Tetrathiomolybdic acid for use in the treatment of copper metabolism-related diseases or disorders (Wilson's disease)

Abstract

The present disclosure relates to methods for treating a copper metabolism-related disease or disorder, such as Wilson's disease (WD). In one embodiment, the present disclosure provides a method for treating a copper metabolism disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of tetrathiomolybdic acid ("TTM") or a pharmaceutically acceptable salt thereof, wherein the subject is at least 12 years of age, and the subject has had an incomplete response to and / or is intolerant to standard of care treatment. For purposes of this disclosure, a subject who has had an incomplete response may also be referred to as an "incomplete responder" or "inadequate responder."

Description

[Technical Field]

[0001] The present disclosure relates to methods of treating copper metabolism-related diseases or disorders, such as Wilson's disease (WD). [Background technology]

[0002] 2. Description of Related Art Wilson disease (WD) is an autosomal recessive disorder of copper transport dysfunction. Mutations in the ATP7B gene result in defective production of the copper transporter ATPase2, which leads to impaired incorporation of copper into ceruloplasmin (Cp), impaired biliary excretion of copper, increased exchangeable copper, and copper accumulation in the liver, brain, and other tissues, resulting in organ damage and dysfunction. Ceruloplasmin is a serum ferroxidase and contains more than 95% of the copper found in plasma in healthy humans.

[0003] The prevalence of genetic markers associated with WD is approximately 1 per 30,000 population worldwide. Of those with an identified mutation, disease symptoms are present in approximately 50%. The majority of patients are diagnosed before the age of 30. A recent nationwide population-based epidemiological study based in France found a diagnosed prevalence of WD of 1.5 per 100,000 population.

[0004] The typical clinical presentation of WD is in adolescence to early adulthood. Genetic screening and genotype-phenotype correlation are complicated by the large number (>500) associated ATP7B mutations, and most individuals with WD are compound heterozygotes. Initial signs and symptoms of WD are primarily hepatic (approximately 40%), neurological (approximately 40%), or psychiatric (approximately 20%), although patients often develop mixed hepatic and neuropsychiatric disorders. Untreated or inappropriately treated patients experience progressive morbidity, and mortality is usually secondary to cirrhosis. Liver transplantation is the only effective therapy for WD-related acute liver failure; other causes of death associated with WD include hepatic malignancies and neurological deterioration with severe starvation debilitation.

[0005] Disease control in patients with neurological symptoms at the time of WD diagnosis is an area of ​​particular interest. More than one-third of patients with neurological symptoms show no improvement after four years of treatment with chelating agents. This failure to respond to chelation therapy with neurological findings may reflect irreversible damage to the nervous system. Furthermore, in a recent study, approximately 50% of patients had residual neurological symptoms despite several years of therapy with copper regulators. Deterioration of neurological symptoms upon initiation of treatment has been reported in approximately 25% of patients initiated on penicillamine and trientine, and up to 50% of these patients do not recover. The mechanism behind this deterioration is thought to be that mobilization of copper from the liver leads to an increase in brain copper, which is associated with neurological progression. This theory is supported by non-clinical data. Copper accumulation in the central nervous system is an evolutionary, long-term process. Excess copper throughout the body (not just from the liver) can gradually accumulate in the central nervous system over time.

[0006] Currently available medications have high discontinuation rates due to adverse events (AEs) and treatment failure. Furthermore, these medications must be administered two to five times daily and must be taken in an empty stomach. The AE profile and complex dosing regimens of these medications result in poor adherence and high treatment failure rates, which are major concerns in diseases requiring lifelong treatment, such as WD. Furthermore, although standard treatment for WD is considered to have an acceptable safety profile, continuous monitoring is required to timely identify potential adverse effects, confirm treatment efficacy, and ensure adherence to drug therapy.

[0007] Thus, there remains a need for improvements to the standard of care treatments for copper metabolism-related diseases or disorders. Summary of the Invention

[0008] The present disclosure generally provides methods useful for treating a copper metabolism-related disease or disorder, such as Wilson's disease, in a subject.

[0009] In one embodiment, the present disclosure provides a method for treating a copper metabolism disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of tetrathiomolybdic acid ("TTM") or a pharmaceutically acceptable salt thereof, wherein the subject is at least 12 years of age, and the subject has had an incomplete response to and / or is intolerant to standard of care treatment. For purposes of this disclosure, subjects who have had an incomplete response may also be referred to as "incomplete responders" or "inadequate responders."

[0010] In some embodiments of the methods, uses, or compositions described herein, the copper metabolism disease or disorder is Wilson's disease.

[0011] In another embodiment, the present disclosure provides tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof for treating a copper metabolism-related disease or disorder in a subject, wherein a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered to the subject, wherein the subject is at least 12 years of age, and the subject has had an incomplete response to and / or is intolerant to standard of care treatment.

[0012] In another embodiment, the present disclosure provides use of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a copper metabolism-related disease or disorder in a subject, wherein a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered to the subject, the subject is at least 12 years of age, and the subject has had an incomplete response to and / or is intolerant to standard of care treatment.

[0013] These and other features and advantages of the claimed invention will be more fully understood from the following detailed description taken in conjunction with the appended claims, which should be noted that the scope of the claims is defined by the recitations in the claims, rather than by a specific discussion of the features and advantages described herein. [Brief explanation of the drawings]

[0014] The accompanying drawings are included to provide a further understanding of the compositions and methods of the present disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiments of the present disclosure and, together with the description, serve to explain the principles and operation of the present disclosure.

[0015] [Figure 1A] Schematic diagram of the study provided in Example 1. Abbreviations: SoC = standard of care. [Figure 1B] FIG. 1 is a schematic diagram of the enrollment and study design of the study provided in Example 1. [Figure 2] Means and 95% CIs (full analysis set) for plasma total copper, directly measured nonceruloplasmin-bound copper (dNCC), and 24-hour urinary copper over time by cohort in TTM-treated participants are shown. The dashed red line is the lower limit of the normal reference range for plasma total copper, 11.3 μmol / L. [Figure 3] Means and 95% CIs (full analysis set) for plasma total copper, directly measured NCC, and 24-hour urinary copper over time by cohort in SoC-treated participants are shown. The dashed red line is the lower limit of the normal reference range for plasma total copper, 11.3 μmol / L. [Figure 4] Means and 95% CIs (full analysis set) for plasma total copper, directly measured NCC, and 24-hour urinary copper over time by cohort in zinc monotherapy-treated participants are shown. The dashed red line is the lower limit of the normal reference range for plasma total copper, 11.3 μmol / L. Cohort 2 participants were not treated with zinc monotherapy. [Figure 5] Means and 95% CIs (full analysis set) for plasma total copper, directly measured NCC, and 24-hour urinary copper over time by cohort in penicillamine (+ / - zinc)-treated participants are shown. The dashed red line is the lower limit of the normal reference range for plasma total copper, 11.3 μmol / L. [Figure 6]Means and 95% CIs (full analysis set) for plasma total copper, directly measured NCC, and 24-hour urinary copper over time by cohort in trientine (+ / - zinc)-treated participants are shown. The dashed red line is the lower limit of the normal reference range for plasma total copper, 11.3 μmol / L. [Figure 7] Box plots of plasma CpC / Cp ratios by treatment (TTM vs. SoC) in Study 301 are shown. [Figure 8] Box plots of calculated mean daily AUC (weeks 0-48) values ​​for plasma total and ultrafiltrate molybdenum by age group (adult vs. adolescent) are shown (PK analysis set). [Figure 9] Box plots of calculated mean daily AUEC (weeks 0–48) values ​​for plasma total copper (PTC), dNCC, and LBC by age group (adult vs. adolescent) are shown (PD and biomarker analysis set). [Figure 10] The increase from baseline in directly measured NCC (μmol / L) in plasma for each of the three patients in Study 204 is shown. [Figure 11] The increase from baseline in daily fecal copper excretion (mg) for each of the three patients in Study 204 is shown. [Figure 12] The decrease from baseline in mean daily net copper balance (mg) for each of the three patients in Study 204 is shown. [Figure 13] Least squares means and standard errors of UWDRS Part II scores (range 0-40) improvement from baseline over 5 years of TTM (pooled full analysis set, studies 301 and 201). X-axis legend: red = number of participants, black = weeks since initiation of TTM treatment. [Figure 14] Least squares means and standard errors of UWDRS Part III scores (range 0-175) improvement from baseline over 5 years of TTM are shown (pooled full analysis set, studies 301 and 201). Note: X-axis legend: Red = number of participants, black = weeks since initiation of TTM treatment. [Figure 15]Least squares means and standard errors of UWDRS Part III functioning subscale scores (range 0-10) are shown for improvement from baseline over 5 years of TTM (pooled full analysis set, studies 301 and 201). Note: X-axis legend: Red = number of participants, black = weeks since initiation of TTM treatment. [Figure 16] ALT mean over time and 95% CI are shown (primary evaluation period - safety set). [Figure 17] GGT mean over time and 95% CI are shown (primary evaluation period - safety set). [Figure 18] Total cholesterol mean over time and 95% CI are shown (primary evaluation period - safety set). Note: Upper limit of normal: 5.17 mmol / L = 200 mg / dL. [Figure 19] Triglyceride mean over time and 95% CI are shown (Primary Evaluation Period - Safety Set). Note: Upper limit of normal: 1.69 mmol / L = 150 mg / dL. [Figure 20] Figure 1 shows improvement in UWDRS part II scores for most groups at week 24. a Symptomatic patients were those with a UWDRS part II score of greater than 0 at baseline. Data for these subgroups are from a post-hoc analysis. [Figure 21] Figure 1 shows improvement in UWDRS part III scores for most groups at week 24. a Symptomatic patients were those with a UWDRS part III score of greater than 0 at baseline. Data for these subgroups are from a post-hoc analysis. [Figure 22] Figure 1 shows improvement in CGI-I scores at TTM at 48 weeks relative to SoC. [Figure 23] 24-hour urinary copper concentrations (μmol / day, mean (SD)) are shown. P / T, penicillamine / trientine; Zn, zinc. [Figure 24] Net Promoter Score for UWDRS Part II Total Score for the incomplete or intolerant responder group is shown. [Figure 25] 1 shows the heterogeneity of symptoms at baseline for the incomplete or intolerant responder groups. [Figure 26] Individual symptom responses are shown for the incomplete or intolerant responder group when treated with TTM and standard therapy. [Figure 27] Figure 1 shows the least squares means and standard errors of the improvements from baseline over 5 years of TTM treatment in UWDRS Part III scores (range 0-175). DETAILED DESCRIPTION OF THE INVENTION

[0016] Before the disclosed processes and materials are described, it is to be understood that aspects described herein are not limited to specific embodiments, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and unless specifically defined herein, is not intended to be limiting.

[0017] In light of the present disclosure, the methods, uses, and compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) described herein can be adapted by one of skill in the art to meet desired needs. The present disclosure provides improvements in the treatment of copper metabolism-related diseases or disorders.

[0018] Approximately half of newly diagnosed WD patients are under 18 years of age. Standard treatments for WD are approved for use in children or adolescents, but significant unmet needs remain regarding the efficacy, safety, and simplicity of dosing regimens. All currently available WD treatments are associated with adverse effects (e.g., neurological deterioration) in a subset of patients, which may require treatment adjustment, substitution, or even discontinuation. These adverse effects also reduce patient adherence to treatment, which may itself lead to clinical deterioration and even death. All require multiple daily doses to achieve adequate copper control. The burden of multiple daily doses for standard treatments can negatively impact medical adherence and clinical outcomes, particularly among patients who discontinue treatment altogether.

[0019] As described above, there is a need in the art for improving the standard of care treatment for copper metabolism-related diseases or disorders, particularly WD. Tetrathiomolybdic acid ("TTM") or its pharmaceutically acceptable salts are an alternative to standard of care treatment. For example, bis-choline tetrathiomolybdate ("BC-TTM") (also known as ALXN1840, thiomolybdate choline, and thiomolybdic acid; formerly known as WTX101) is an investigational oral first-in-class copper protein-binding molecule being developed for the treatment of WD. BC-TTM has the following structure: [ka] and is described in detail in International Publication No. WO 2019 / 110619, which is incorporated herein by reference in its entirety. It is expected that improved long-term adherence to TTM treatment compared to current treatment options may be achieved through improved tolerability and the convenience of a simplified once-daily (QD) dosing regimen. Furthermore, the once-daily dosing and small tablet diameter (5 mm) of the 7.8 mg dose of TTM may increase treatment adherence.

[0020] In one embodiment, the disclosure described herein provides a method for treating a copper metabolism-related disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof, wherein the subject is at least 12 years of age, and the subject has had an incomplete response to and / or is intolerant to standard of care treatment. For example, in at least one embodiment, a subject who has had an incomplete response may also be referred to as an "incomplete responder" or "inadequate responder."

[0021] Another aspect of the present disclosure provides tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof for treating a copper metabolism-related disease or disorder in a subject as described herein. The method for treating a copper metabolism-related disease or disorder in a subject using tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof comprises administering to the subject a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof as described herein, wherein the subject is at least 12 years of age, and the subject has had an incomplete response to and / or is intolerant to standard of care treatment as described herein. For example, in at least one embodiment, a subject who has had an incomplete response may also be referred to as an "incomplete responder" or "inadequate responder."

[0022] Another aspect of the present disclosure provides a use of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a copper metabolism-related disease or disorder in a subject. The use comprises administering to the subject a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof as described herein, wherein the subject is at least 12 years of age, and the subject has had an incomplete response to and / or is intolerant to standard of care treatment as described herein. For example, in at least one embodiment, a subject who has had an incomplete response may also be referred to as an "incomplete responder" or "inadequate responder."

[0023] In certain embodiments of the disclosed methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the copper metabolism-related disease or disorder is Wilson's disease.

[0024] In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the copper metabolism-related disease or disorder is copper toxicity (e.g., from high exposure to copper sulfate fungicides, consumption of high-copper drinking water, excessive use of copper supplements, etc.). In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the copper metabolism-related disease or disorder is copper deficiency, Menkes disease, or aceruloplasminemia. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the copper metabolism-related disease or disorder is selected from the group consisting of poor academic performance, acne, attention-deficit / hyperactivity disorder, amyotrophic lateral sclerosis (ALS), atherosclerosis, autism, Alzheimer's disease, Candida overgrowth, chronic fatigue, cirrhosis, depression, elevated adrenergic activity, elevated copper protein, elevated norepinephrine activity, emotional meltdown, fibromyalgia, frequent anger, age-related copper excretion dysfunction, high anxiety, hair loss, liver disease, hyperactivity, hypothyroidism, estrogen intolerance, contraceptive intolerance, Kayser-Fleischer rings, learning disability, low dopamine activity, multiple sclerosis, neurological problems, oxidative stress, Parkinson's disease, poor concentration, poor attention span at least one selected from the group consisting of: nausea, vomiting, nausea, vomiting, nausea, vomiting of the tongue, nausea, vomiting of the tongue, nausea and ...

[0025] As used herein, the terms "treatment" and "treating" mean (i) ameliorating the referenced disease state, condition, or disorder (or symptoms thereof), e.g., ameliorating the disease, condition, or disorder (i.e., reversing or improving the pathology and / or symptomology) in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder, e.g., reducing the severity of the disease or its symptoms or inhibiting the progression of the disease, or (ii) eliciting the referenced biological effect.

[0026] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and refer to any animal, including a mammal, and in at least one embodiment of a method, use, or composition of the present disclosure (e.g., comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a human. In certain embodiments of a method, use, or composition of the present disclosure (e.g., comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject is a healthy subject. In certain embodiments of a method, use, or composition of the present disclosure (e.g., comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject suffers from WD. In certain embodiments of a method, use, or composition of the present disclosure described herein (e.g., comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has cirrhosis. In certain other embodiments of a method, use, or composition of the present disclosure (e.g., comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject does not have cirrhosis. In certain embodiments of the disclosed methods, uses, or compositions (eg, those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject is at least 18 years of age.

[0027] In some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received treatment with a standard of care for a copper metabolism-related disease or disorder for at least 28 days.

