterity and coordination items were grouped together (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 patient cohort with WD. WTX101 treatment rapidly improved disability and neurological status in a 24-week phase 2 prospective trial in patients with 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 II study of Example 1 was further analyzed to characterize the details of neurological symptoms in Wilson's disease (WD) patients and specific neurological changes after 24 weeks of treatment with WTX101. The analysis of this data was generally performed as described in Example 5.

[0233] While neurological symptoms can be neutralized very quickly, previous existing treatments do not always alleviate symptoms, sometimes causing the well-known paradoxical early exacerbation of neurological disorders and / or poor patient tolerance. In a 24-week phase 2 study (NCT02273596; EudraCT 2014-001703-41), bischolinetetrathiomolybdate (WTX101) demonstrated a favorable safety profile with rapid control of non-ceruloplasmin-bound copper (NCC) levels and 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 improvement without paradoxical early exacerbations. Changes in neurological symptoms in the study were examined using data from Part III (Neurological Condition) of the UWDRS. Furthermore, this example explores quantitative relationships between patients with reported Wilson's disease (Part II) and patients with clinically assessed (Part III) neurological symptoms.

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

[0236] A 24-week Phase II open-label study was conducted in Europe and the United States. During the first 4–8 weeks, patients were adjusted for baseline N levels (excluding baseline) relative to plasma molybdenum. Depending on the CC concentration, patients received 15-60 mg of WTX101 once daily. Subsequently, the dosage was adjusted according to laboratory (including NCC concentrations adjusted for plasma molybdenum) and clinical evaluations (maximum daily dose administered: 120 mg).

[0237] Disability and neurological status were assessed using Parts II and III of the UWDRS at baseline and at weeks 4, 8, 12, 18, and 24, respectively. Disability (Part II): A 10-item questionnaire reported by the patient (total score range: 0–40; higher scores indicate greater disability). Neurological status (Part III): A 23-item clinician-assessed score (total score range: 0–143; higher scores indicate worse neurological status). The data (total scores of UWDRS Parts II and III, as well as AEs) were briefly summarized to indicate the status of the outcomes.

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

[0239] The least squares mean (standard error [SE], 95% confidence interval [CI]) values ​​were calculated for the change from baseline in the UWDRS total score using repeated measures analysis of a mixed model, and significance was assessed using two-sided p-values. To investigate and quantify the relationships between UWDRS total scores for Parts II and III, random coefficient analysis was performed using each patient's score from all study visits. Summary statistics were calculated for other results.

[0240] result In total, 28 patients received WTX101 (Table 12). Six patients discontinued treatment. Three experienced non-neurological adverse events, two had psychiatric disorders and were unable to adhere to the protocol, and one had neurological exacerbations due to disease progression. [Table 16]

[0241] UWDRS Disorders and Neurological Conditions: Total Score Mean (SD) total scores improved by 4.1 (8.2) for disability and 16.6 (17.7) for neurological status at week 24. The improvement was -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, and was significant in both cases (least squares mean [SE, 95% CI] change from baseline). A significant positive linear relationship existed between the total scores of UWDRS Part II and Part III (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 differences between items (i.e., 4 or 8), handwriting and speech were the most severely affected (Figures 10A and 10B).

[0243] Item group: Tremor was reported by the highest proportion of patients (23 patients, 82%), followed by gait (17 patients, 61%), dystonia (15 patients, 54%), limb agility and coordination (15 patients, 54%), and rigidity (12 patients, 43%). Considering the maximum possible score differences between item groups (Table 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 limb agility and coordination (1.3 [0.5]).

[0244] Changes from baseline to week 24 Individual items: Based on descriptive statistics, the mean percentage improvement was greatest in handwriting and foot agility (Figures 11A and 11B), and few patients showed a deterioration in either score. Figure 12). Two patients had aggravations of 2 points (finger tapping), while all other aggravations were 1 point.