[0028] In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has received standard of care treatment for WD for at least 4 weeks. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the standard of care treatment has been for at least 6 weeks, or at least 12 weeks, or at least 24 weeks, or at least 36 weeks, or at least 48 weeks, or at least 52 weeks, or at least 72 weeks. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received standard of care treatment for a copper metabolism-related disease or disorder for at least 28 months, at least 36 months, at least 42 months, or at least 48 months. For example, in some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received treatment with a standard of care for a copper metabolism-related disease or disorder for at least 72 months, at least 96 months, at least 120 months, or at least 142 months.

[0029] Standard of care treatment need not be continuous. For example, in certain embodiments of the methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) of the present disclosure, a subject may receive treatment intermittently, for a total of at least 4 weeks (e.g., at least 6, or at least 12, or at least 24, or at least 36, or at least 48, or at least 52, or at least 72 weeks, or at least 28 months, or at least 28 months, at least 36 months, at least 42 months, or at least 48 months, at least 72 months, at least 96 months, at least 120 months, or at least 142 months). However, in certain embodiments of the methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) of the present disclosure, standard of care treatment is continuous.

[0030] In the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) described herein, the subject has completed standard of care treatment at least two weeks prior to administration of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has completed standard of care treatment at least three weeks, at least four weeks, or at least six weeks prior to administration of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments of the disclosed methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has symptoms associated with a copper metabolism-related disease or disorder after receiving standard of care treatment for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

[0032] As noted above, in various embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) described herein, the subject has had an incomplete response to and / or is intolerant to standard of care treatment. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject is an incomplete responder to standard of care treatment. As used herein, an incomplete responder (also known as an "inadequate responder") has an incomplete or inadequate response to standard of care treatment. For example, in some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), an incomplete or inadequate responder has symptoms associated with a copper metabolism-related disease or disorder after receiving standard of care treatment for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

[0033] In some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), an incomplete or inadequate responder has a Unified Wilson Disease Rating Scale (UWDRS) Part II total score of greater than 0 or a Unified Wilson Disease Rating Scale (UWDRS) Part III total score of greater than 0 prior to administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof. For example, in certain embodiments of the methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) described herein, a subject who has had an incomplete or inadequate response to treatment with standard of care has a Unified Wilson Disease Rating Scale (UWDRS) Part II total score of greater than 0 and a Unified Wilson Disease Rating Scale (UWDRS) Part III total score of greater than 0 prior to administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments of the methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), subjects who had an incomplete or inadequate response to standard of care treatment prior to administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof have a Unified Wilson Disease Rating Scale (UWDRS) Part II score of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

[0035] In some embodiments of the methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), subjects who had an incomplete or inadequate response to treatment with standard of care prior to administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof have a Unified Wilson Disease Rating Scale (UWDRS) Part II score of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

[0036] In some embodiments of the methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), subjects who had an incomplete or inadequate response to treatment with standard of care prior to administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof have a Unified Wilson Disease Rating Scale (UWDRS) Part III score of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

[0037] In some embodiments of the methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), subjects who had an incomplete or inadequate response to treatment with standard of care prior to administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof have a Unified Wilson Disease Rating Scale (UWDRS) Part III score of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

[0038] In some embodiments of the methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject is intolerant to standard of care treatment. For example, in some embodiments of the methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously been determined by a medical professional to be intolerant to standard of care treatment or has had an adverse event after receiving standard of care treatment and prior to administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof. In some embodiments of the methods, uses, or compositions of the present disclosure (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously been determined by a medical professional to be intolerant to standard of care treatment and has had an adverse event after receiving standard of care treatment and prior to administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof. In some embodiments of the methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has symptoms associated with a copper metabolism-related disease or disorder after receiving standard of care treatment for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

[0039] The disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) are also useful as second-line and / or first-line maintenance treatments for WD. Thus, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received treatment with the standard of care (SoC) for WD. For example, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received trientine (also known as triethylenetriamine; N'-[2-(2-aminoethylamino)ethyl]ethane-1,2-diamine). Trientine may be sold in the form of a tetrahydrochloride salt under the name CUPRIOR® (GMP-Orphan United Kingdom Ltd) or CUVRIOR™ (Orphalan), in the form of a hydrochloride salt under the name SYPRINE® (Aton Pharma, Inc., Bausch Health), or in the form of a dihydrochloride salt under the name CUFENCE (Univar, Inc.). In certain other embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received trientine and zinc. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received D-penicillamine (also known as penicillamine; (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid). D-penicillamine may be sold under the name CUPRIMINE® (Bausch Health) or DEPEN® (Meda Pharmaceuticals). In certain other embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received D-penicillamine and zinc.In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received zinc. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received trientine, D-penicillamine, and / or zinc. In certain other embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the subject has previously received trientine and / or D-penicillamine. For example, in some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the standard of care treatment includes trientine, D-penicillamine, and / or zinc. In certain other embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the standard of care treatment includes trientine and / or D-penicillamine.

[0040] As provided above, tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered in the methods, uses, and compositions of the present disclosure. In some embodiments of the methods, uses, or compositions of the present disclosure described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks. In certain embodiments of the methods, uses, or compositions of the present disclosure (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered to a subject in a fasting state.

[0041] Therapeutically effective amounts of tetrathiomolybdic acid have been previously established. For example, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), tetrathiomolybdic acid may be administered in the range of about 7.8 to 60 mg per day. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), tetrathiomolybdic acid is administered in an amount of about 7.8 mg every other day (or alternatively, 3.9 mg per day). In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), tetrathiomolybdic acid is administered in an amount of about 7.8 mg per day.

[0042] In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), increasing the therapeutically effective amount of tetrathiomolybdic acid during treatment may provide additional benefits. Thus, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the therapeutically effective amount of tetrathiomolybdic acid increases after 6 weeks (i.e., 42 days) of treatment. For example, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the initial therapeutically effective amount of tetrathiomolybdic acid (i.e., days 1 through 42) is about 7.8 mg every other day. The increased subsequent therapeutically effective amount of tetrathiomolybdic acid (i.e., after day 42, e.g., day 43 or later) is about 7.8 mg per day in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof).

[0043] In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), decreasing the therapeutically effective amount of tetrathiomolybdic acid during treatment may provide additional benefits. Thus, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the therapeutically effective amount of tetrathiomolybdic acid decreases after 6 weeks (i.e., 42 days) of treatment. For example, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the initial therapeutically effective amount of tetrathiomolybdic acid (i.e., days 1-42) is about 7.8 mg per day. The reduced subsequent therapeutically effective amount of tetrathiomolybdic acid (i.e., after day 42, e.g., day 43 or later) is about 7.8 mg every other day in certain embodiments of a method, use, or composition of the disclosure (e.g., one comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof).

[0044] As described above, in some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the tetrathiomolybdic acid may be in the form of a pharmaceutically acceptable salt. "Pharmaceutically acceptable salt" refers to a salt of a compound disclosed herein that possesses the desired pharmacological activity of the parent compound. The salt is not particularly limited. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2]sulfonic acid, 4-methyl-2 ... or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or salts formed when an acidic proton present in the parent compound is coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine.For example, in some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the tetrathiomolybdic acid is a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt may be bis(triethylmethylammonium), bis(triethylphenylammonium), bis(acetylcholine), bis[2-(methoxy)ethyltrimethylammonium], bis[alkyldimethyl(phenylmethyl)ammonium], bis(1-ethyl-3-methyl-1H-imidazolium), bis(phenyltrimethylammonium), bis(benzyltrimethylammonium), pentane-1,5-bis(trimethylammonium). ammonium), bis(2-hydroxyiminomethyl-1-methyl-pyridinium), bis(1,1-dimethylpyrrolidinium), ethylene bisammonium, bis(1,4-dimethylpyridinium), bis(vinyltrimethylammonium), bis(cyclopropylmethyltrimethylammonium), bis(benzylphenyldimethylammonium), hexane-1,6-bis(trimethylammonium), bis[(2-hydroxyethyl)trimethylammonium], propane-1,3-bis(trimethylammonium), tetrapropylammonium, ammonium, butane-1,4-bis(trimethylammonium), or ethylene bis(trimethylammonium). For example, in some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the tetrathiomolybdic acid is a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt is a bis-choline salt, e.g., bis-choline tetrathiomolybdate. In some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), bis-choline tetrathiomolybdate (also known as ALXN1840, BC-TTM, thiomolybdate choline, thiomolybdic acid, and WTX101) is administered in the disclosed methods, uses, or compositions.In some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the pharmaceutically acceptable salt is not an ammonium salt.

[0045] TTM targets the following medical needs: Rapid and sustained control of copper and clinical symptoms, and a low risk of neurological deterioration, via the rapid formation of irreversible copper tetrathiomolybdate-protein complexes, which result in rapid copper mobilization and sequestration, which can protect patients with WD from tissue toxicity, including neurological deterioration.

[0046] Results from previous studies support the proposed mechanism of action of TTM, in which copper is mobilized to the bloodstream and sequestered via the formation of a stable trimolecular complex (TPC) containing TTM, copper, and albumin.

[0047] A treatment option that is effective, well tolerated, and suitable for all untreated and previously treated patients, including those with neurological symptoms and who are at greatest risk of neurological deterioration during the early phase of chelation therapy.

[0048] Improved adherence over long-term treatment through improved tolerability and the convenience of a simplified dosing regimen (once daily [QD]) compared with current treatment options (multiple daily dosing in the fasted state).

[0049] BC-TTM is being evaluated in patients with WD in Phase 2 Study 201 (registered at ClinicalTrials.gov under number NCT02273596; Weiss et al., 2017, Lancet Gastroenterol Hepatol. 2(12):869-76, which is incorporated by reference in its entirety), which enrolled 28 patients with WD. Study 201 is described in Example 2 of U.S. Provisional Patent Application No. 63 / 339,307, filed May 6, 2022, which is incorporated by reference herein. Final results from the main 24-week study demonstrated that TTM monotherapy significantly reduced mean serum cNCC 補正 At 24 weeks, cNCC was reduced by 72% compared to baseline, a significant reduction (p<0.0001). 補正 The reductions in plasma copper were sustained for 72 weeks or longer. An initial increase in total plasma copper, exchangeable copper, and labile bound copper (LBC, mostly bound to albumin) was observed, followed by a gradual decline to baseline or even below. These results suggest that TTM mobilizes copper from tissues into the blood, forming a copper-albumin-tetrathiomolybdate complex, thereby fulfilling the therapeutic goal of therapy for WD, which is to remove excess copper from tissues, such as the liver.

[0050] TTM treatment also resulted in significant improvements in neurological status (p<0.0001) and patient-reported disability (p<0.001), measured as change from baseline in the Unified WD Rating Scale (UWDRS) Part III and Part II, respectively. In the extension period of Study 201, 48-week follow-up data showed that the overall improvement in disability, as indicated by the mean reduction in UWDRS Part II scores, was maintained, and the overall improvement in neurological status, as indicated by the mean reduction in UWDRS Part III, was maintained.

[0051] In addition, liver status, as measured by the modified Nazer score, stabilized or improved in the majority of patients. Treatment with TTM was generally well tolerated, with most reported AEs being mild (grade 1) to moderate (grade 2). The most frequently reported drug-related AEs were changes in hematological parameters, fatigue, sulfur eruption, and other gastrointestinal symptoms. Reversible liver function test elevations were observed in 39% of patients; these elevations were mild to moderate, asymptomatic, associated with no significant increase in bilirubin, and normalized with dose reduction or treatment interruption. No paradoxical neurological deterioration was observed upon initiation of treatment with TTM. All patients who completed the 24-week study period were enrolled in a 36-month extension period. Available preliminary follow-up data at 48 weeks from the ongoing 36-month extension period of the study were consistent with the 24-week study period results.

[0052] In patients with WD, the most commonly reported AE associated with multiple TTM dosing is reversible dose-dependent liver test elevations (transaminases) observed after initiating treatment at doses of 30 mg or more per day. In Phase 2 Study 201, reversible liver test elevations were observed in 39% of patients. These elevations were generally mild to moderate, asymptomatic, and normalized with dose adjustment. No initial drug-induced neurological deterioration was observed upon initiation of treatment with TTM. Because tetrathiomolybdate is a copper-modulating agent, there is a risk of copper deficiency with long-term TTM dosing. Changes in hematological parameters (thrombocytopenia and leukopenia) have been observed, which investigators attributed to overtreatment and resulting copper deficiency. Therefore, multiple-dose WD studies, such as Study 301, include frequent monitoring for these potential adverse hematological and hepatic effects of TTM.

[0053] Based on the efficacy results from Study 201 (reduction in free copper, stabilization or improvement in liver status, and improvement in neurological symptoms) and the risk mitigation measures included within the protocol to account for the most common AEs reported in the study, TTM is considered to have acceptable benefit / risk in adult patients. The pathophysiology of copper overload does not differ substantially between adolescents and adults with WD, and the approved treatment options and goals for copper control are also the same for adolescents and adults.

[0054] In some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) described herein, the therapeutically effective amount of bis-choline tetrathiomolybdate is administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the therapeutically effective amount of bis-choline tetrathiomolybdate is administered to a subject in a fasting state.

[0055] Therapeutically effective amounts of BC-TTM have been previously established. For example, in certain embodiments of the methods, uses, or compositions (e.g., those comprising BC-TTM) of the present disclosure, BC-TTM may be administered in the range of about 7.5 to 60 mg per day, e.g., 15 to 60 mg per day. In certain embodiments of the methods, uses, or compositions (e.g., those comprising BC-TTM) of the present disclosure, BC-TTM is administered in an amount of about 15 mg every other day (or alternatively, 7.5 mg per day). In certain embodiments of the methods, uses, or compositions (e.g., those comprising BC-TTM) of the present disclosure, BC-TTM is administered in an amount of about 15 mg per day. In certain embodiments, BC-TTM is administered in an amount of about 30 mg per day (e.g., about 15 mg taken twice daily, or two 15 mg tablets taken once daily). In certain embodiments, BC-TTM is administered in an amount of about 45 mg per day (e.g., about 15 mg taken three times per day, or three 15 mg tablets taken once per day). In certain embodiments, BC-TTM is administered in an amount of about 60 mg per day (e.g., about 15 mg taken four times per day, or four 15 mg tablets taken once per day).

[0056] In certain other embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), BC-TTM may be administered in the range of about 15-60 mg every other day. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising BC-TTM), BC-TTM is administered in an amount of about 15 mg every other day. In certain embodiments, BC-TTM is administered in an amount of about 30 mg every other day. In certain embodiments, BC-TTM is administered in an amount of about 45 mg every other day. In certain embodiments, BC-TTM is administered in an amount of about 60 mg every other day.

[0057] In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), increasing the therapeutically effective amount of BC-TTM during treatment may provide additional benefits. Thus, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the therapeutically effective amount of BC-TTM increases after 6 weeks (i.e., 42 days) of treatment. For example, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the initial therapeutically effective amount of BC-TTM (i.e., days 1-42) is about 15 mg per day. The increased subsequent therapeutically effective amount of BC-TTM (i.e., after day 42, e.g., day 43 or later) is, in certain embodiments, about 30 mg per day. In certain embodiments, the increased subsequent therapeutically effective amount of BC-TTM is about 45 mg per day. In certain embodiments, the increased subsequent therapeutically effective amount of BC-TTM is about 60 mg per day. For example, in certain other embodiments, the initial therapeutically effective amount of BC-TTM is about 30 mg per day. In certain embodiments, the increased subsequent therapeutically effective amount of BC-TTM is about 45 mg per day. In certain embodiments, the increased subsequent therapeutically effective amount of BC-TTM is about 60 mg per day. For example, in certain embodiments of the methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) of the present disclosure, the initial therapeutically effective amount of BC-TTM is about 15 mg every other day. In certain embodiments of the methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) of the present disclosure, the increased subsequent therapeutically effective amount of BC-TTM is about 15 mg per day.