[0245] Item group improvements in tremor (mean [SD], 34.2% [61.7]) and limb agility and coordination (29.2% [72.2]) were generally similar to improvements in individual items. Of the 22 patients analyzed, there were decreases of 4 and 3 points in scores, respectively (5 cases of worsening by 1 point, 1 case of worsening by 3 points [tremor], and 1 case of worsening by 4 points [limb agility and coordination]). Overall worsening of rigidity (26.9% [169.6]), dystonia (15.0% [135.2]), and gait (4.2% [77.8]) was 4, 3, and 6, respectively, and was attributable to individual factors (worsening between 1 and 8 points for rigidity, 2 and 4 points for dystonia, and 1 and 6 points for overall gait).

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

[0247] Example 7: Analysis of patients with or without cirrhosis Mortality in Wilson's disease is typically secondary to decompensated cirrhosis and liver failure; therefore, liver function is a crucial factor in determining the appropriate treatment regimen. The outcomes for patients with and without cirrhosis used in the patient pool of Example 1 were supplemented and analyzed with 48-week data generated during the 3-year extension of the initial trial. Example 1 was an open-label, single-arm, 24-week continuation study using WTX101 initially at 15–60 mg / day, followed by individualized response induction dosing (maximum dose of 120 mg / day). The extension was an open-label, single-arm, 3-year study using continued individualized response induction 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 estimated AST-to-platelet ratio index (APRI) (AST refers to aspartate aminotransferase). Summary statistics are 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's Disease Assessment Scale, and adverse events (AEs) were calculated. Of the 15 patients with cirrhosis, 13 completed the core study, and all are continuing in the extension study. Of the 13 patients without cirrhosis, 9 completed the core study, and all are continuing in the extension study. The patient flow in the extension study is shown in Figure 12.

[0249] NCC at baseline 補正 The cirrhosis level was 3.6 μmol / L in patients with cirrhosis and 3.7 μmol / L in patients without cirrhosis. WTX101 was effective in reducing NCC levels in patients with and without cirrhosis from baseline to 24 weeks. 補正 The level was reduced to a similar degree, and the improvement seen at week 24 was maintained until week 48. NCC 補正 The levels are shown in Figure 13.

[0250] In the core study, elevated ALT levels requiring dose adjustment occurred in 5 patients with cirrhosis and 7 patients without cirrhosis. Elevated ALT levels were associated with study discontinuation in 3 patients without cirrhosis. Elevated ALT levels during the core study were not accompanied by increased bilirubin levels. From week 24 to week 48, no elevated ALT levels requiring dose adjustment occurred, and ALT levels remained stable regardless of cirrhosis status. Figure 14 shows ALT levels in patients with and without cirrhosis. MELD score (severity of liver disease; score range) The scores (6-40) (Figure 15) and the modified Nazer score (prognostic index; score range, 0-20) (Figure 16) were low at baseline and remained stable through the core trial and up to week 48.

[0251] Mean albumin concentration (Figure 17A) and international normalized ratio (INR) (Figure 17B) remained stable in both patients with and without cirrhosis during the core study and up to week 48. Mean albumin concentration (Figure 17A) and blood clotting time (Figure 18) were within the normal range at baseline. These remained stable in both patients with and without cirrhosis during the core study and up to week 48. Patient-reported impairment and clinician-assessed neurological status were evaluated using the UWDRS. Improvements occurred during the core study and up to week 48, regardless of cirrhosis status (Figures 19A and 19B). The tolerance profile for WTX101 was favorable and similar in both 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 adverse events (AEs) were elevated ALT and GGT levels (in 3 patients with cirrhosis and 5 patients without cirrhosis, respectively), elevated AST levels (in 4 patients in each group), and tremor (in 4 patients without cirrhosis). During the extension period, fewer patients experienced AEs compared to the core study (9 patients with cirrhosis and 6 patients without cirrhosis). The most common AE was urinary tract infection (in 4 patients with cirrhosis). Severe adverse events (SAEs) occurred between weeks 0 and 48 in 4 patients with cirrhosis and 6 patients without cirrhosis. During the extension period, 2 patients in the cirrhosis group experienced SAEs that may be associated with WTX101. One patient had neutropenia and the other had hepatolenticular degeneration.

[0252] This analysis showed that the improvement in copper level control with WTX101 treatment compared to baseline was maintained from week 24 to week 48 of WTX101 treatment in both patient groups. Liver function remained stable with WTX101 for up to 48 weeks in patients with and without cirrhosis. The resistance profile of WTX101 was favorable and unaffected by the presence of cirrhosis. Therefore, WTX101 treatment remains effective and maintains good resistance regardless of whether treated patients had cirrhosis prior to treatment.

[0253] Those skilled in the art will understand that certain thresholds disclosed herein may vary somewhat depending on the specific conditions of the test and assay methods. Furthermore, those skilled in the art will understand that thresholds described as “greater than” or “less than” may, in certain embodiments, mean “equal to or greater than” or “equal to or less than,” respectively. Similarly, those skilled in the art will understand that thresholds described as “greater than or equal to” or “less than or equal to” may, in certain embodiments, mean “greater than” or “less than,” respectively.

[0254] The aforementioned detailed description is provided solely for clarity of understanding, and since the modifications are obvious to those skilled in the art, no unnecessary limitations should be inferred from it.

[0255] While the present invention is described in relation to its particular embodiments, it is subject to further modification, and this application is generally intended to encompass any variations, uses, or adaptations of the present invention in accordance with the principles of the present disclosure, and it will be understood that the present invention falls within the scope of known or customary practices in the relevant art and includes departures from the present disclosure that are applicable to the essential features described above and below within the appended claims.

[0256] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated in their entirety for all purposes. However, any references, articles, publications, patents, patent publications, and patent applications cited herein constitute part of common general knowledge in any country worldwide. It does not, and should not, acknowledge as constituting valid prior art or be considered a proposal of any form.

Claims

1. A method for treating Wilson's disease in a patient requiring treatment, comprising administering 15 mg of biscolinetetrathiomolybdate once daily.

2. A method for treating Wilson's disease in a patient requiring treatment, comprising administering 15 mg of biscolinetetrathiomolybdate once daily.

3. The method according to claim 1 or 2, wherein the 15 mg of biscolinetetrathiomolybdate is administered as a delayed-release formulation.

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

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

6. The patient's NCC measured before administration 補正 In comparison, NCC measured after 24 weeks of administration 補正 The method according to any one of claims 1 to 5, which shows a decrease in [something].

7. The patient's NCC measured before administration 補正 In comparison, NCC measured after 24 weeks of administration 補正 The method according to claim 6, which exhibits a reduction of at least 20%.

8. The patient's NCC measured before administration 補正 In comparison, NCC measured after 24 weeks of administration 補正 The method according to claim 6, which exhibits a reduction of at least 35%.

9. The patient's NCC measured before administration 補正 In comparison, NCC measured after 24 weeks of administration 補正 The method according to claim 6, which exhibits a reduction of at least 50%.

10. the NCC of the patient when measured prior to administration 補正 compared to the NCC when measured after 24 weeks of administration 補正 The method according to claim 6, showing at least a 75% decrease

11. The patient's NCC measured before administration 補正 In comparison, NCC measured after 48 weeks of administration 補正 The method according to any one of claims 1 to 5, which shows a decrease in [something].

12. The patient's NCC measured before administration 補正 In comparison, NCC measured after 48 weeks of administration 補正 The method according to claim 11, which exhibits a reduction of at least 20%.

13. The patient's NCC measured before administration 補正 In comparison, NCC measured after 48 weeks of administration 補正 The method according to claim 11, which exhibits a reduction of at least 35%.

14. The patient's NCC measured before administration 補正 In comparison, NCC measured after 48 weeks of administration 補正 The method according to claim 11, which exhibits a reduction of at least 50%.

15. The patient's NCC measured before administration 補正 Compared to 48 weeks NCC measured after administration 補正 The method according to claim 11, which exhibits a reduction of at least 75%.

16. A method for treating Wilson's disease in patients requiring treatment, comprising administering 30 to 90 mg of biscolinetetrathiomolybdate 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) Platelets greater than 30,000 / μL, and e) 10 ３ A method comprising one or more neutrophils greater than / μL.