[0058] In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), reducing the therapeutically effective amount of BC-TTM during treatment may provide additional benefits. Thus, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the therapeutically effective amount of BC-TTM is reduced after 6 weeks (i.e., 42 days) of treatment. For example, in certain embodiments, the initial therapeutically effective amount of BC-TTM (i.e., days 1-42) is about 60 mg per day. The reduced subsequent therapeutically effective amount of BC-TTM (i.e., after day 42, e.g., day 43 or later) is, in certain embodiments, about 45 mg per day. In certain embodiments, the reduced subsequent therapeutically effective amount of BC-TTM is about 30 mg per day. In certain embodiments, the reduced subsequent therapeutically effective amount of BC-TTM is about 15 mg per day. For example, in certain other embodiments, the initial therapeutically effective amount of BC-TTM is about 30 mg per day. The reduced, subsequent therapeutically effective amount of BC-TTM is, in certain embodiments, about 15 mg per day. For example, in certain other embodiments of the methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) of the present disclosure, the initial therapeutically effective amount of BC-TTM is about 15 mg per day. The reduced, subsequent therapeutically effective amount of BC-TTM is, in certain embodiments of the methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof) of the present disclosure, about 15 mg every other day.

[0059] In some embodiments of the methods, uses, or compositions of the present disclosure described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to inhibit the progression of neurological damage in a subject who has had an incomplete (or inadequate) response to or is intolerant of treatment with standard of care (SoC). In some embodiments of the methods, uses, or compositions of the present disclosure described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to inhibit the progression of liver damage in a subject who has had an incomplete (or inadequate) response to or is intolerant of treatment with SoC.

[0060] In some embodiments of the methods, uses, or compositions of the present disclosure described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve or maintain one or more of a neurological symptom, a psychiatric symptom, a clinical symptom, a disability status, or treatment satisfaction in a subject, where the subject has had an incomplete (or inadequate) response to or is intolerant to treatment with an SoC. In certain embodiments of the methods, uses, or compositions of the present disclosure described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more of a neurological symptom, a psychiatric symptom, a clinical symptom, a disability status, or treatment satisfaction in a subject, where the subject has had an incomplete (or inadequate) response to or is intolerant to treatment with an SoC. For example, in some embodiments of the disclosed methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), improvement is observed at least 24 weeks, at least 36 weeks, or at least 48 weeks after administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments of the methods, uses, or compositions of the present disclosure described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the Unified Wilson Disease Rating Scale (UWDRS) Part II total score or the Unified Wilson Disease Rating Scale (UWDRS) Part III total score of a subject who has had an incomplete (or inadequate) response to or is intolerant to treatment with an SoC. In certain embodiments of the methods, uses, or compositions of the present disclosure described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the Unified Wilson Disease Rating Scale (UWDRS) Part II total score and the Unified Wilson Disease Rating Scale (UWDRS) Part III total score of a subject who has had an incomplete (or inadequate) response to or is intolerant to treatment with an SoC. For example, in some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve a subject's UWDRS Part II total score by at least 5%, at least 10%, at least 15%, or at least 20%, and the subject has had an incomplete (or inadequate) response to or is intolerant of treatment with SoC. In some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve a subject's UWDRS Part III total score by at least 5%, at least 10%, at least 15%, or at least 20%, and the subject has had an incomplete (or inadequate) response to or is intolerant of treatment with SoC.In some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), improvement in UWDRS Part II total score and / or UWDRS Part III total score is observed at least 24 weeks, at least 36 weeks, or at least 48 weeks after administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments of the disclosed methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more neurological symptoms in a subject (e.g., a subject who has had an incomplete (or inadequate) response or is intolerant, as described herein), as measured according to Unified Wilson's Disease Rating Scale (UWDRS) Part II and / or Part III, wherein the one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis. For example, in some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), improvement according to Unified Wilson's Disease Rating Scale (UWDRS) Part II and / or Part III is observed at least 24 weeks, at least 36 weeks, or at least 48 weeks after administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments of the disclosed methods, uses, or compositions described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more neurological symptoms in a subject (e.g., a subject who has had an incomplete (or inadequate) response or is intolerant, as described herein), as measured according to the Unified Wilson's Disease Rating Scale (UWDRS) Part II and / or Part III, wherein the one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor. For example, in some embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), improvement according to Unified Wilson's Disease Rating Scale (UWDRS) Part II and / or Part III is observed at least 24 weeks, at least 36 weeks, or at least 48 weeks after administration of a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments of the methods, uses, or compositions of the present disclosure described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the methods, uses, or compositions comprising tetrathiomolybdate acid or a pharmaceutically acceptable salt thereof further comprise evaluating the subject (e.g., a subject who has had an incomplete (or inadequate) response or who is intolerant, as described herein) for improvement in disability and neurological symptoms as measured according to the Unified Wilson Disease Rating Scale (UWDRS) Part II and / or Part III. In some embodiments of the methods, uses, or compositions of the present disclosure described herein (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the methods, uses, or compositions comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof further comprise evaluating the subject (e.g., a subject who has had an incomplete (or inadequate) response or who is intolerant, as described herein) for improvement in disability status, psychiatric symptoms, clinical symptoms, treatment satisfaction, or a combination thereof.

[0065] In certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), when values ​​are expressed as approximations by use of the preceding "about," it is understood that the particular value forms one possible embodiment of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), and that variation of the given value is possible (e.g., about 80 can include 80±10%). It is further understood that the endpoints of each of the ranges are meant both in relation to the other endpoint, and independently of the other endpoint.

[0066] As used herein, "total copper" refers to the sum of all copper species in blood (e.g., serum or plasma). Total copper includes both ceruloplasmin (Cp)-bound copper and all species of non-ceruloplasmin-bound copper. Generally, total copper can be measured directly by mass spectrometry, e.g., inductively coupled plasma mass spectrometry (ICP-MS), with high sensitivity and specificity.

[0067] The term "NCC" refers to the portion of total copper that is not bound to ceruloplasmin (i.e., "non-ceruloplasmin-bound copper"). Under commonly used estimation methods, NCC is estimated using direct measurement of total copper and Cp in blood (e.g., serum or plasma) and the following formula:

number

[0068] The term "cNCC" refers to NCC when calculated using this formula. The calculation is based on the assumption that six copper atoms are always bound to a single Cp molecule, and NCC and ceruloplasmin concentrations are directly correlated. In reality, Cp can exhibit considerable heterogeneity in the number of copper atoms associated per Cp molecule. This formula assumes that six copper atoms are bound per Cp molecule, but the copper / Cp ratio fluctuates with the disease state. In reality, six to eight copper atoms can actually bind to Cp, and in WD, typically fewer than six copper atoms are associated per Cp molecule.

[0069] In subjects treated with TTM, non-ceruloplasmin-bound copper includes the portion of total copper bound to albumin, transcuprein, and other less abundant plasma proteins (collectively referred to as LBC), or the portion in the tetrathiomolybdate-Cu-albumin trimolecular complex (TPC). Although the concentration of TPC is not directly measurable, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the concentration of TPC can be estimated using molybdenum concentration as a surrogate.

[0070] "NCC 補正 The term "NCC" refers to the portion of total copper, or the portion in the TPC (i.e., LBC), that is not bound to ceruloplasmin, and is calculated by subtracting a direct measurement of molybdenum in the blood (e.g., serum or plasma) from the estimated NCC (or cNCC).補正 " is a correction of the cNCC value to take into account the presence of the molybdenum-copper-albumin trimolecular complex in the blood of TTM-treated subjects.

[0071] The term "dNCC" refers to NCC when measured directly using an NCC assay. For example, in certain embodiments of the disclosed methods, uses, or compositions (e.g., those comprising tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), dNCC is measured directly using the NCC assay disclosed in PCT Patent Application Publication No. 2021 / 050850, filed September 11, 2020, which is incorporated herein by reference in its entirety.

[0072] The term "LBC" or "labile bound copper" refers to the portion of total copper that is bound to albumin, transcuprein, and other less abundant plasma proteins. Thus, LBC includes the portion of total copper that is not bound to either ceruloplasmin or TPC. In certain embodiments of the disclosed methods, uses, or compositions (e.g., those containing tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof), the LBC portion is measured directly using an LBC assay. For example, in certain embodiments, the LBC assay is that disclosed in PCT Patent Application Publication No. 2021 / 050850, filed September 11, 2020, which is incorporated herein by reference in its entirety. In biological samples in which TPC is absent, the NCC and LBC portions are the same. The disclosed methods and uses are further illustrated by the following examples, which are not to be construed as limiting the disclosure in scope or spirit to the specific procedures and compounds described herein. [Example]

[0073] Example 1: Overall Design Study 301 (registered at ClinicalTrials.gov under number NCT03403205) was conducted to evaluate the efficacy and safety of BC-TTM versus standard of care (SoC) in patients with Wilson's disease (WD) who were aged 12 years or older or 18 years or older. Currently available medications have high treatment discontinuation rates due to tolerability and efficacy issues. Furthermore, these medications must be administered two to four times daily and must be taken in an empty stomach. The AE profile and complex dosing regimens of these medications result in poor treatment adherence and high treatment failure rates, which are major concerns in WD, a disease requiring lifelong treatment.

[0074] Unlike currently available treatments for WD, TTM provides an alternative copper protein transport mechanism and is designed to rapidly form copper-protein complexes with very high specificity for copper, rapidly treating the underlying disease by mobilizing excess tissue copper. [Table 1-1] [Table 1-2] [Table 1-3]

[0075] Figure 1 provides a schematic of the study design. This was a randomized, assessor-blinded, multicenter study evaluating the efficacy and safety of TTM versus standard of care (SoC). This study is referred to throughout as Study 301. In the primary evaluation period, efficacy and safety were evaluated for an individualized TTM dosing regimen administered for 48 weeks compared with SoC in patients with WD aged 12 years or older or 18 years or older.

[0076] Patients who met all inclusion criteria and no exclusion criteria were enrolled in the study and studied as outpatients. Eligible patients with WD were enrolled in one of two cohorts. Cohort 1: Patients who had previously received SoC therapy (i.e., chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc therapy) for more than 28 days. Cohort 2: Patients who were treatment-naïve or had received SoC therapy for 28 days or less All patients were enrolled in a 3:1 ratio per cohort and randomized within cohorts in a 2:1 ratio to treatment with TTM or SoC (either as continuation therapy in Cohort 1 or as continuation or initial therapy in Cohort 2). Treatment was randomly assigned and stratified by cohort using an interactive voice / web response system (Figure 1B).

[0077] Patients randomized to receive TTM were required to withhold treatment with SoC for at least 48 hours immediately prior to the first study assessment on Day 1. Patients randomized to TTM received BC-TTM as delayed-release tablets for oral administration at doses ranging from 15 mg every other day (QOD) to 60 mg QD. Efficacy and safety assessments were performed at scheduled visits, and AEs and concomitant medications were continuously monitored throughout the study. Patients randomized to SoC initiated or continued treatment on their current regimen, when possible, without compromising individual patient safety.

[0078] The primary evaluation period consisted of a maximum 28-day screening period, a 1-day enrollment visit, a 48-week treatment period, and a follow-up visit 4 weeks after the last dose for patients who did not elect to continue in the extension period.

[0079] Patients in Study 301 who completed the 48-week treatment period were offered the opportunity to participate in an extension period of up to 60 months to evaluate the long-term safety and efficacy of TTM.

[0080] Control of exchangeable copper is important for the management of hepatic and neuropsychiatric symptoms in patients with WD. Results from related studies support the proposed mechanism of action of TTM, in which copper is mobilized into the bloodstream and sequestered via the formation of stable TPC, resulting in a lower risk of neurological deterioration due to copper exchange from the chelator and a lower affinity for copper. Study 301 is the first prospective, randomized study to compare tetrathiomolybdate with penicillamine, trientine, or zinc in WD.

[0081] The primary endpoint will integrate copper mobilization and sequestration (i.e., copper control) throughout the 48-week first-line treatment period by assessing the average daily area under the effect-time curve (AUEC) of directly measured non-ceruloplasmin-bound copper (dNCC) concentrations. AUEC characterizes and measures the cumulative effect of TTM. Measurement of dNCC in plasma is sensitive and accurate, requiring no special formulas or assumptions. As proposed, dNCC AUEC 0~48W is an indirect measure of copper mobilization and sequestration. Results from companion study 201 strongly suggested a rapid onset of TPC formation within hours after TTM administration and a robust mobilization of excess copper from tissues into plasma that persisted through week 12 and appeared nearly complete by week 24. Over the course of 24 to 48 weeks of treatment with TTM in study 201, plasma dNCC concentrations continued to gradually decrease to baseline. The gradual, sustained reduction in plasma dNCC concentrations over time indicates that copper mobilized by TTM is not simply redeposited back into tissues because both plasma concentrations of tetrathiomolybdate (from a 30 mg daily-weighted average dose of BC-TTM) and circulating albumin (the other two components of TPC) remained essentially constant and sufficiently available for TPC formation throughout the study. Therefore, the daily average dNCC AUEC 0~48w is suitable as a quantitative measure of the therapeutic effect of TTM in WD based on its mechanism of action.

[0082] Measurement of AUEC for dNCC as the primary outcome measure overcomes many of the limitations of estimated cNCC methods. Calculated NCC estimates rely on separate measurements of plasma total copper and ceruloplasmin protein. The amount of copper in Cp is further estimated based on an assumed ratio of six copper atoms per molecule of Cp, which may be an overestimate in WD. Overestimation of ceruloplasmin-bound copper (CpC) results in approximately 20% of samples obtaining physiologically impossible negative values ​​for cNCC. In patients treated with TTM, cNCC estimation requires additional correction for the presence of copper in TPC. TPC copper is not directly measurable but instead must be estimated based on the plasma concentration of molybdenum.

[0083] For the primary efficacy and safety assessments, a 1-year treatment period was selected to allow sufficient time for evaluation of changes in copper biochemical measures, as well as changes in liver function and neurological impairment, and for adequate assessment of safety and tolerability.

[0084] After the primary evaluation period, patients randomized to SoC during the primary evaluation period were switched to treatment with TTM in an extension period, which provided further evaluation of changes in copper, liver function, and neurological dysfunction. An additional extension period of up to 5 years will allow further evaluation of long-term efficacy, safety, tolerability, and clinical outcomes in patients treated with TTM.

[0085] The UWDRS scoring system was developed specifically for motor and movement disorders associated with chronic copper neurotoxicity in WD. In addition to UWDRS Parts I, II, and III, several individual items / subscales of UWDRS Part III (chair rise, gait, handwriting, and speech) were assessed overall to further define the range of burdensome signs and symptoms of WD and thereby better understand the assessment of treatment effects in patients with WD. UWDRS scores for consciousness (Part I) and abnormal neurological examination findings (Part III) were determined by experienced neurologist raters blinded to study treatment randomization. These scores were used to provide a rigorous data set for assessing change from baseline.

[0086] The inclusion of adolescents aged 12 years and older in this protocol is justified by the natural history of WD. In a large European cohort of 1,357 patients, the mean age at diagnosis of WD was 19.8 years, and half of all patients were diagnosed before the age of 18. Compared to adults, children and adolescents are more likely to present with hepatic symptoms rather than neuropsychiatric signs. The goal of treatment in adolescents is the same as in adults: rapid and effective removal of excess copper from tissues.

[0087] Medication The daily BC-TTM dosage intended for use in this study was based on doses established as safe and effective in previous WD studies conducted with BC-TTM. Daily doses of 30–60 mg have been shown to be effective in decopperizing patients newly diagnosed with WD or maintaining normal copper levels in patients with WD previously treated with SoC. Asymptomatic elevated liver transaminases and / or gamma-glutamyltransferase were found in 39% of patients with WD treated with TTM. Liver enzyme elevations were dose-dependent and reversible with TTM discontinuation or dose reduction. Therefore, the dose of BC-TTM in the current study was initiated at 15 mg daily (i.e., 7.8 mg daily TTM) and limited to a maximum of 60 mg daily, which was the highest dose studied and considered to have a favorable safety profile in healthy volunteers. The intent was to individually titrate the dose of BC-TTM to an appropriate dose based on cNCC levels, hematological values, and liver function tests adjusted for molybdenum plasma concentrations, as is done with currently available chelators. Thus, the dosing regimen for BC-TTM included the following features: initial QD dosing, as described below, and an uptitration design and individualized dosing as indicated by neurological and liver function tests.

[0088] In line with currently available WD treatments, the dose of BC-TTM was adjusted in individual patients, if appropriate, based on protocol-specified guidelines, depending on clinical response and safety. A detailed dosing guide for BC-TTM dose modifications is outlined below in Table 1.