17. The method according to claim 16, comprising administering 30 mg of biscolinetetrathiomolybdate daily.

18. The method according to claim 16, comprising administering 45 mg of biscolinetetrathiomolybdate daily.

19. The method according to claim 16, comprising administering 60 mg of biscolinetetrathiomolybdate daily.

20. The method according to claim 16, comprising administering 75 mg of biscolinetetrathiomolybdate daily.

21. The method according to claim 16, comprising administering 90 mg of biscolinetetrathiomolybdate daily.

22. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient exhibits an alanine aminotransferase (ALT) level at at least twice the ALT level shown at the time of initiation of biscolinetetrathiomolybdate therapy, and the method This involves reducing the dose of bischolinetetrathiomolybdate. If the patient is receiving 15 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate every other day. If the patient is receiving 30 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate once daily. If the patent is for biscolinetetrathiomolybdate administered once daily at a dose of 45 mg, then reducing the dose to 30 mg of biscolinetetrathiomolybdate administered once daily. If the aforementioned patent is for a dose of 60 mg of biscolinetetrathiomolybdate once daily, then reducing the dose to 45 mg of biscolinetetrathiomolybdate once daily. If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 75 mg, then reducing the dose to 60 mg of biscolinetetrathiomolybdate administered once daily, or If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 90 mg, a method comprising reducing the dose to biscolinetetrathiomolybdate administered once daily at a dose of 75 mg.

23. For patients with Wilson's disease receiving bischolinetetrathiomolybdate therapy A method for modifying scoline tetrathiomolybdate administration, wherein the patient exhibits an alanine aminotransferase (ALT) level at at least twice the upper limit of normal (ULN), and the method is This involves reducing the dose of bischolinetetrathiomolybdate. If the patient is receiving 15 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate every other day. If the patient is receiving 30 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate once daily. If the patent is for biscolinetetrathiomolybdate administered once daily at a dose of 45 mg, then reducing the dose to 30 mg of biscolinetetrathiomolybdate administered once daily. If the aforementioned patent is for a dose of 60 mg of biscolinetetrathiomolybdate once daily, then reducing the dose to 45 mg of biscolinetetrathiomolybdate once daily. If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 75 mg, then reducing the dose to 60 mg of biscolinetetrathiomolybdate administered once daily, or If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 90 mg, a method comprising reducing the dose to biscolinetetrathiomolybdate administered once daily at a dose of 75 mg.

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

25. The method according to claim 23, wherein the ULN is 34 IU / mL.

26. The method according to claim 23, wherein the ULN is 40 IU / mL.

25. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient's hemoglobin level is 70% or less of the hemoglobin level shown at the start of biscolinetetrathiomolybdate therapy, and the method is This involves reducing the dose of bischolinetetrathiomolybdate. If the patient is receiving 15 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate every other day. If the patient is receiving 30 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate once daily. If the patent is for biscolinetetrathiomolybdate administered once daily at a dose of 45 mg, then reducing the dose to 30 mg of biscolinetetrathiomolybdate administered once daily. If the aforementioned patent is for a dose of 60 mg of biscolinetetrathiomolybdate once daily, then reducing the dose to 45 mg of biscolinetetrathiomolybdate once daily. If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 75 mg, then reducing the dose to 60 mg of biscolinetetrathiomolybdate administered once daily, or If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 90 mg, a method comprising reducing the dose to biscolinetetrathiomolybdate administered once daily at a dose of 75 mg.

26. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient's platelet level is 70% or less of the platelet level shown at the time of initiation of biscolinetetrathiomolybdate therapy, and the method is This involves reducing the dose of bischolinetetrathiomolybdate. If the patient is receiving 15 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate every other day. If the patient is receiving 30 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate once daily. If the patent is for biscolinetetrathiomolybdate administered once daily at a dose of 45 mg, then reducing the dose to 30 mg of biscolinetetrathiomolybdate administered once daily. If the aforementioned patent is for a dose of 60 mg of biscolinetetrathiomolybdate once daily, then reducing the dose to 45 mg of biscolinetetrathiomolybdate once daily. If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 75 mg, then reducing the dose to 60 mg of biscolinetetrathiomolybdate administered once daily, or If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 90 mg, a method comprising reducing the dose to biscolinetetrathiomolybdate administered once daily at a dose of 75 mg.

27. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient exhibits neutrophil levels less than or equal to 70% of the neutrophil levels observed at the start of biscolinetetrathiomolybdate therapy, and the method is This involves reducing the dose of bischolinetetrathiomolybdate. If the patient is receiving 15 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate every other day. If the patient is receiving 30 mg of biscolinetetrathiomolybdate once daily, the dose should be reduced to 15 mg of biscolinetetrathiomolybdate once daily. If the patent is for biscolinetetrathiomolybdate administered once daily at a dose of 45 mg, then reducing the dose to 30 mg of biscolinetetrathiomolybdate administered once daily. If the aforementioned patent is for a dose of 60 mg of biscolinetetrathiomolybdate once daily, then reducing the dose to 45 mg of biscolinetetrathiomolybdate once daily. If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 75 mg, then reducing the dose to 60 mg of biscolinetetrathiomolybdate administered once daily, or If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 90 mg, a method comprising reducing the dose to biscolinetetrathiomolybdate administered once daily at a dose of 75 mg.

28. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient's alanine aminotransferase (ALT) levels are affected by the biscolinetetrathiomolybdate treatment. The ALT level shown at the start is greater than five times the ALT level shown, and the method is a) Discontinue biscoline tetrathiomolybdate, b) After the patient's ALT level is less than twice the level shown when bischoline tetrathiomolybdate treatment is initiated, If the patient was receiving 15 mg of biscolinetetrathiomolybdate every other day before discontinuing biscolinetetrathiomolybdate, administer 15 mg of biscolinetetrathiomolybdate every other day, or A method comprising administering 15 mg of biscolinetetrathiomolybdate once daily to the patient if the patient was taking biscolinetetrathiomolybdate at a dose of 15 to 90 mg once daily before discontinuing biscolinetetrathiomolybdate.

29. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient exhibits an alanine aminotransferase (ALT) level greater than 200 IU / mL, and the method is a) Discontinue biscoline tetrathiomolybdate, b) After the patient's ALT level is less than twice the level shown when bischoline tetrathiomolybdate treatment is initiated, If the patient was receiving 15 mg of biscolinetetrathiomolybdate every other day before discontinuing biscolinetetrathiomolybdate, administer 15 mg of biscolinetetrathiomolybdate every other day, or A method comprising administering 15 mg of biscolinetetrathiomolybdate once daily to the patient if the patient was taking biscolinetetrathiomolybdate at a dose of 15 to 90 mg once daily before discontinuing biscolinetetrathiomolybdate.

30. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient has a hemoglobin level less than 8 g / dL in the absence of bleeding, and the method is a) Discontinue biscoline tetrathiomolybdate, b) After the patient's hemoglobin level is equivalent to that shown when bischoline tetrathiomolybdate treatment is initiated, If the patient was receiving 15 mg of biscolinetetrathiomolybdate every other day before discontinuing biscolinetetrathiomolybdate, administer 15 mg of biscolinetetrathiomolybdate every other day, or A method comprising administering 15 mg of biscolinetetrathiomolybdate once daily to the patient if the patient was taking biscolinetetrathiomolybdate at a dose of 15 to 90 mg once daily before discontinuing biscolinetetrathiomolybdate.

31. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient has a platelet level less than 30,000 μL, and the method is a) Discontinue biscoline tetrathiomolybdate, b) After the patient's platelet levels are equivalent to those shown when bischoline tetrathiomolybdate therapy is initiated, If the patient was receiving 15 mg of biscolinetetrathiomolybdate every other day before discontinuing biscolinetetrathiomolybdate, administer 15 mg of biscolinetetrathiomolybdate every other day, or A method comprising administering 15 mg of biscolinetetrathiomolybdate once daily to the patient if the patient was taking biscolinetetrathiomolybdate at a dose of 15 to 90 mg once daily before discontinuing biscolinetetrathiomolybdate.

32. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient has a neutrophil level of 1.0 × 10⁻⁶ ３ The amount shown is less than / μL, and the above method is a) Discontinue biscoline tetrathiomolybdate, b) After the patient has shown neutrophil levels equivalent to those shown when bischolinetetrathiomolybdate therapy is initiated, If the patient was receiving 15 mg of biscolinetetrathiomolybdate every other day before discontinuing biscolinetetrathiomolybdate, administer 15 mg of biscolinetetrathiomolybdate every other day, or A method comprising administering 15 mg of biscolinetetrathiomolybdate once daily to the patient if the patient was taking biscolinetetrathiomolybdate at a dose of 15 to 90 mg once daily before discontinuing biscolinetetrathiomolybdate.

33. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient exhibits a bilirubin level greater than 2.4 mg / dL and an alanine aminotransferase (ALT) level greater than 120 IU / mL, and the method is a) Discontinue biscoline tetrathiomolybdate, b) After the patient shows bilirubin levels below the upper limit of normal, If the patient was receiving 15 mg of biscolinetetrathiomolybdate every other day before discontinuing biscolinetetrathiomolybdate, administer 15 mg of biscolinetetrathiomolybdate every other day, or A method comprising administering 15 mg of biscolinetetrathiomolybdate once daily to the patient if the patient was taking biscolinetetrathiomolybdate at a dose of 15 to 90 mg once daily before discontinuing biscolinetetrathiomolybdate.

34. A method for administering biscoline tetrathiomolybdate to treat a patient with Wilson's disease, wherein the patient has shown abnormal test results, and the method is (a) During the first period, administer to the patient a first dose level containing approximately 15 to 90 mg of biscoline tetrathiomolybdate per day, followed by, (b) A method comprising administering a second dose level during a second period, which contains at least about 15 mg / day less biscolinetetrathiomolybdate than the first dose level.

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

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

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

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

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

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

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

42. The method according to any one of claims 34 to 40, wherein the abnormal test result includes a hemoglobin level of 70% or less of the baseline hemoglobin level measured before administration of bischolinetetrathiomolybdate.

43. The method according to any one of claims 34 to 40, wherein the abnormal test result includes a platelet level of 70% or less of the baseline platelet level measured before administration of bischolinetetrathiomolybdate.

44. The method according to any one of claims 34 to 40, wherein the abnormal test result includes a neutrophil level of 70% or less of the baseline neutrophil level measured before administration of bischolinetetrathiomolybdate.

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

46. The method according to any one of claims 34 to 40, wherein the abnormal test result includes a hemoglobin level of 70% or less of the normal hemoglobin level.

47. The method according to any one of claims 34 to 40, wherein the abnormal test result includes a platelet level of 70% or less of the normal platelet level.

48. The method according to any one of claims 34 to 40, wherein the abnormal test result includes a neutrophil level of 70% or less of the normal neutrophil level.

49. The aforementioned abnormal test results include an ALT level at least five times higher than the baseline alanine aminotransferase (ALT) measured before administration of bischoline tetrathiomolybdate, and the method is (c) The method of claim 34, further comprising interrupting treatment during a third period between steps (a) and (b) until the patient shows an alanine aminotransferase (ALT) level less than twice the baseline ALT measured before administration of biscoline tetrathiomolybdate.

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

51. The aforementioned abnormal test results include a hemoglobin level lower than 8 g / dL in the absence of bleeding. (c) The method according to claim 34, wherein treatment is interrupted during a third period between steps (a) and (b) until the patient's hemoglobin level is equivalent to the hemoglobin level measured before administration of bischolinetetrathiomolybdate.

52. The aforementioned abnormal test results include platelet levels less than 30,000 μL, and the method is (c) The method according to claim 34, further comprising interrupting treatment during a third period between steps (a) and (b) until the patient's platelet level is equivalent to the platelet level measured before administration of bischolinetetrathiomolybdate.