[0089] To the extent possible, without compromising individual patient safety, the type and dose of SoC medication remained unchanged throughout the 48-week study period.

[0090] BC-TTM was supplied as a white, round, delayed-release tablet for oral administration. Each tablet contained 15 mg of bis[2-hydroxyethyl)trimethylammonium]tetrathiomolybdate, the bis-choline salt of tetrathiomolybdate, and the following excipients: tricalcium phosphate, sodium carbonate, sodium starch glycolate, and magnesium stearate. The tablets were coated with an inner precoat (Opadry 03K19229 clear) and an outer enteric coat (Acryl-EZE white). The tablets were debossed on one side with a hexagonal shape.

[0091] BC-TTM was supplied in a treatment kit containing 28 tablets, which consisted of a thermoformed blister strip mounted within a cardboard wallet.

[0092] BC-TTM was administered on Day 1. BC-TTM was administered orally at doses ranging from 15 mg QD to 60 mg QD. BC-TTM was administered QD or QOD in the fasted state (1 hour before or 2 hours after a meal).

[0093] Individualized TTM dosing was utilized throughout the study based on the following parameters: Clinical criteria: Dose titration based on hepatic and neurological status; ●NCC 補正 Dose titration indicated based on cNCC levels adjusted for the amount of copper bound to TTM TPC; Safety monitoring: Dose modification criteria were based on regularly scheduled evaluation of the perceived hematological effects of Cu reduction, liver tests, and neurological tests.

[0094] In all patients, BC-TTM was administered at a starting dose of 15 mg QD (equivalent to 7.8 mg TTM) on day 1 and continued for the first 4 weeks. After 4 weeks, uptitration to 30 mg QD BC-TTM was permitted at the investigator's discretion if the disease was cNCC / cNCC. 補正If the patient's clinical condition and free blood copper level, as measured by BC-TTM, were not adequately controlled and none of the dose modification criteria applied, further dose escalation was possible at the investigator's discretion, in increments of 15 mg BC-TTM at intervals of at least 4 weeks, according to the same criteria above. If any of the relevant dose modification criteria were met, the dose was to be reduced or discontinued.

[0095] cNCC 補正 When levels fall within the normal range (<2.3 μmol / L) and / or the patient's clinical condition has stabilized or improved for two consecutive study visits, TTM dosage may be maintained or reduced, at the investigator's discretion. To avoid overtreatment, doses may be maintained or reduced, at the investigator's discretion, according to the following guidelines, if the patient's clinical condition indicates the possibility of overtreatment and / or if cNCC / cNCC 補正 It may be reduced at any time if values ​​are below the normal range. Specific criteria for dose modification of BC-TTM are detailed in Table 1.

[0096] To the extent possible, without compromising individual patient safety, the type of SoC medication should not change throughout the 48-week study period unless required as part of treatment (e.g., if the patient begins SoC at the start of the study). Similarly, to the extent possible, without compromising individual patient safety, the dosing of SoC medication should remain consistent throughout the 48-week study period unless required as part of treatment (e.g., if SoC titration is initiated at the start of the study). [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0097] All patients were treated with TTM in the extension period. Patients who received TTM in the primary evaluation period of Study 301 continued to receive the same dose they received at the last study visit in the primary evaluation period, and then individualized dosing was administered as described herein. Patients who transitioned from SoC in the extension period were administered TTM as described herein. Dose modifications, if necessary, were performed as described herein.

[0098] Efficacy evaluation The Week 48 visit marked the end of the Primary Evaluation Period (PEP) and the beginning of the Extension Period (i.e., the Week 48 visit and the Extension Day 1 visit occurred on the same day). All assessments for the Week 48 visit were performed before dosing with TTM. Dosing with TTM on Extension Day 1 marked the beginning of the Extension Period. Patients who did not participate in the Extension Period discontinued dosing at Week 48 and had a final study visit for safety follow-up at Week 52.

[0099] Copper assessment: Measurement of plasma dNCC concentrations was the primary evaluation of the efficacy of TTM treatment in WD. The AUEC for plasma dNCC concentrations over time aims to quantify the dynamic tissue Cu mobilization and Cu sequestration effects of TTM. This evaluation is also applicable to treatment with SoC. In addition, plasma Cp, CpC, plasma total copper, and LBC were measured with AUEC calculated for plasma total copper and LBC.

[0100] The LBC method measures exchangeable plasma copper that is not bound to either Cp or TPC.

[0101] Unified Wilson's Disease Rating Scale (Parts I, II, and III): The UWDRS is a clinical rating scale designed to assess the neurological manifestations of WD, which can be broadly divided into three movement disorder syndromes: dystonic, ataxic, and parkinsonian. The UWDRS includes three parts: UWDRS Part I (Level of Consciousness, Item 1), UWDRS Part II (Patient-Reported Overview of Activities of Daily Living [Disability], Items 2-11), and UWDRS Part III (Detailed Neurological Examination, Items 12-34).

[0102] UWDRS Parts I and III were assessed by a neurologist blinded to treatment randomization, whereas UWDRS Part II could be reported by the patient, family, or caregiver to an unblinded member of the study team. The UWDRS was not formally assessed in adolescents. However, the components of Parts I (level of consciousness), II (patient- or caregiver-reported impairment), and III (neurologic examination findings) were essentially similar between adults and adolescents. Patients aged 12 years and older were expected to be able to comply with the UWDRS assessment.

[0103] Clinical Global Impression-Severity of Improvement Scale and Clinical Global Impression-Severity of Improvement Scale: The Clinical Global Impression (CGI) rating scale has been a commonly used measure of symptom severity, treatment response, and treatment effectiveness in treatment studies of adult and pediatric patients with psychiatric disorders.

[0104] The Clinical Global Impression-Severity Scale (CGI-S) is a 7-point scale that requires clinicians to rate the severity of a patient's illness at the time of assessment relative to the clinician's past experience with patients with the same diagnosis. Taking into account their total clinical experience, patients were rated for severity of illness at the time of assessment as 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, significantly ill; 6, severely ill; or 7, extremely ill.

[0105] The Clinical Global Impression-Improvement scale (CGI-I) is a 7-point scale that requires clinicians to rate how much a patient's condition has improved or worsened relative to the baseline state at the start of the intervention, rating the CGI-I as 1, very improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worsened; 6, much worsened; or 7, very worsened.

[0106] Adverse events and serious adverse events An AE is any adverse medical occurrence in a participant administered a pharmaceutical product or clinical investigation participant, which does not necessarily have a causal relationship to this treatment (ICH E2A).

[0107] An SAE, at any dose, is defined as any adverse medical event that results in death; is life-threatening; requires inpatient hospitalization or an extension of existing hospitalization; results in persistent disability / incapacity; is a congenital anomaly / birth defect, or other situation that results in, for example, invasive or malignant cancer, intensive care in the emergency room or at home for allergic bronchospasm, blood dyscrasia or convulsions not resulting in hospitalization, or the development of drug dependence or drug abuse.

[0108] Adverse events were reported by the patient (or, when appropriate, by a caregiver, surrogate, or legally authorized representative of the patient). The investigator and any authorized designee were responsible for detecting, documenting, and recording events that met the definition of an AE or SAE. The investigator and any authorized designee remained responsible for following up on AEs that were serious or considered related to the study intervention or procedure or that caused the patient to discontinue the study.

[0109] Adverse Events of Special Note: Any new neurological symptom or clinically significant worsening of an ongoing neurological symptom after initiation of study drug (BC-TTM or SoC), whether serious or non-serious, was designated as an AESI.

[0110] If a patient has an AESI, in addition to any assessments deemed clinically relevant by the investigator, the following assessments should be administered to the extent possible to facilitate evaluation of the AE and patient status: UWDRS Part III, Nonverbal Stroop Interference Test, Digit Span Test, and CGI-I and CGI-S. The investigator or sub-investigator may administer additional assessments or clinical tests at the investigator's or sub-investigator's discretion.

[0111] Pharmacokinetics, Pharmacodynamics, and Biomarkers Pre-dose whole blood samples were collected at each designated visit to measure the following TTM PK, PD, and biomarker analyses:

[0112] Pharmacokinetics: Blood samples for PK analysis were collected to measure plasma total molybdenum and plasma ultrafiltrate (PUF) molybdenum.

[0113] Pharmacodynamics: Blood samples were collected to directly measure plasma total copper, PUF copper, dNCC, and LBC. Calculations were performed for cNCC and cNCC 補正 The latter of which is non-ceruloplasmin-bound and non-molybdenum-albumin-bound copper.

[0114] Biomarkers and Biobank Samples: Blood samples were collected to measure plasma Cp and CpC. Urine samples were collected to analyze urinary copper and molybdenum. Additional biomarker or biobank samples were collected to analyze treatment-related molybdenum and / or copper species.

[0115] Statistical considerations A general description of the statistical methods used to analyze efficacy and safety data is outlined below.

[0116] Statistical analyses were performed using SAS® version 9.3 or later, SAS Institute, Cary, North Carolina, USA. Baseline for all assessments was defined as the last assessment resulting in a non-missing valid value measured before the first dose of study medication (BC-TTM or SoC). Analysis populations included:

[0117] The full analysis set includes all randomized patients who received at least one dose of randomized treatment. Patients were analyzed as randomized.

[0118] Safety analyses were performed in the safety analysis set. This data set included all patients who received at least one dose of randomized treatment. Patients were summarized according to the treatment they actually received.

[0119] The per-protocol set included all patients who were randomized and had at least baseline and 48-week efficacy assessments for dNCC in the primary evaluation period. Patients with major protocol deviations that could have affected the primary efficacy analysis were excluded from the per-protocol set.

[0120] The extension analysis set includes all patients who participated in the extension period and received at least one dose of BC-TTM in the extension period.

[0121] Primary efficacy analysis The primary objective of the study was the difference between TTM and SoC in patients with WD in mean daily dNCC AUEC from 0 to 48 weeks, regardless of less than perfect adherence or use of another medication affecting plasma dNCC, and without benefit from treatment after death.

[0122] The AUEC for dNCC concentrations was calculated using the trapezoidal rule and then divided by the number of days to obtain the mean daily AUEC plasma dNCC concentrations (expressed as μmol / L, AUEC 0~48W (described as ) was obtained.

[0123] AUEC 0~48W The mean mean (TTM) and mean (SoC) were compared using an analysis of covariance (ANCOVA) statistical model. Treatment arm, baseline plasma dNCC concentration, and cohort were included in the model. Tests were performed at a significance level of 0.05 (two-sided).

[0124] AUEC 0~48W Model-based estimates of the difference between randomized treatments (TTM-SoC) in were provided along with two-sided 95% CIs and p-values. Superiority was concluded when the lower two-sided 95% CI exceeded 0 μM.

[0125] Cohort 1: Patients treated >28 days previously. The supportive analysis of the primary endpoint within Cohort 1 mirrored that described for the overall population analysis, except that the analysis removed Cohort 2 from the model.

[0126] Cohort 2: Patients who were treatment-naïve or previously treated for 28 days or less. 0~48W The analyses were descriptive, with no formal statistical comparisons made between randomized treatment arms. 0~48W was estimated using the same model terms as described for the analysis of Cohort 1 patients.

[0127] Patient population Participants were eligible for inclusion in the study only if all of the following criteria applied: 1. Established diagnosis of WD with a Leipzig score of 4 or greater documented by testing outlined in the 2012 European Association for the Study of Liver WD Clinical Practice Guidelines. 2. Informed consent / age 12 years or older at the time of consent (age 18 years or older in Germany). 3. Willingness to withhold treatment with SoC for at least 48 hours immediately prior to the first study assessment on Day 1. 4. Willingness to avoid the use of vitamins and / or minerals containing copper, zinc, or molybdenum for the entire duration of the study. 5. Willingness to avoid intake of foods and beverages with high copper content for the entire duration of the study.

[0128] Patients were excluded from the study if any of the following criteria applied: 1. Decompensated cirrhosis MELD (Model for End-Stage Liver Disease) score greater than 2.13 Modified Nazer score above 3.7 4. Clinically significant GI bleeding within the past 3 months 5. For patients treated with WD therapy for more than 28 days (Cohort 1), alanine aminotransferase >2 × upper limit of normal (ULN) 6. For treatment-naive patients or patients who have been treated for 28 days or less (Cohort 2), alanine aminotransferase >5×ULN 7. Significant neurological illness requiring either nasogastric feeding or intensive inpatient medical care Hemoglobin less than 8.9 g / dL 9. Participation in a clinical study of an experimental or unlicensed / unlicensed therapy during the screening period or within 4 weeks prior to informed consent 10. History of seizure activity within the last 6 months prior to informed consent 11. Pregnant (or planning to become pregnant) or breastfeeding women 12. Known sensitivity to BC-TTM, BC-TTM excipients (dicalcium phosphate anhydrous, sodium carbonate anhydrous), or any of the ingredients contained within BC-TTM or related compounds. 13. Active infection with hepatitis B virus (positive hepatitis B surface antigen) or hepatitis C virus (patients with a positive hepatitis C antibody result require confirmation of active disease with a positive hepatitis C polymerase chain reaction test), or seropositivity for human immunodeficiency virus (HIV) 14. Previous treatment with tetrathiomolybdate 15. Any disease, disability, illness, or abnormal laboratory test value that, in the opinion of the investigator, compromises patient safety or interferes with the collection or interpretation of study results. 16. Patients with end-stage renal disease (chronic kidney disease stage 5 [CKD5]) on dialysis or creatinine clearance less than 30 mL / min.

[0129] Patients in the primary evaluation period were randomized to either TTM or SoC treatment and enrolled in one of the two cohorts described above. All patients in the extension period will receive TTM treatment.

[0130] Approximately 180 eligible patients with WD aged 12 years and older (18 years and older in Germany) were enrolled in this study. Allocation per cohort and treatment is provided in Table 2. [Table 3]

[0131] Ultimately, 214 patients were enrolled, all with preserved liver function, and 79% had neurological symptoms. Of the 214 patients, 207 were randomized: 137 were randomized to TTM (104 to Cohort 1 and 33 to Cohort 2), and 70 were randomized to SoC (56 to Cohort 1 and 14 to Cohort 2). Overall patient demographics are provided in Tables 3-1 and 3-2, and prior treatment history for WD is provided in Table 4. [Table 4] [Table 5] [Table 6]

[0132] Ultimately, 184 patients completed the 48-week treatment period; 119 participated in TTM (91 in Cohort 1 and 28 in Cohort 2), 65 in SoC (52 in Cohort 1 and 13 in Cohort 2), 178 in the extension period, 117 in TTM (89 in Cohort 1 and 28 in Cohort 2), and 61 in SoC (49 in Cohort 1 and 12 in Cohort 2).

[0133] The number of patients in the SoC group receiving each treatment was as follows: zinc monotherapy: Cohort 1, n = 23 (41%), Cohort 2, n = 0 (0%), Overall, n = 23 (33%); penicillamine (with or without zinc): Cohort 1, n = 19 (39%), Cohort 2, n = 10 (71%), Overall, n = 29 (41%); trientine (with or without zinc): Cohort 1, n = 14 (25%), Cohort 2, n = 4 (29%), Overall, n = 18 (26%).

[0134] Copper mobilization and sequestration The primary objective of the study was to evaluate the efficacy of TTM administered for 48 weeks compared with standard of care (SoC) for copper control in WD patients aged 12 years and older (or 18 years and older in Germany). The primary endpoint in the primary evaluation period was the mean daily average endoscopic copper concentration (AUEC) of dNCC. 0~48W Results from the study are provided in Table 4. These results demonstrated that the primary efficacy endpoint was mean daily dNCC AUEC 0~48週 This shows the superiority of TTM over SoC in copper mobilization, as demonstrated by the ΔΨ value for TTM of 3.18 (standard error [SE] = 0.167) and the ΔΨ value for SoC of 1.00 (SE = 0.219), with p < 0.0001 for the difference. [Table 7]

[0135] The results of the study show that TTM is statistically superior to SoC in mobilizing copper from tissues (Figure 2). Overall, the mean daily dNCC AUEC 0~48WThe mean value (μmol) for patients treated with TTM was 3.2-fold higher than that for SoC. The overall results and those for each cohort were statistically significant (P<0.00001). The mean value for patients treated with TTM was 2.9-fold higher in treatment-experienced patients (Cohort 1) and 4.9-fold higher in treatment-naive patients (Cohort 2). Although more copper was mobilized in treatment-naive patients (Cohort 2) than in treatment-experienced patients (Cohort 1), these results indicate that tissue-bound copper still accumulates in tissues even in patients who have received SoC therapy for many years, e.g., an average of more than 10 years. As can be seen from the results in Table 4, the magnitude of the effect differed between cohorts, but the duration of previous treatment did not significantly affect the magnitude of the benefit. In contrast to SoC, BC-TMM has a significant effect on the mobilization and safe sequestration of copper from tissues.

[0136] TTM mobilized copper even in Cohort 1 participants who had received SoC therapy for an average of more than 10 years. As shown in Table 5, mean daily dNCC AUECs of SoC assessed at TTM-equivalent time points were significantly higher than those of Cohort 1 participants. 0~48週 The SoC is measurable but low (<1.0) regardless of previous treatment status.

[0137] A plot of plasma dNCC over time in participants treated with TTM shows an immediate rise, a peak at 4-6 weeks, and a gradual return to baseline by 48 weeks (Figure 2). Tissue copper mobilization was found in both cohorts, even in Cohort 1 participants who had been treated with SoC for an average of 10 years. Furthermore, Figure 2 also shows that the time to return to baseline for dNCC was greater (longer) for Cohort 2 compared to Cohort 1, reflecting greater mobilization of excess tissue copper stores among participants with little or no prior treatment.

[0138] For participants treated with SoC, plots of plasma dNCC (where available) at equivalent time points were essentially flat (Figures 3, 4, 5, and 6), indicating minimal change in circulating non-ceruloplasmin-bound copper. Figure 23 shows that 24-hour urinary copper was lower with TTM than with SoC chelator therapy. Overall, there was little change in either plasma total copper or non-ceruloplasmin-bound copper levels during treatment with SoC. The superiority of TTM over SoC in mobilizing copper from tissues is demonstrated.

[0139] To assess whether tissue copper mobilization from TTM treatment had any effect on the most important plasma copper carrier, ceruloplasmin (Cp), and the number of copper atoms transported per ceruloplasmin molecule (CpC), Table 6 summarizes the plasma CpC / Cp ratio. An average of 3 to 4 copper molecules were bound per ceruloplasmin molecule at pre-dose baseline. The data are also presented in Figure 7 for visual inspection. The mean CpC / Cp values ​​after dosing throughout the 48-week treatment period remained relatively stable for TTM and slightly decreased for SoC. This means that both TTM and SoC have limited influence on the CpC / Cp ratio over the 48-week treatment period. This observation could be due to either the much higher binding affinity of ceruloplasmin to copper or the limited, if any, influence of TTM and SoC on holoceruloplasmin formation by the liver. [Table 8]

[0140] A preliminary population PK analysis including data from healthy participants (Studies 104, 106, 107, 108, and 109) and those with WD (Studies 201 and 301) indicates that age is not a significant covariate for plasma total molybdenum clearance. Elimination half-life was also similar across age subgroups. Study 106 is a phase 1 study evaluating the pharmacokinetics (PK), pharmacodynamics (PD), biomarkers, and safety of TTM in healthy Japanese and non-Japanese subjects, and is described in Example 1 of U.S. Provisional Patent Application No. 63 / 339,307, filed May 6, 2022, which is incorporated herein by reference. Study 104 is registered with EudraCT under study number 2019-000516-28, study 107 is registered with ClinicalTrials.gov under number NCT04560816, study 108 is registered with ClinicalTrials.gov under number NCT04594252, and study 109 is registered with ClinicalTrials.gov under number NCT04610580.

[0141] Calculated plasma total molybdenum AUC after 48 weeks of treatment with TTM in Study 301 (0~48週) (Table 7 and Figure 8), as well as plasma total copper, dNCC, and LBC AUEC ( ) Values ​​for (Table 8 and Figure 9) show comparable median values ​​for adults and adolescents. [Table 9] [Table 10]

[0142] Study 204 is an exploratory study with the goal of investigating the effects of TTM on Cu balance in participants with WD. Study 204 is registered with ClinicalTrials.gov under number NCT04573309 and described in Example 1 of U.S. Provisional Patent Application No. 63 / 237,120, filed August 25, 2021, which is incorporated herein by reference. Study 204 specifically evaluates the effects of 15 mg and 30 mg doses of BC-TTM and duration of treatment on Cu balance. Participants remained on a Cu-controlled diet, and Cu and Mo balances were measured in all intakes (i.e., study drug, food, and liquids) and all excretions (urine and stool). The Cu and Mo concentrations of each sample were determined by inductively coupled plasma mass spectrometry (ICP-MS). The copper and Mo content of all intakes and excretions was calculated based on the volume or weight of intakes and excretions and the concentrations of representative samples.

[0143] Collection periods for feces and urine varied from 3 to 15 days in duration to support assessment of Cu and Mo balance both before and during steady state for both the 15 mg and 30 mg diets. The equilibration period for the Cu / Mo control diet was a minimum of 48 hours. Copper balance was calculated as the average daily Cu balance over each of the four collection periods. Interpretation of Cu balance was based on previously established criteria when conducting Cu balance studies with zinc treatment. For assessment of TTM effects on Cu balance, the period for analysis considered a mean intestinal transit of approximately 40 hours (males: 33 hours, females: 47 hours).

[0144] Interim results from Study 204 demonstrated a net increase in daily fecal copper excretion after exposure of participants with WD to TTM. Results are available for the first three participants enrolled in this open-label copper balance / molybdenum mass balance study. These participants had all intakes (food and beverages) and excretions (urine and feces) collected on days -4 to -1 (baseline), 1 to 8, and 25 to 39. These participants were scheduled to receive BC-TTM at 15 mg / day for 28 days (Period 1), followed by 30 mg / day for 11 days (Period 2). However, only one participant was able to titrate to a higher dose, and the other two had their dose reduced to 15 mg QOD due to elevated alanine aminotransferase (ALT).

[0145] Patient information for Study 204 is provided in Table 9. Results from the primary endpoint of Study 204, mean daily Cu balance, are provided in Table 10. As described above, mean daily Cu balance is measured by the calculated difference between Cu intake (in food and drink) and Cu excretion (in stool and urine) during the TTM accumulation and steady-state periods for each dose. [Table 11] [Table 12-1] [Table 12-2]

[0146] Based on interim results from three participants with WD in Study 204, copper mobilization as a result of treatment with 15 mg / day (or every other day) or 30 mg / day for a total duration of 39 days was significant compared to pre-dose baseline. Consistent results among the three participants who have completed the study to date indicate that TTM results in rapid and sustained mobilization of copper from tissues into the blood, where it is safely sequestered in the trimolecular complex. This is evidenced by the rapid and sustained increase from baseline in dNCC shown in Table 11 and Figure 10, and the increase from baseline in fecal copper excretion shown in Table 12 and Figure 11. [Table 13-1] [Table 13-2] [Table 14] [Table 15]

[0147] Per protocol, the dose of BC-TTM was to be increased from 15 mg daily (days 1–28) to 30 mg daily on days 29–39. In two participants, this dose escalation was not completed due to elevated liver enzymes (maximum grade 2 on the Common Terminology Criteria for Adverse Events (CTCAE) toxicity scale). Participant 0344-1001 received 15 mg daily on days 1–31, followed by 15 mg daily on days 32–39. Participant 0344-1003 received 15 mg daily on days 1–24, followed by 15 mg daily on days 25–39. The lower mean daily dose of TTM in Period 2 may explain the smaller changes in dNCC between days 31–35 and 36–39.

[0148] The increased mobilization of copper by TTM is evidenced by the decrease from baseline in net copper balance (net balance = copper in - copper out) shown in Table 13 and FIG. [Table 16]

[0149] Key secondary endpoints of Study 301 Key secondary endpoints of Study 301, intended to provide evidence of direct clinical benefit, were: Change from baseline in UWDRS Part II total score (activities of daily living) Change from baseline in UWDRS Part III functioning subscales Changes from baseline in UWDRS Part III individual functional items: chair rising, walking, speech, and handwriting After adjusting for multiplicity using hierarchical testing, none of the key secondary efficacy endpoints were statistically significantly different between TTM and SoC, as demonstrated in Table 14. There was a trend toward stability / improvement for both treatment groups. A possible explanation for the relative lack of improvement in neurology scores is the good baseline status of the majority of patients, as demonstrated by the data in Table 15. Approximately 50% of patients had a baseline UWDRS score of 0, and patients with scores above 0 had little room for improvement due to their relatively low UWDRS Part II (score range: 0-40) and UWDRS Part III (score range: 0-175) scale ranges, respectively. Additional UWDRS scores by cohort are presented in Figures 20 and 21.

[0150] The Transformed CGI-I (TCGI-I) assesses how the condition of WD patients has changed compared to baseline, and the CGI-I can indicate the overall clinical improvement of patients in the study for each treatment arm compared to baseline. Analysis outside the multiplicity study series showed significant improvements in the Transformed CGI-I scores at week 48 in cohort 1 and overall, as shown in Figure 22. [Table 17-1] [Table 17-2]

[0151] Another possible explanation for the relative lack of significant change in neurology scores is the low total baseline UWDRS scores in the overall population (data in Table 15). Overall, 55.9% and 51.4% of TTM and SoC participants, respectively, had a baseline UWDRS Part II total score of 0, and 21.3% and 18.6% of TTM and SoC participants, respectively, had a baseline UWDRS Part III total score of 0. Combined, 19.4% (40 / 206) of participants had a baseline total UWDRS score of 0 for both Part II and Part III. The impact of this is the low overall population means for Part II (3.5-4.0 on a 40-point scale) and Part III (6.50-15.97 on a 175-point scale). At the population comparison level, there was little room for overall improvement. However, at the individual participant level, changes in scores on individual items can potentially capture meaningful clinical change for individual participants over time. [Table 18]

[0152] A moderate reduction from baseline was found in UWDRS scores of 0-48W for symptomatic patients. Part II score change (mean) was -1.7 for TTM and -0.8 for SoC, and Part III score change (mean [95% CI]) was -2.91 [-4.74, -1.09] for TTM and -1.17 [-3.20, 0.86] for SoC. Table 15-1 summarizes the UWDRS Part III score change at 48W for patients who were symptomatic at baseline. [Table 19]

[0153] Symptoms and associated impacts of WD are generally divided into neurological, psychiatric, and hepatic categories. Previous studies involving concept-eliciting interviews with WD patients have provided insight into the complexity and heterogeneity among patients. Consistent with this, participants enrolled in Study 301 presented with a variety of symptoms, which have different types of impact on participants' lives.

[0154] Exit interviews were conducted with a sample of participants (n=10) to understand their experiences with TTM treatment. These exit interviews reflect the variability in neurological dysfunction and the need for a review of participant-level data to better understand treatment experiences. Overall, qualitative information suggests that participants who were symptomatic at the start of treatment with TTM experienced improvement or maintenance across several neurological symptoms (including gait, balance, speech, and tremor), and that improvement or maintenance was considered meaningful. Conversely, participants who did not report experiencing any symptoms at the start of the study did not develop any symptoms during treatment, and no deterioration (experience of symptoms or deterioration) was considered meaningful. Exit interview insights provide deeper insight into the experiences of interviewed participants and add to the observation that there is little room for overall improvement at the group comparison level.

[0155] Data from participants who took TTM for more than 48 weeks are being analyzed to evaluate the longer-term safety and efficacy (continued copper control and clinical benefit) of this therapy. This includes 19 participants from Phase 2 Study 201 who entered the Study 301 Extension and have received treatment with TTM for more than 5 years, as well as participants enrolled in Study 301 who were randomized to and treated with TTM in either the primary evaluation period or the open-label extension. Pooled results from all such participants are integrated together into one timeline, allowing for analysis of changes in UWDRS, long-term copper control, and long-term safety laboratory data.

[0156] UWDRS Part II total score results for this pooled population are presented in Table 16 and Figure 13, and UWDRS Part III total score results are in Table 17 and Figure 14. UWDRS Part III functional subscale (including items chair rise, walking, handwriting, and speech) results for this pooled population are presented in Table 18 and Figure 15. All tables document a decrease in mean and least squares mean (LSM) values ​​over time, with generally greater decreases at later time points. This indicates improvement in the overall population, as lower scores indicate improvement in signs and symptoms. Significance in mean and LSM was reached after 36 weeks of exposure to TTM (0 is excluded from mean and LSM 95% CI), and significance in mean and LSM is maintained in virtually all cases. Graphical representations show a downward sloping line over time, indicating slow but steady improvement during treatment with TTM. These results show that participant-reported UWDRS Part II scores, and clinician / neurologist-reported UWDRS Part III and Part III functional subscale scores all demonstrated continued improvement over up to 5 years of TTM treatment, with continued improvement evidenced by statistically significant reductions from baseline. [Table 20] [Table 21] [Table 22-1] [Table 22-2]

[0157] Table 18-1 provides some interim long-term safety and efficacy results over the extension period of Study 301. These results represent a pooled dataset of Study 301 participants who either started on TTM or transitioned to TTM after the 48-week primary period. These results demonstrate statistically significant improvements from baseline in key secondary endpoints, e.g., UWDRS and CGI, in patients treated with TTM. In addition, these results demonstrate that the level of improvement increases over time with continued TTM treatment. [Table 23-1] [Table 23-2] [Table 23-3]

[0158] Adverse Events of Special Interest (AESI): Neurological events Acute worsening of neurological symptoms, typically within 6 months of initiating therapy, is a known complication associated with chelation therapy for WD. The postulated mechanism is rapid mobilization of unbound copper in treated patients, resulting in higher blood NCC and triggering cytotoxic effects in neurological tissue and subsequent neurological deterioration. Neurological AESIs for Study 301 were considered as all AEs in the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) "Nervous System Disorders" or any other AE adjudicated by the investigator as an AESI.

[0159] Overall, neurological AESIs were reported in 47 (34.3%) and 5 (3.6%) participants under the SOCs "Nervous system disorders" and "Psychiatric disorders," respectively. Adverse events reported as AESIs in both of these SOCs are described below.

[0160] Nervous System Disorders (SOC) The incidence of AEs reported in the SOC "Nervous System Disorders" was higher in the TTM treatment group compared with the SoC group (34.3% vs. 21.4%). Commonly reported AEs in both groups were headache (8.0% vs. 8.6%) and tremor (7.3% vs. 2.9%). Among neurological AEs, a significant difference between treatment groups (TTM and SoC) was observed for tremor events. Twelve tremor events occurred in 10 (7.3%) participants. All events were non-serious and low grade (grade 1 and grade 2). Of the 10 (7.3%) participants, six reported the events as "worsening" or "increased tremor." The dose was discontinued due to three tremor events; for two events, the outcome was "resolved" and for one event, the outcome was "not resolved." For the remaining 9 events, the dose was not modified and the outcomes were "not recovered" for 3 events, "recovered" for 4 events, and "recovering" for 2 events.

[0161] The incidence of participants with the highest severity grade AEs was similar for grade 1 AEs in both treatment groups (24.1% vs. 21.4%) and higher for grade 2 AEs in the TTM treatment group (13.9% vs. 4.3%). No grade 3 AEs were observed in either treatment group, and grade 4 and grade 5 AEs were observed in one participant each in the TTM treatment group. One AE (Preferred Term "neurological deterioration") led to treatment withdrawal.

[0162] Similar to overall AEs, the incidence of SAEs was higher in the TTM treatment group compared with the SoC group [6 (4.4%) vs. 1 (1.4%)]. Seven SAEs were reported in 6 participants. In the TTM treatment group, SAE severity was reported as grade 1 in 1 participant, grade 2 in 4 participants, no grade 3 events, grade 4 in 1 participant (the same participant also experienced a grade 2 SAE), and grade 5 in 1 participant with an SAE of "hepatic encephalopathy." All SAEs in both treatment groups were assessed as unrelated.

[0163] The most common SAE system organ class for TTM was nervous system disorders (n=6 [4.4%]), and the SoCs were gastrointestinal disorders and musculoskeletal and connective tissue disorders (n=2 [2.9%] each).