53. The aforementioned abnormal test results include neutrophil levels lower than 1.0 × 10³ / μL, (c) The method according to claim 34, wherein treatment is interrupted during a third period between steps (a) and (b) until the patient shows neutrophil levels equivalent to those measured before administration of bischolinetetrathiomolybdate.

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

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

56. The aforementioned patient a) NCC 補正 level, b) Alanine aminotransferase (ALT) levels, c) Hemoglobin level, d) Platelet level, and e) The method according to any one of claims 6 to 55, further comprising measuring at least one of the neutrophil levels.

57. A method for modifying biscolinetetrathiomolybdate administration to a patient with Wilson's disease receiving biscolinetetrathiomolybdate therapy, wherein the patient exhibits neurological deterioration, the patient exhibits a baseline UWDRS Part III score less than 20 as measured before biscolinetetrathiomolybdate administration, and the neurological deterioration includes an increase of at least 4 points in the baseline UWDRS Part III score above the baseline UWDRS Part III score, wherein the method is: a) Discontinue biscoline tetrathiomolybdate, b) After the patient no longer shows signs of neurological deterioration, If the patient is receiving 15 mg of biscolinetetrathiomolybdate once daily, administer 15 mg of biscolinetetrathiomolybdate every other day. If the patient is receiving 30 mg of biscolinetetrathiomolybdate once daily, administer 15 mg of biscolinetetrathiomolybdate once daily. If the patent is for biscolinetetrathiomolybdate administered once daily at a dose of 45 mg, then administer 15 or 30 mg of biscolinetetrathiomolybdate once daily. If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 60 mg, then administer 30 mg of biscolinetetrathiomolybdate once daily. If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 75 mg, then administer 30 to 45 mg of biscolinetetrathiomolybdate once daily. or If the aforementioned patent is for biscolinetetrathiomolybdate administered once daily at a dose of 90 mg, the method comprises administering 45 mg of biscolinetetrathiomolybdate once daily.

58. The method according to claim 1, wherein biscolinetetrathiomolybdate is administered to a fasted state.

59. The method according to claim 5, wherein the tablet is an enteric-coated tablet.

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

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

62. A composition comprising biscoline tetrathiomolybdate for use in a method of treating Wilson's disease in patients.

63. The composition for use according to claim 62, wherein the method comprises administering 15 mg to 120 mg of biscolinetetrathiomolybdate on a daily or every other day basis.

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

65. The composition for use according to any one of claims 62 to 64, 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.

66. a) The total tremor phenotype includes one or more neurological symptoms of Wilson's disease, as defined by the Unified Wilson's Disease Rating Scale (UWDRS) Part III, which includes resting tremor, head tremor, arm-postural tremor and flapping tremor, postural tremor-leg tremor, and jaw tremor. b) The total gait phenotype includes one or more neurological symptoms of Wilson's disease, selected from chair-asking, postural-trunk dystonia, stance ataxia, and parkinsonism, gait-leg dystonia, ataxia, and parkinsonism, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III: c) The dystonic phenotype includes one or more neurological symptoms of Wilson's disease, selected from palatomandibular dystonia, cervical dystonia, arm and hand dystonia, trunk dystonia, and gait-leg dystonia, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III. d) Limb agility and coordination phenotypes include one or more neurological symptoms of Wilson's disease, as determined by the Unified Wilson's Disease Assessment Scale (UWDRS) Part III, which consists of finger tapping, rapid alternating hand movements, handwriting, finger-to-nose test, and leg agility. e) The composition for use according to claim 65, wherein the rigidity phenotype comprises one or more neurological symptoms of Wilson's disease, selected from the arms, legs, and neck, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III.

67. a) The total tremor phenotype is characterized by a UWDRS Part III score of 30–45, b) The total gait phenotype is characterized by 20–32 UWDRS Part III scores, c) The dystonia phenotype is characterized by a UWDRS Part III score of 15–28, d) Limb agility and coordination phenotypes are characterized by 20–36 UWDRS Part III scores, e) The composition for use according to claim 66, wherein the rigid phenotype is characterized by a UWDRS Part III score of 10 to 20.