[0164] Mental Disorders (SOC) Neurological AESIs in the SOC "Psychiatric Disorders" were observed only in the TTM treatment group. Seven events were reported in five (3.6%) participants: depression, enuresis, insomnia, paranoia, sleep disturbance, and blunted affect and irritability (both in one participant). All but one event was non-serious and low grade (Grade 1 and Grade 2). Of the seven events, only two resulted in dose modifications (one dose reduction and one dose increase). The outcome for three events was "resolved," and the outcome for four events was "ongoing." Only one SAE was reported ("paranoia exacerbation"). No Grade 4 or 5 events were reported, and no events resulted in study drug discontinuation.

[0165] Other significant events and laboratory findings Hepatic effects (increase in liver transaminase levels) Overall, liver enzyme elevation (ALT, aspartate aminotransferase [AST], and / or GGT) AEs were reported in a higher percentage of participants treated with TTM compared with SoC in Study 301 (see Table 19). The most commonly reported event for the TTM group was increased ALT (14.6% vs. 2.9% for SoC), accounting for 4.3% (25 / 577) of treatment-emergent adverse events (TEAEs) in the TTM group. These events typically occurred in the first 4 to 12 weeks and were generally mild to moderate in severity, asymptomatic, reversible, and normalized with dose adjustment and / or discontinuation. Liver enzyme elevation AEs are summarized in Table 19.

[0166] Based on laboratory data, 29 participants treated with TTM had a post-baseline ALT elevation of ≥3 times the upper limit of normal (ULN). Fourteen participants (10.2%) had ALT >3×ULN to ≦5×ULN Ten participants (7.3%) had ALT >5×ULN to ≦10×ULN One participant (0.7%) had an ALT >10×ULN to ≦20×ULN Four (2.9%) participants had elevated ALT >20 × ULN

[0167] Among participants treated with SoC, six had a post-baseline increase in ALT ≥ 3 × ULN, and three (4.3%) participants had ALT > 3 × ULN to ≤ 5 × ULN and ALT > 5 × ULN to ≤ 10 × ULN, respectively.

[0168] One TTM-treated participant experienced an ALT >3×ULN and a concomitant total bilirubin >2×ULN. The participant's underlying liver disease was a confounding factor, and this case was adjudicated by an independent liver evaluation panel as not likely related to TTM. Treatment with TTM was resumed, and liver tests remained normal.

[0169] The means and 95% CI for ALT and GGT values ​​over time are shown in Figures 16 and 17, respectively. In the TTM group, ALT levels increased from baseline, peaked at week 6, and then trended toward baseline by week 24. GGT levels increased from baseline to week 6 in the TTM group, stabilized by week 12, and then trended toward baseline by week 36. Overall, no clinically significant changes from baseline in ALT and GGT were observed in the SoC group. [Table 24]

[0170] Dyslipidemia: Routine lipid monitoring was not originally included within the clinical study. Through medical surveillance and review of available local laboratory data, three 301 participants were identified who experienced elevated liver enzymes and concurrent elevations in cholesterol and TG. Review of data from Study 201 showed that seven participants experienced increases in total cholesterol above the ULN, and all seven had concurrent ALT elevations. Therefore, routine lipid monitoring was added to Study 301, and a retrospective analysis was performed using available retained samples in all participants.

[0171] Retrospective analysis identified disparities in baseline lipid outcomes between the TTM and SoC groups. Elevated baseline cholesterol was found in 19% of TTM and 10% of SoC patients; 13 (9.5%) of TTM and 5 (7.1%) of SoC patients had decreased high-density lipoprotein (HDL); 10.9% of TTM and 7.1% of SoC patients had elevated low-density lipoprotein (LDL). The proportion of elevated TG was similar in both groups at baseline (16.8% of TTM and 17.1% of SoC patients).

[0172] A shift analysis from baseline to worst values ​​during the study for cholesterol and TG was performed. The results showed that a higher percentage of participants in the TTM group experienced grade 1 (43.8% vs. 32.9%), grade 2 (5.1% vs. 0), and grade 3 (3.6% vs. 0) cholesterol elevations compared with the SoC group. The worst values ​​during the study were higher in the TTM group compared with the SoC group for grade 2 (12.4% vs. 2.9%), grade 3 (5.1% vs. 1.4%), and grade 4 (2.9% vs. 0) TG. The shift from baseline to worst values ​​during the study for cholesterol and triglycerides is presented in Table 20. [Table 25]

[0173] The mean and 95% CI for total cholesterol over time are shown in Figure 18, where an increase above baseline is found in the TTM group but not in the SoC group throughout the primary study analysis period. In the TTM group, cholesterol levels increased from baseline, peaked at approximately week 6, then tended to decrease to baseline by week 24, and finally stabilized at a level slightly higher than baseline. In Figure 19, changes in TG were primarily limited to the early part of the treatment period, increasing from baseline by week 6, then gradually returning to baseline by week 36.

[0174] Analysis of lipid profiles was performed retrospectively using frozen plasma biomarker samples collected at scheduled study visits. Events under the cardiac disorders SOC were reviewed and only one AE was identified as potentially correlated with dyslipidemia.

[0175] Additionally, events under the gastrointestinal disorders SOC were reviewed, and no events (e.g., pancreatitis) were identified as potentially correlated with dyslipidemia. As noted above, lipid abnormalities and liver enzyme elevations were reported during the primary analysis period of Study 301, and these elevations were more frequent in the TTM group than in the SOC. Generally, lipid abnormalities were asymptomatic, transient, and not associated with any significant clinical outcomes.

[0176] Cytopenias: Copper is an essential micronutrient involved in the catalytic function of several key enzymes involved in a variety of processes throughout the body, including processes in the bone marrow and central nervous system. Acquired or inherited copper deficiency can manifest in multiple organ systems, but hematological abnormalities are the most common. Copper deficiency manifests with anemia, neutropenia, and, less frequently, thrombocytopenia.

[0177] Hematological AEs were observed in the clinical program for TTM. Hematological AEs are presented in Table 21. The majority of hematological events were non-serious, low grade, and resolved with dose modification. Treatment with TTM was discontinued in one participant each due to neutropenia (grade 2) and anemia (grade 1) AEs. Overall, the incidence of hematological AEs was similar among the TTM and SoC treatment groups. [Table 26]

[0178] At baseline, decreased neutrophil levels (0.7% vs. 1.4%) were similar between the TTM and SoC groups, decreased platelet levels (21.9% vs. 28.6%) were higher in the SoC group compared with the TTM group, and decreased hemoglobin levels (17.5% vs. 14.3%) were slightly higher in the TTM group compared with the SoC group.

[0179] The shifts from baseline to worst values ​​during the study for neutrophils, platelets, and hemoglobin are presented in Table 22. Overall, the results showed similar percentages in the shift from baseline to worst values ​​for neutrophils, platelets, and hemoglobin, except for grade 1 hemoglobin (41.6% vs. 24.3%), grade 1 platelets (24.1% vs. 17.1%), and grade 3 neutrophils (6.6% vs. 2.9%), which were higher in the TTM group than in the SoC group. [Table 27]

[0180] Safety findings in participants who switched from SoC to TTM during the extension period Analyses were performed on preliminary data to compare AEs from Study 301 participants who received SoC during the primary evaluation period (week 48) with AEs from the subset of participants who switched to TTM during the extension period. Analyses were performed to identify imbalances in AE reporting after switching from SoC to TTM and compare the results to the imbalances observed in events with SoC during the primary evaluation period [TTM vs. SoC].

[0181] During the primary evaluation period in Study 301, disproportionate SoC (greater than 5% difference) between TTM and SoC included ear and labyrinth disorders (5.1% vs. 0%), general system disorders and administration site conditions (21.2% vs. 10.0%), hepatobiliary disorders (6.6% vs. 1.4%), clinical examination (33.6% vs. 2.9%), nervous system disorders (34.3% vs. 21.4%), psychiatric disorders (19.0% vs. 4.3%), and skin and subcutaneous tissue disorders (21.9% vs. 5.7%). These are presented in Table 23.

[0182] Among participants who switched from SoC to TTM, there were four identified SoCs in which a higher percentage of participants (defined as a difference of >5%) experienced AEs, including general systemic disorders and administration site conditions (10% vs. 18%), laboratory tests (2.9% vs. 29.5%), metabolic and nutritional disorders (4.3% vs. 11.5%), and skin and subcutaneous tissue disorders (5.7% vs. 13.1%). As shown in Table 24, the disparities observed within each SoC were driven by events of fatigue, ALT elevation, lipid elevation (i.e., hyperlipidemia, hypertriglyceridemia, and dyslipidemia), and pruritus.

[0183] There was no disparity in AE reporting identified from any of the other SoCs (see Table 24-1). Notably, and in contrast to the disparities observed in the primary assessment period, the switch analysis showed no disparities in the nervous system or psychiatric disorders SoCs. [Table 28] [Table 29] [Table 30]

[0184] Overall, most AEs observed in Study 301 were non-serious, mild or moderate, manageable, and did not lead to treatment discontinuation. Commonly observed (>10%) AEs included increased ALT and nasopharyngitis. Risks observed in participants treated with TTM, including hepatic effects (elevations in hepatic transaminase levels), dyslipidemia, and cytopenias, were generally asymptomatic, reversible with dose modification, and not associated with any clinical outcome.

[0185] Consistent with the above, analysis of data in participants who switched from treatment with SoC to TTM showed an increased incidence of laboratory abnormalities (increased ALT, increased cholesterol and increased TG, decreased neutrophils), further supporting the association with TTM.

[0186] Neurological deterioration is a known concern with SoC, primarily associated with penicillamine but also observed with trientine and zinc. The mechanism of neurological deterioration is unknown, although a link to unbound copper has previously been hypothesized. Data from the primary evaluation period in Study 301 demonstrated an imbalance in neurological and psychiatric events, with a higher incidence in participants treated with TTM versus SoC. However, these imbalances were not observed in participants who switched from SoC treatment to TTM during the extension period. Because Study 301 was an open-label study, there is the potential for biased reporting by participants known to be receiving investigational medication. The noted findings suggest a lack of association between TTM and neurological and psychiatric AEs.

[0187] Overall, TTM had an acceptable safety profile and was generally well tolerated in participants with WD.

[0188] Cirrhosis at Baseline and Albumin Levels During TTM Treatment: Across Studies 301, 201, and 205, 102 participants had cirrhosis at baseline. Study 205 is registered with ClinicalTrials.gov under number NCT04422431 and is incorporated by reference in its entirety. Of the total 102, 13 participants experienced changes in albumin levels (indicating changes in composite liver function) over the course of treatment with TTM. Albumin levels in the other 89 participants remained stable during the study (indicating stable liver function). The changes in albumin levels in these 13 participants are listed below in Table 25 (units shown are mg / dL throughout). [Table 31-1] [Table 31-2]

[0189] These results demonstrate that of 102 participants with cirrhosis at baseline, 87% maintained liver function (as measured by albumin levels) during TTM treatment. Of the 13 cirrhotic participants who experienced changes in liver function, 7 participants who underwent TTM treatment experienced improvement, such that albumin levels that were outside the normal range returned to the normal range during TTM treatment.

[0190] Example 2: Cohort 1 - Further evaluation of incomplete and intolerant responders As noted above, patients with Wilson's disease (WD) who have been treated with standard of care (SoC) for several years may still be neurologically symptomatic despite perceived overall disease stability. Existing treatments also have burdensome dosing schedules and / or side effects and are associated with low adherence. The efficacy and safety of thiomolybdate choline (BC-TTM; INN: thiomolybdic acid; USAN: thiomolybdate choline; also known as ALXN1840; formerly known as WTX101) were investigated in patients with ongoing neurological symptoms or a history of intolerance to standard of care (SoC) treatment.

[0191] As described in Example 1, in the open-label, phase 3 FoCus trial (NCT03403205), 214 patients were stratified by the duration of their previous SoC (Cohort 1: >28 days; Cohort 2: 0-28 days) and then randomized 2:1 to receive BC-TTM (15-60 mg QD) or SoC (penicillamine, trientine, and / or zinc) for 48 weeks (W). The statistical analysis plan for Study 301 included prespecified analysis subsets of study participants who were intolerant to or had an incomplete response to prior therapy with penicillamine, trientine, and / or zinc. These groups were more precisely defined as intolerant (identified by a history of prior treatment or adverse events before Day 1 of TTM treatment) or incomplete responders (those with a baseline UWDRS Part II or Part III total score >0). The definitions for this analysis subset from Study 301 are referred to herein as Subpart E. For purposes of this disclosure, study participants who had an incomplete response to prior therapy with penicillamine, trientine, and / or zinc may also be referred to as "incomplete responders" or "inadequate responders."

[0192] For analysis, the participant pool was expanded to include those from Studies 201 and 205 who also met these criteria (see Table 26). The Subpart E population was restricted to participants with more than 28 days of prior treatment (identified as Cohort 1 in the studies described herein) to ensure that participants had a minimum course of another treatment before switching to TTM treatment. Note that Study 201 did not collect data that would have allowed participants to be declared intolerant to their prior treatment. This resulted in a Subpart E population of 164 study participants. [Table 32]

[0193] Endpoints (directly measured non-ceruloplasmin-bound copper [dNCC], UWDRSIII (rater-blinded) total and individual item scores, Clinical Global Impression-Improvement [CGI-I]) were assessed at baseline (BL) and at week 48 (W48). Total and individual UWDRSIII item scores were assessed for normalization (reduction to 0), improvement (decrease of ≥1 point), stability (no change), or deterioration (increase of ≥1 point) at W48.

[0194] Subpart E Population Justification Patients with WD who experience an incomplete or intolerable response to standard treatment represent a high unmet medical need. Patients with an incomplete response to current therapies have persistent symptoms despite treatment. Scientific literature reports hepatic deterioration in patients treated with SoC over more than 10 years of follow-up, with 5-24% of presymptomatic patients developing hepatic symptoms, which in some cases progress to liver failure (Merle et al., 2007, Gut, 56:115-120; Dziezyc et al., 2014, Eur J Neurol, 21(2):332-337). Long-term follow-up studies have shown that hepatic treatment failure was more frequent in patients receiving zinc (14 / 88 treatments) than in patients receiving metal chelators (4 / 313 treatments) (Weiss et al., 2011, Gastroenterology, 140(4):1189-198). The literature also reports that neurological deterioration in patients with baseline neurological symptoms occurred after 6 to 48 months of treatment in 5% to 7% of patients treated with penicillamine and 16% to 20% of patients treated with trientine, depending on whether the treatment was first- or second-line (Weiss et al., 2013, Clin Gastroenterol Hepatol., 11(8):1028-1035). The literature also reports that neurological disease progression has been observed in long-term studies (>10 years). For example, in patients with neurological symptoms at diagnosis and followed up for an average of 16.7 years, neurological deterioration occurred in 24% (14 / 58) of treated patients (Merle et al., 2007, Gut, 56:115-120). Furthermore, in prodromal patients treated and followed up for more than 10 years, neuropsychiatric symptoms developed in 19% of patients (Merle et al., 2007, Gut, 56:115-120; Dziezyc et al., 2014, Eur J Neurol, 21(2):332-337).

[0195] In Study 301, participants who had been previously treated for more than 28 days and had intolerance or an incomplete response to previous therapy presented with persistent symptoms or organ damage at baseline, with 100% of participants having neurological deficits (UWDRS Part II >0 and / or UWDRS Part III >0, according to the definition of incomplete response), 79% of participants having psychiatric symptoms (BPRS >24), and 40% of participants having compensated cirrhosis. This represents a high disease burden despite a mean duration of prior treatment of 11.2 years.

[0196] Patients with intolerance to SoC may require a change in treatment and would benefit from additional treatment options. Medical literature suggests that penicillamine may be less well tolerated than other first-line treatment options for WD because it can be associated with severe side effects requiring drug withdrawal in approximately 30% of patients (Schilsky et al., 2022, Hepatology, 00:1-49). Safety concerns requiring immediate discontinuation of penicillamine include early sensitivity reactions, which can occur during the first 1-3 weeks, later reactions including nephrotoxicity, bone marrow toxicity including severe thrombocytopenia, or global aplasia, which may be irreversible despite cessation of therapy (Schilsky et al., 2022, Hepatology, 00:1-49). Dermatological toxicities may include premature aging changes in the skin and perforating elastosis serpingosa, pemphigus or pemphigoid lesions, lichen planus, and aphthous stomatitis (Schilsky et al., 2022, Hepatology, 00:1-49). Trientine has minimal side effects, and colitis may occur in rare cases (Schilsky et al., 2022, Hepatology, 00:1-49). Zinc has very minimal side effects, with gastric irritation or gastritis being the most common adverse effect occurring in approximately one-third of patients, which may depend on the type of zinc salt (Schilsky et al., 2022, Hepatology, 00:1-49).