68. A 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 agility, and combinations thereof.

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

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

71. The aforementioned patient, a) Total tremor phenotypes 5-25, b) 5 to 20 total walking phenotypes, c) Dystonia phenotypes 5-15, d) Agility and coordination phenotypes of 5-20 limbs, and e) The composition for use according to claim 70, which shows a reduction in one or more UWDRS Part III scores from 5 to 15 rigid phenotypes.

72. The composition for use according to claim 70, wherein the patient exhibits one or more of the following: a decrease in the UWDRS Part III score for handwriting 1 to 3, a decrease in the UWDRS Part III score for leg agility 1 to 6, and a decrease in the UWDRS Part III score for handwriting and leg agility 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's NCC measured before administration 補正 In comparison, NCC measured after 24 weeks of administration 補正 A composition for use according to claim 73, which shows a reduction in [amount].

75. The patient's NCC measured before administration 補正 In comparison, NCC measured after 48 weeks of administration 補正 A composition for use according to claim 73, which shows a reduction in [amount].

76. The aforementioned 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) Platelets greater than 30,000 / μL, and e) 10 ３ The composition for use according to claim 73, comprising one or more neutrophils greater than / μL.

77. The method according to any one of claims 1 to 61, 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.

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

79. a) The total tremor phenotype includes one or more neurological symptoms of Wilson's disease, as defined by the Unified Wilson's Disease Rating Scale (UWDRS) Part III, which includes resting tremor, head tremor, arm-postural tremor and flapping tremor, postural tremor-leg tremor, and jaw tremor. b) The total gait phenotype includes one or more neurological symptoms of Wilson's disease, selected from chair-asking, postural-trunk dystonia, stance ataxia, and parkinsonism, gait-leg dystonia, ataxia, and parkinsonism, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III: c) The dystonic phenotype includes one or more neurological symptoms of Wilson's disease, selected from palatomandibular dystonia, cervical dystonia, arm and hand dystonia, trunk dystonia, and gait-leg dystonia, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III. d) Limb agility and coordination phenotypes include one or more neurological symptoms of Wilson's disease, as determined by the Unified Wilson's Disease Assessment Scale (UWDRS) Part III, which consists of finger tapping, rapid alternating hand movements, handwriting, finger-to-nose test, and leg agility. e) The method according to claim 77 or 78, wherein the rigidity phenotype comprises one or more neurological symptoms of Wilson's disease, selected from the arms, legs, and neck, according to the Unified Wilson's Disease Rating Scale (UWDRS) Part III.

80. a) The total tremor phenotype is characterized by a UWDRS Part III score of 30–45, b) The total gait phenotype is characterized by 20–32 UWDRS Part III scores, c) The dystonia phenotype is characterized by a UWDRS Part III score of 15–28, d) Limb agility and coordination phenotypes are characterized by 20–36 UWDRS Part III scores, e) The method according to claim 79, wherein the rigid phenotype is characterized by a UWDRS Part III score of 10 to 20.

81. The method according to claims 1 to 61 or 77 to 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 agility, and combinations thereof.

82. The method according to claim 81, wherein the patient shows a handwriting score according to UWDRS Part III 2-4, a leg agility score according to UWDRS Part III 2-8, or a handwriting and leg agility score according to UWDRS Part III 4-12.

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

84. The aforementioned patient, a) Total tremor phenotypes 5-25, b) 5 to 20 total walking phenotypes, c) Dystonia phenotypes 5-15, d) Agility and coordination phenotypes of 5-20 limbs, and e) The method according to claim 83, wherein one or more UWDRS Part III scores from 5 to 15 rigid phenotypes show a decrease.

85. The method according to claim 83, wherein the patient exhibits one or more of the following: a decrease in the UWDRS Part III score for handwriting 1 to 3, a decrease in the UWDRS Part III score for leg agility 1 to 6, and a decrease in the UWDRS Part III score for handwriting and leg agility 2 to 9.

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