[0197] An unmet need, for example, in patients with an incomplete or intolerable response to current treatment, is adherence and persistence to therapy. With current SoCs dosing up to three times daily, real-world adherence to SoC treatment for WD can be problematic in approximately one-third of patients (Jacquelet et al., 2021, J Inherit Metab Dis., 44(6):1481-1488; Maselbas et al., 2019, BMC Neurol. 19(278):1-6). Patients who did not persist on therapy experienced worsening of WD more frequently than persisters (52.3% vs. 2.4%) (Maselbas et al., 2019, BMC Neurol. 19(278):1-6). Indeed, in Study 301, in contrast to the real-world evidence referenced herein, adherence to SoC was greater than 90%.

[0198] Analysis subpopulations The efficacy of TTM in Wilson disease was evaluated in a population of treatment-experienced patients who had an incomplete response (as determined by residual neurological signs and symptoms) to or were intolerant to penicillamine, trientine, or zinc. These patients were derived from 1) one single-arm phase 2 study (Study 201), which contributed 10 adult patients; 2) one single-arm phase 2 study (Study 205), which contributed 23 adult patients; and 3) one phase 3 study (Study 301), which contributed 131 patients (adults and adolescents aged 12–17 years). Study 301 also allowed for a comparison of treatment with TTM with therapies available at the time (the chelators penicillamine or trientine, with or without zinc, or zinc alone).

[0199] A single-arm study of TTM in patients with Wilson's disease Study 201, a single-arm phase 2 study, evaluated the efficacy of BC-TTM over 24 weeks in adult patients with Wilson disease. Individualized dosing was allowed, and the median dose administered to the 10 patients who met the analysis definition was 18.7 mg / day.

[0200] A single-arm liver biopsy study of TTM in patients with Wilson's disease Study 205, a single-arm phase 2 study, evaluated the effects of thiomolybdate choline treatment on the liver during a 48-week treatment period in adult patients with Wilson disease. Biopsies were performed at baseline and at week 48 to assess changes in liver copper concentrations. The median dose administered to the 23 patients who met the analysis definition was 16.5 mg / day.

[0201] Comparison of TTM and SoC in patients with Wilson's disease Study 301, a randomized, active-controlled study, compared the efficacy of TTM with a chelating agent (penicillamine or trientine with or without zinc) or zinc alone in adult and adolescent patients with Wilson's disease. The endpoint was copper mobilization, measured as the average daily area under the effect-time curve (AUEC) for total plasma concentration from time 0 to week 48 (AUEC 0~48週 TTM was superior to the control arm receiving standard of care (SoC) in copper mobilization.

[0202] clinical findings The clinical benefit for the analysis subpopulation is supported by the following: The superiority of TTM treatment over SoC treatment in mobilizing copper from tissues was demonstrated by the efficacy endpoint dNCC AUEC 0~48週 Superiority, as demonstrated by [μmol / L] (p-value < 0.0001 for Subpart E total population) A rapid, within-group, clinically meaningful improvement from baseline in UWDRS Part II score (patient / caregiver reported), observed as early as 24 weeks and sustained through 48 weeks; A rapid, within-group, clinically meaningful improvement from baseline in UWDRS Part III score (blinded neurological examination) that is observed as early as 24 weeks and sustained through 48 weeks; Significant between-group (TTM vs. SoC) improvement in CGI-I at week 48; odds ratio of 4.9 for TTM-treated participants vs. SoC-treated participants (p=0.0004); significant between-group improvement in mean CGI-I at week 48; and ●Significant between-group (TTM vs. SoC) improvement of at least 1 point on CGI-S at week 48; odds ratio of 3.6 for TTM-treated participants vs. SoC-treated participants; meaningful within-group improvement in mean CGI-S at week 48. The long-term clinical benefit of TTM is demonstrated by the following data pooled from the 301, 201, and 205 studies. ● Clinically meaningful, within-group, long-term improvement from baseline in UWDRS Part II score (patient / caregiver reported) and UWDRS Part III score (blinded neurological examination) over 48 weeks and up to 5 years.

[0203] Long-term treatment data (up to 240 weeks) available for these outcomes show that both participant-reported and clinical / neurologist-reported scores showed improvement over 240 weeks of TTM treatment.

[0204] As noted above, the key secondary endpoints of Study 301, which were intended to provide evidence of direct clinical benefit, were: Change from baseline in UWDRS Part II total score (activities of daily living), Change from baseline in UWDRS Part III functioning subscales • Change from baseline in UWDRS Part III individual function items: chair rise, walking, speech, and handwriting. Key secondary efficacy endpoints were statistically significantly different between TTM and SoC within the subpopulation with an incomplete response to or intolerance to SoC. As demonstrated in Table 27, patients in subpart E who received TTM treatment had improved UWDRS Part III total scores compared to baseline values. The 95% confidence intervals did not cross zero, indicating that the p-value was significant. Furthermore, these changes from baseline were greater than those of patients who received standard treatment. Furthermore, the 95% confidence interval for standard treatment did indeed cross zero, indicating that the changes observed in UWDRS Part III for these patients were not statistically significant. [Table 33]

[0205] Similarly, Table 28 shows that patients receiving TTM treatment had a greater net promoter score for UWDRS Part III than those receiving standard care. To calculate the net promoter score, we first defined the minimal clinically meaningful difference (MCID). Although there is no current definition of the MCID for patients with neurological signs of WD, the literature defines a worsening as a 4-point increase in UWDRS Part III (Czlonkowska et al., 2014, European Journal of Neurology, 21:599-606) or an increase of 20% (Poujois et al., 2020, Neurology, 94(21):e2189-e2202).

[0206] Therefore, a distribution-based method was used to compute the MCID threshold, half standard deviation (SD), and standard error of measurement (SEM) for the full study 301 and subpart E populations. The proportion of patients who demonstrated an improvement in UWDRS Part III score greater than the MCID threshold and the proportion of patients who demonstrated a deterioration in UWDRS Part III score greater than the MCID threshold were then calculated. The difference between these two populations represented the "Net Promoter Score."

[0207] Applying the distribution-based method for the overall cohort, the half-SD and SEM MCID values ​​were 6.611 and 5.032, respectively. Analysis of the incomplete and / or intolerant subgroups yielded a lower MCID of half-SD of 6.371 and SEM of 4.849. The provisional MCID and responder definition for UWDRS Part III in WD was approximately a 5-6 point improvement in the overall population and a 4-6 point improvement in the incomplete and intolerant subgroups. Applying a 5-point change in UWDRS Part III as the responder threshold to Study 301 data, 44.8% (n = 30) of patients in the TTM treatment group versus 29.4% (n = 5) of patients in the SoC treatment group improved by 5 points or more by week 48; similar results were observed with a 4-point change threshold for the incomplete and / or intolerant subgroup: 43.1% (n = 22) of patients in the TTM treatment group versus 29.4% (n = 5) of patients in the SoC treatment group. [Table 34]

[0208] Thus, among incomplete and intolerant responders, more patients improved their UWDRS Part III total score with TTM treatment than with SoC. This is further illustrated in Figure 24, where each line represents one patient (negative = improvement from baseline, positive = worsening from baseline, blank = no change).

[0209] As noted above, when examining the entire population, key secondary efficacy endpoints were not statistically significantly different between the TTM and SoC treatment groups, as demonstrated in Table 14 in Example 1, although there was a trend toward stability / improvement for both treatment groups. A possible explanation for the relative lack of improvement in neurological scores is the favorable baseline status of the majority of patients, as demonstrated by the data in Table 15 in Example 1. However, upon further examination of baseline measures of neurological deficit (UWDRS-III) for the subgroup of patients with an incomplete response or intolerance to treatment with SoC prior to WD treatment, significant symptom heterogeneity was found at baseline ("BL"). Wilson disease symptom heterogeneity is demonstrated by the distribution of symptoms experienced by patients in Figure 25. As shown in Figure 25, WD heterogeneity in the study population was found in disease severity across treatment groups.

[0210] Due to this heterogeneity, the effect of TTM treatment on individual manifestations of UWDRS parameters was evaluated. Table 29 reports these results. [Table 35]

[0211] Table 29 demonstrates that specific symptoms experienced by patients were improved over those on standard care.

[0212] This is further illustrated in Figure 26. Of the 160 treated patients in Cohort 1, 133 (88 TTM, 45 SoC) had an incomplete response to or were intolerant of a previous SoC, with 6 patients only intolerant. At BL, the cumulative mean (SD) duration of previous SoC treatment was 149.0 (137.3) and 153.7 (161.9) months in the TTM and SoC groups, respectively. At BL, scores above 0 were most frequently reported for speech (n = 68), finger tap left (n = 63), positional tremor right (n = 63), and left (n = 63). The least squares mean (LSM) difference (standard error [SE]) for TTM versus SoC from W0 to W48 was 1.64 (0.297), p<0.0001 for dNCC area under the effect curve, -0.53 (1.426), p=0.7084 for UWDRS III total, and -0.4 (0.15), p=0.0051 for CGI-I. For TTM-treated patients, the within-group change (LSM [SE]) from baseline was -2.52 (0.826), 95% confidence interval (CI) (-4.15, -0.88), and for SoC-treated patients, it was -1.99 (1.162), 95% CI (-4.28, 0.31). The percentage of patients with normalization, improvement, stability, or worsening in the UWDRS III total score, and the most frequently reported individual items at W48, are shown in Figure 26. The most common treatment-emergent AE occurring in TTM was alanine aminotransferase elevation. Neurological AEs were observed in 31.8% and 22.2% of patients in the TTM and SoC groups, respectively, and were primarily non-serious, mild to moderate, and resolved without dose modification. Withdrawals due to AEs occurred in the TTM (n=5) and SOC (n=1) groups.

[0213] Overall, in Cohort 1 patients with an incomplete response or intolerance to SoC, 48 weeks of treatment with TTM or SoC was associated with disease stabilization and improvement in neurological symptoms. Treatment with TTM was generally safe and well tolerated. Furthermore, patients who were considered stable on standard treatment but still had long-term symptoms also improved.

[0214] Additionally, rapid, clinically meaningful improvements in UWDRS Part III scores were observed within this subgroup after TTM treatment in UWDRS-III scores at weeks 24 and 48. Table 30 shows these results. [Table 36]

[0215] Furthermore, these improvements are seen over 5 years of TTM treatment. These results are reported in Table 31 and Figure 27. [Table 37]

[0216] Subpart E patients who received TTM treatment for 48 weeks also experienced significant global clinical improvement as measured by CGI-I and significant improvement in disease severity as measured by CGI-S relative to treatment with SoC. These data are reported in Tables 32 and 33, respectively. [Table 38] [Table 39]

[0217] TTM was generally safe and well tolerated in the overall safety population of patients with WD and in the subpart E population who had an incomplete response to or were intolerant to SoC therapy at baseline. The majority of AEs observed in TTM-treated patients were non-serious, mild or moderate in severity, and did not result in treatment discontinuation. Long-term data, with a median exposure of approximately 2.5 years (maximum, approximately 6.5 years) and a total exposure of 645.6 patient-years, in patients with WD treated with TTM demonstrate a safety profile consistent with data from the primary evaluation period (Study 301).

[0218] The risks assessed as associated with TTM treatment were biochemical abnormalities without any significant adverse clinical outcomes. These abnormalities included elevated liver enzymes, elevated lipids, and neutropenia. These were generally non-serious, low-grade in severity, and with very limited treatment discontinuations. With appropriate monitoring and mitigation strategies, these risks are manageable. Preliminary efficacy and safety data support a positive balance of benefits and risks for TTM treatment in the Subpart E population.

[0219] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are incorporated within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications mentioned herein are incorporated herein by reference for all purposes.

Claims

1. 1. Tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof for treating a copper metabolism-related disease or disorder in a subject, comprising: a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered to the subject; the subject is at least 12 years old; Tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof, wherein the subject has had an incomplete response to and / or is intolerant to treatment with standard of care.

2. 2. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to claim 1, wherein the copper metabolism-related disease or disorder is Wilson's disease.

3. 3. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein the subject is at least 18 years old.

4. 4. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the subject has previously received treatment with the standard of care for the copper metabolism-related disease or disorder for at least 28 days.

5. 5. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the subject has previously received treatment with a standard therapy for the copper metabolism-related disease or disorder for at least 4 weeks, at least 6 weeks, at least 12 weeks, at least 48 weeks, or at least 72 weeks.

6. 6. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the subject has previously received treatment with a standard of care for the copper metabolism-related disease or disorder for at least 28 months, at least 36 months, at least 42 months, or at least 48 months.

7. 7. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 1 to 6, wherein the subject has previously received treatment with a standard of care for the copper metabolism-related disease or disorder for at least 72 months, at least 96 months, at least 120 months, or at least 142 months.

8. 8. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein the subject has symptoms associated with the copper metabolism-related disease or disorder after receiving the standard of care treatment for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

9. 9. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the subject has an incomplete response to treatment with the standard of care.

10. 10. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the subject has an inadequate response to treatment with the standard of care.

11. 11. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of claim 9 or 10, wherein the subject has symptoms associated with the copper metabolism-related disease or disorder after receiving treatment with the standard of care for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

12. 12. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 11, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part II total score of greater than 0 or a Unified Wilson Disease Rating Scale (UWDRS) Part III total score of greater than 0 before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered.

13. 12. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 11, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part II total score of greater than 0 and a Unified Wilson Disease Rating Scale (UWDRS) Part III total score of greater than 0 before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered.

14. 14. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 13, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part II score of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

15. 15. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 14, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part II score of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

16. 16. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 15, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part III score of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

17. 17. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 16, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part III of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

18. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the subject is intolerant to treatment with the standard therapy.

19. 19. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of claim 18, wherein the subject has symptoms associated with the copper metabolism-related disease or disorder after receiving the standard of care treatment for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

20. 20. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of claim 18 or 19, wherein the subject has previously been determined by a medical professional to be intolerant to treatment with the standard of care or has had an adverse event after receiving treatment with the standard of care and before the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof is administered.

21. 21. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 18 to 20, wherein the subject has previously been determined by a medical professional to be intolerant to treatment with standard of care and has had an adverse event after receiving treatment with standard of care and before administering the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof.

22. 22. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein the standard of care treatment comprises trientine, D-penicillamine, and / or zinc.

23. 23. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein the standard of care treatment comprises trientine and / or D-penicillamine.

24. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

25. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered to the subject in a fasting state.

26. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is in the range of about 7.8 mg to about 60 mg per day.

27. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is about 7.8 mg per day.

28. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is about 7.8 mg every other day.

29. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein the tetrathiomolybdic acid is a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt is a bis-choline salt.

30. 30. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of claim 29, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

31. 31. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to claim 29 or 30, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is administered to the subject in a fasting state.

32. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 79 to 81, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is in the range of about 15 mg to about 60 mg per day.

33. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 29 to 32, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is about 15 mg per day.

34. 34. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 29 to 33, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is about 15 mg every other day.

35. 35. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof is sufficient to inhibit progression of neurological damage in the subject.

36. 36. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 35, wherein the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof is sufficient to inhibit progression of liver damage in the subject.

37. 37. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve or maintain one or more of a neurological symptom, a psychiatric symptom, a clinical symptom, a disability status, or treatment satisfaction in the subject.

38. 38. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof is sufficient to improve one or more of neurological symptoms, psychiatric symptoms, clinical symptoms, disability status, or treatment satisfaction in the subject.

39. 40. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of claim 38, wherein the improvement is observed after the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof has been administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

40. 40. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 1 to 39, wherein the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof is sufficient to improve the subject's Unified Wilson Disease Rating Scale (UWDRS) Part II total score or Unified Wilson Disease Rating Scale (UWDRS) Part III total score.

41. 40. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 1 to 39, wherein the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof is sufficient to improve the subject's Unified Wilson Disease Rating Scale (UWDRS) Part II total score and Unified Wilson Disease Rating Scale (UWDRS) Part III total score.

42. 42. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 1 to 41, wherein the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof is sufficient to improve the UWDRS Part II total score in the subject by at least 5%, at least 10%, at least 15%, or at least 20%.

43. 43. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 1 to 42, wherein the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof is sufficient to improve the UWDRS Part III total score in the subject by at least 5%, at least 10%, at least 15%, or at least 20%.

44. 44. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 40 to 43, wherein the improvement is observed after the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof has been administered for a minimum of 24 weeks, at least 36 weeks, or at least 48 weeks.

45. 45. The tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 44, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more neurological symptoms in the subject as measured according to Unified Wilson Disease Rating Scale (UWDRS) Part II and / or Part III, wherein the one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

46. 46. ​​The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of claim 45, wherein the improvement is observed after the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof has been administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

47. 47. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 1 to 46, wherein the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof is sufficient to improve one or more neurological symptoms in the subject as measured according to Unified Wilson Disease Rating Scale (UWDRS) Part II and / or Part III, wherein the one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

48. 48. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of claim 47, wherein the improvement is observed after the therapeutically effective amount of tetrathiomolybdic acid or pharmaceutically acceptable salt thereof has been administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

49. 49. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 1 to 48, wherein the subject is further evaluated for improvement in disability and neurological symptoms as measured according to the Unified Wilson's Disease Rating Scale (UWDRS) Part II and / or Part III.

50. 50. The tetrathiomolybdic acid or pharmaceutically acceptable salt thereof of any one of claims 1 to 49, wherein the subject is further evaluated for improvement in disability status, psychiatric symptoms, clinical symptoms, treatment satisfaction, or a combination thereof.

51. 1. A method for treating a copper metabolism-related disease or disorder in a subject, the method comprising: administering to the subject a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof; the subject is at least 12 years old; The method, wherein the subject has had an incomplete response to and / or is intolerant to treatment with standard of care.

52. 52. The method of claim 51, wherein the copper metabolism-related disease or disorder is Wilson's disease.

53. 53. The method of claim 51 or 52, wherein the subject is at least 18 years of age.

54. 54. The method of any one of claims 51 to 53, wherein said subject has previously received treatment with said standard of care for said copper metabolism-related disease or disorder for at least 28 days.

55. 55. The method of any one of claims 51-54, wherein the subject previously received treatment with a standard of care for the copper metabolism-related disease or disorder for at least 4 weeks, at least 6 weeks, at least 12 weeks, at least 48 weeks, or at least 72 weeks.

56. 56. The method of any one of claims 51-55, wherein the subject has previously received treatment with a standard of care for the copper metabolism-related disease or disorder for at least 28 months, at least 36 months, at least 42 months, or at least 48 months.

57. 57. The method of any one of claims 51-56, wherein the subject has previously received treatment with a standard of care for the copper metabolism-related disease or disorder for at least 72 months, at least 96 months, at least 120 months, or at least 142 months.

58. 58. The method of any one of claims 51-57, wherein the subject has symptoms associated with the copper metabolism-related disease or disorder after receiving treatment with the standard of care for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

59. 59. The method of any one of claims 51 to 58, wherein the subject has an incomplete response to treatment with the standard of care.

60. 60. The method of claims 51-59, wherein the subject has an inadequate response to treatment with the standard of care.

61. 61. The method of claim 59 or 60, wherein the subject has symptoms associated with the copper metabolism-related disease or disorder after receiving treatment with the standard of care for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

62. 62. The method of any one of claims 59-61, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part II total score of greater than 0 or a Unified Wilson Disease Rating Scale (UWDRS) Part III total score of greater than 0 prior to said administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

63. 62. The method of any one of claims 59-61, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part II total score of greater than 0 and a Unified Wilson Disease Rating Scale (UWDRS) Part III total score of greater than 0 prior to said administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

64. 64. The method of any one of claims 59-63, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) part II of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms prior to the administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

65. 65. The method of any one of claims 59-64, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) part II of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms prior to the administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof, wherein the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

66. 56. The method of any one of claims 59-55, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part III of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms prior to the administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

67. 57. The method of any one of claims 59-56, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) part III of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms prior to the administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof, wherein the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

68. 59. The method of any one of claims 51 to 58, wherein the subject is intolerant to treatment with the standard of care.

69. 69. The method of claim 68, wherein the subject has symptoms associated with the copper metabolism-related disease or disorder after receiving treatment with the standard of care for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

70. 70. The method of claim 68 or 69, wherein the subject has previously been determined by a medical professional to be intolerant to treatment with standard of care or has had an adverse event after receiving treatment with standard of care and prior to administering the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

71. 71. The method of any one of claims 68-70, wherein the subject has previously been determined by a medical professional to be intolerant to treatment with standard of care and has had an adverse event after receiving treatment with standard of care and prior to administering the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

72. 72. The method of any one of claims 51-71, wherein the standard of care treatment comprises trientine, D-penicillamine, and / or zinc.

73. 73. The method of any one of claims 51 to 72, wherein the standard of care treatment comprises trientine and / or D-penicillamine.

74. 74. The method of any one of claims 51-73, wherein said administering said therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

75. 75. The method of any one of claims 51 to 74, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered to the subject in a fasting state.

76. 76. The method of any one of claims 51 to 75, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof ranges from about 7.8 mg to about 60 mg per day.

77. 77. The method of any one of claims 51 to 76, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is about 7.8 mg per day.

78. 78. The method of any one of claims 51-77, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is about 7.8 mg every other day.

79. 78. The method of any one of claims 51 to 77, wherein the tetrathiomolybdic acid is a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt is a bis-choline salt.

80. 80. The method of claim 79, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

81. 81. The method of claim 79 or 80, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is administered to the subject in a fasting state.

82. 82. The method of any one of claims 79-81, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate ranges from about 15 mg to about 60 mg per day.

83. 83. The method of any one of claims 79 to 82, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is about 15 mg per day.

84. 84. The method of any one of claims 79-83, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is about 15 mg every other day.

85. 85. The method of any one of claims 51-84, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to inhibit progression of neurological damage in the subject.

86. 86. The method of any one of claims 51-85, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to inhibit progression of liver damage in the subject.

87. 87. The method of any one of claims 51-86, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve or maintain one or more of a neurological symptom, a psychiatric symptom, a clinical symptom, a disability status, or treatment satisfaction in the subject.

88. 88. The method of any one of claims 51-87, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more of a neurological symptom, a psychiatric symptom, a clinical symptom, a disability status, or treatment satisfaction in the subject.

89. 89. The method of claim 88, wherein the improvement is observed at least 24 weeks, at least 36 weeks, or at least 48 weeks after administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

90. 90. The method of any one of claims 51-89, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the subject's Unified Wilson Disease Rating Scale (UWDRS) Part II total score or Unified Wilson Disease Rating Scale (UWDRS) Part III total score.

91. 90. The method of any one of claims 51-89, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the subject's Unified Wilson Disease Rating Scale (UWDRS) Part II total score and Unified Wilson Disease Rating Scale (UWDRS) Part III total score.

92. 92. The method of any one of claims 51-91, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the subject's UWDRS Part II total score by at least 5%, at least 10%, at least 15%, or at least 20%.

93. 93. The method of any one of claims 51-92, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the subject's UWDRS Part III total score by at least 5%, at least 10%, at least 15%, or at least 20%.

94. 94. The method of any one of claims 90-93, wherein the improvement is observed at least 24 weeks, at least 36 weeks, or at least 48 weeks after administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

95. The method of any one of claims 51 to 4494, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more neurological symptoms in the subject as measured according to Unified Wilson Disease Rating Scale (UWDRS) Part II and / or Part III, wherein the one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

96. 96. The method of claim 95, wherein the improvement is observed at least 24 weeks, at least 36 weeks, or at least 48 weeks after administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

97. 97. The method of any one of claims 51-96, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more neurological symptoms in the subject as measured according to Unified Wilson Disease Rating Scale (UWDRS) Part II and / or Part III, wherein the one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

98. 98. The method of claim 97, wherein the improvement is observed at least 24 weeks, at least 36 weeks, or at least 48 weeks after administration of the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

99. 99. The method of any one of claims 51-98, further comprising assessing the subject for improvement in disability and neurological symptoms as measured according to the Unified Wilson's Disease Rating Scale (UWDRS) Part II and / or Part III.

100. 100. The method of any one of claims 51-99, further comprising assessing the subject for improvement in disability status, psychiatric symptoms, clinical symptoms, treatment satisfaction, or a combination thereof.

101. 1. Use of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a copper metabolism-related disease or disorder in a subject, comprising: a therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered to the subject; the subject is at least 12 years old; The use wherein the subject has had an incomplete response to and / or is intolerant to treatment with standard of care.

102. 102. The use of claim 101, wherein the copper metabolism-related disease or disorder is Wilson's disease.

103. 103. The use of claim 101 or 102, wherein the subject is at least 18 years old.

104. 104. The use of any one of claims 101 to 103, wherein the subject has previously received treatment with the standard of care for the copper metabolism-related disease or disorder for at least 28 days.

105. 105. The use of any one of claims 101 to 104, wherein the subject has previously received treatment with a standard of care for the copper metabolism-related disease or disorder for at least 4 weeks, at least 6 weeks, at least 12 weeks, at least 48 weeks, or at least 72 weeks.

106. 106. The use of any one of claims 101 to 105, wherein the subject has previously received treatment with standard of care for the copper metabolism-related disease or disorder for at least 28 months, at least 36 months, at least 42 months, or at least 48 months.

107. 107. The use of any one of claims 101 to 106, wherein the subject has previously received treatment with standard of care for the copper metabolism-related disease or disorder for at least 72 months, at least 96 months, at least 120 months, or at least 142 months.

108. 108. The use of any one of claims 101 to 107, wherein the subject has symptoms associated with the copper metabolism-related disease or disorder after receiving treatment with the standard of care for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

109. The use of any one of claims 101 to 108, wherein the subject has an incomplete response to treatment with the standard of care.

110. The use according to claims 101 to 109, wherein the subject has an inadequate response to treatment with said standard of care.

111. 111. The use of claim 109 or 110, wherein the subject has symptoms associated with the copper metabolism-related disease or disorder after receiving treatment with the standard of care for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

112. 112. The use of any one of claims 109 to 111, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part II total score of greater than 0 or a Unified Wilson Disease Rating Scale (UWDRS) Part III total score of greater than 0 before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered.

113. 112. The use of any one of claims 109 to 111, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part II total score of greater than 0 and a Unified Wilson Disease Rating Scale (UWDRS) Part III total score of greater than 0 before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered.

114. 114. The use of any one of claims 109 to 113, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part II score of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

115. 115. The use of any one of claims 109 to 114, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) part II of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

116. 116. The use of any one of claims 109 to 115, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) Part III of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, body posture, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

117. 117. The use of any one of claims 109 to 116, wherein the subject has a Unified Wilson Disease Rating Scale (UWDRS) part III of greater than 0, greater than 1, greater than 2, or greater than 3 for at least one or more neurological symptoms before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered, and the at least one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

118. The use of any one of claims 101 to 108, wherein the subject is intolerant to treatment with the standard of care.

119. 119. The use of claim 118, wherein the subject has symptoms associated with the copper metabolism-related disease or disorder after receiving treatment with the standard of care for at least 26 weeks, at least 52 weeks, at least 72 weeks, at least 84 weeks, or at least 96 weeks.

120. The use of claim 118 or 119, wherein the subject has previously been determined by a medical professional to be intolerant to treatment with standard of care or has had an adverse event after receiving treatment with standard of care and before the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered.

121. 121. The use of any one of claims 118 to 120, wherein the subject has previously been determined by a medical professional to be intolerant to treatment with standard of care and has had an adverse event after receiving treatment with standard of care and before administering the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof.

122. 122. The use of any one of claims 101 to 121, wherein the standard of care treatment comprises trientine, D-penicillamine, and / or zinc.

123. 123. The use of any one of claims 101 to 122, wherein the standard of care treatment comprises trientine and / or D-penicillamine.

124. 124. The use of any one of claims 101 to 123, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

125. 125. The use according to any one of claims 101 to 124, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is administered to the subject in a fasting state.

126. 126. The use of any one of claims 101 to 125, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof ranges from about 7.8 mg to about 60 mg per day.

127. 127. The use of any one of claims 101 to 126, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is in the range of about 7.8 mg per day.

128. 128. The use of any one of claims 101 to 127, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is in the range of about 7.8 mg every other day.

129. 128. The use of any one of claims 101 to 127, wherein the tetrathiomolybdic acid is a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt is a bis-choline salt.

130. 130. The use of claim 129, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

131. 131. The use of claim 129 or 130, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is administered to the subject in a fasting state.

132. 132. The use of any one of claims 129 to 131, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate ranges from about 15 mg to about 60 mg per day.

133. 133. The use of any one of claims 129 to 132, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is about 15 mg per day.

134. 134. The use of any one of claims 129 to 133, wherein the therapeutically effective amount of bis-choline tetrathiomolybdate is about 15 mg every other day.

135. 135. The use of any one of claims 101 to 134, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to inhibit progression of neurological damage in the subject.

136. 136. The use of any one of claims 101 to 135, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to inhibit progression of liver damage in the subject.

137. 137. The use of any one of claims 101 to 136, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve or maintain one or more of a neurological symptom, a psychiatric symptom, a clinical symptom, a disability status, or treatment satisfaction in the subject.

138. 138. The use of any one of claims 101-137, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more of a neurological symptom, a psychiatric symptom, a clinical symptom, a disability status, or treatment satisfaction in the subject.

139. 139. The use of claim 138, wherein the improvement is observed after the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof has been administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

140. 140. The use of any one of claims 101 to 139, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the subject's Unified Wilson Disease Rating Scale (UWDRS) Part II total score or Unified Wilson Disease Rating Scale (UWDRS) Part III total score.

141. 140. The use of any one of claims 101 to 139, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the subject's Unified Wilson Disease Rating Scale (UWDRS) Part II total score and Unified Wilson Disease Rating Scale (UWDRS) Part III total score.

142. 142. The use of any one of claims 101-141, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the UWDRS Part II total score in the subject by at least 5%, at least 10%, at least 15%, or at least 20%.

143. 143. The use of any one of claims 101-142, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve the UWDRS Part III total score in the subject by at least 5%, at least 10%, at least 15%, or at least 20%.

144. 144. The use of any one of claims 140 to 143, wherein the improvement is observed after the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof has been administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

145. 145. The use of any one of claims 101 to 144, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more neurological symptoms in the subject as measured according to Unified Wilson Disease Rating Scale (UWDRS) Part II and / or Part III, wherein the one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, facial expression, finger-nose, finger tapping, gait, handwriting, head tremor, involuntary crying, jaw tremor, leg agility, oculomotor activity, postural arm tremor, postural leg tremor, pyramidal signs, RAM of the hand, rigidity, speech, stereotypy, resting tremor, and asterixis.

146. 146. The use of claim 145, wherein the improvement is observed after the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof has been administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

147. 147. The use of any one of claims 101-146, wherein the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof is sufficient to improve one or more neurological symptoms in the subject as measured according to Unified Wilson's Disease Rating Scale (UWDRS) Part II and / or Part III, wherein the one or more neurological symptoms are selected from the group consisting of chair rising, arm and hand dystonia, cervical dystonia, chorea, finger-nose, finger tapping, handwriting, head tremor, jaw tremor, leg dexterity, hand RAM, rigidity, speech, and resting tremor.

148. 148. The use of claim 147, wherein the improvement is observed after the therapeutically effective amount of tetrathiomolybdic acid or a pharmaceutically acceptable salt thereof has been administered for at least 24 weeks, at least 36 weeks, or at least 48 weeks.

149. 149. The use of any one of claims 101 to 148, wherein the subject is further assessed for improvement in disability and neurological symptoms as measured according to the Unified Wilson's Disease Rating Scale (UWDRS) Part II and / or Part III.

150. 150. The use of any one of claims 101-149, wherein the subject is further assessed for improvement in disability status, psychiatric symptoms, clinical symptoms, treatment satisfaction, or a combination thereof.

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