Methods for Treating Copper Metabolism-Related Diseases or Disorders

Abstract

Disclosed are methods of treating a copper metabolism-related disease or disorder, such as Wilson's Disease (WD) in a subject, particularly in a subject aged from about 3 to about 18 years. Also disclosed are compositions comprising biscoline tetrathiomolybdate for use in treating a copper metabolism-related disease or disorder, such as Wilson's Disease (WD) in a subject, particularly in a subject aged from about 3 to about 18 years. Also disclosed are uses of compositions comprising biscoline tetrathiomolybdate in the manufacture of a medicament for treating a copper metabolism-related disease or disorder, such as Wilson's Disease (WD) in a subject, particularly in a subject aged from about 3 to about 18 years.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 241,441, filed September 7, 2021, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure relates to a method for treating a copper metabolism-related disease or disorder, such as Wilson's disease (WD), in a subject, particularly in a subject between about 3 and about 18 years of age. The present disclosure also relates to a composition comprising biscoline tetrathiomolybdate for use in treating a copper metabolism-related disease or disorder, such as Wilson's disease (WD), in a subject, particularly in a subject between about 3 and about 18 years of age. The present disclosure further relates to a use of a composition comprising biscoline tetrathiomolybdate for the manufacture of a medicament for treating a copper metabolism-related disease or disorder, such as Wilson's disease (WD), in a subject, particularly in a subject between about 3 and about 18 years of age. [Background technology]

[0003] Wilson's disease (WD) is an autosomal recessive genetic disorder of impaired copper transport. Mutations in the ATP7B gene result in insufficient production of the copper-transporter ATPase2, which leads to impaired copper incorporation 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 the serum ferroxidase, and in healthy individuals, it contains more than 95% of the copper found in plasma.

[0004] The prevalence of genetic markers associated with WD is approximately 1 per 30,000 population worldwide. Of those with identified mutations, disease manifestations are seen in approximately 50%. A recent national population-based epidemiological study based in France found a diagnosed prevalence of WD of 1.5 per 100,000 population.

[0005] Typical clinical symptoms of WD occur during adolescence to early adulthood. Genetic screening and genotype-phenotype correlations are complicated by the large number (>500) of associated ATP7B mutations; most individuals with WD are compound heterozygotes. Early signs and symptoms of WD are primarily hepatic (~40%), neurological (~40%) or psychiatric (~20%) disease, but patients often develop combined hepatic and neuropsychiatric disorders. Untreated or inadequately treated patients progress to morbidity and usually die secondary to cirrhosis. Liver transplantation is the only effective treatment for WD-associated acute liver failure; other causes of death associated with WD include hepatic malignancies and neurological deterioration with severe starvation debilitation.

[0006] The liver represents one of the major copper storage organs in humans. In healthy individuals, intracellular copper homeostasis is tightly regulated. Copper is transported into cells by copper transporter 1 (CTR1) and then transferred to copper chaperones, such as copper chaperone for antioxidant 1, cytochrome c oxidase, and superoxide dismutase. Copper associated with the chaperones is delivered to specific copper-requiring enzymes. When excess copper occurs, the excess copper is bound to metallothionein (MT) as monovalent copper (Cu+) via copper thiolate bridges with the abundant cysteine ​​residues in MT, thereby causing detoxification of copper through a decrease in its redox potential.

[0007] In patients with WD, copper is not excreted from tissue compartments due to the defective activity of ATPase2 due to its absence or reduced function. This results in the accumulation of copper mainly in the liver, where the protein is highly expressed in hepatocytes, and then in the brain, as well as other organs. Within the biosynthetic capacity of MT, copper toxicity is not evident since MT binds copper tightly. However, beyond the copper buffering capacity of MT, free copper ions are observed, and this excessive amount of free intracellular copper induces pro-oxidant properties and causes the resulting clinical symptoms along with an increased risk of tissue / organ damage. Historically, it has been hypothesized that copper hepatotoxicity in WD is mediated by copper that is not bound to ceruloplasmin or MT. The increased non-ceruloplasmin-bound copper (NCC) from the liver then enters the circulation in a form that is largely not bound to albumin and is available for uptake in other organs where it may cause damage. Thus, plasma NCC (NCC) concentration may serve as an important biomarker for tissue copper overload. However, achievement of normalized plasma NCC concentrations does not necessarily reflect normalized tissue copper levels, especially in organs where copper exchange is relatively slow, such as the brain.

[0008] The optimal therapeutic goal for effective treatment of WD is to excrete excess copper from tissues or to safely sequester copper. Current treatments for WD are the common chelator therapies D-penicillamine (Cuprimine, Depen) and trientine (Syprine), which nonspecifically chelate copper and promote urinary copper excretion. In addition, zinc, which blocks dietary uptake of copper, is primarily used for maintenance treatment. Zinc impairs copper absorption by induction of MT in enterocytes of the gastrointestinal (GI) tract. Because tissue copper concentrates are not easily obtained, the adequacy of therapeutic copper control is currently monitored through periodic assessment of 24-hour urinary copper excretion. Both daily urinary copper excretion rates and plasma NCC concentrations are highly variable, and neither is ideal for monitoring therapeutic copper control.

[0009] Currently available drugs have high discontinuation rates due to adverse events (AEs) and treatment failure. They also require administration 2-5 times per day and must be taken in the fasting state. Their AE profile and complex dosing regimens result in low treatment compliance and high treatment failure rates, which are of major concern in diseases requiring lifelong treatment such as WD.

[0010] Bischoline tetrathiomolybdate ("BC-TTM") (also known as ALXN1840, choline thiomolybdate, 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]

[0011] Previous studies have suggested that BC-TTM improves Cu control through the rapid and irreversible formation of Cu-tetrathiomolybdate-albumin ternary complex (TPC), resulting in rapid sequestration of excess Cu without mobilization of free Cu that can cause tissue toxicity, including neurological deterioration. It is expected that improved long-term compliance with BC-TTM treatment may be achieved through improved tolerability compared to current treatment options and the convenience of a simplified once-daily (QD) dosing regimen.

[0012] WD is most commonly diagnosed in teenagers and young adults and rarely presents symptoms before the age of 5 years. In a European cohort of 1357 patients, the mean age at WD diagnosis was 19.8 years (± 10 years) and half of all patients were diagnosed by the age of 18 years. The age of onset of WD is generally greater than 5 years. Based on the literature and feedback from leading European and US associated clinical centers managing pediatric patients with WD, it is exceptional and rare for cases of WD to be diagnosed in children under the age of 6 years. These exceptionally early newly diagnosed patients may include siblings or patients who may present symptoms as early as 3 years of age. Summary of the Invention [Problem to be solved by the invention]

[0013] Standard treatments approved and used in adults with WD (penicillamine, trientine, zinc) are also approved for use in children and adolescents, but significant unmet needs remain with regard to efficacy, safety, tolerability, simplicity and frequency of dosing regimens, and adequate compliance with treatment, especially in younger participants. [Means for solving the problem]

[0014] The present disclosure generally provides methods useful for treating a copper metabolism-related disease or disorder, such as Wilson's disease, in a subject between about 3 years of age and about less than 18 years of age, such as a subject between about 3 years of age and about less than 12 years of age. Such methods include administering to the subject a therapeutically effective amount of biscoline tetrathiomolybdate.

[0015] The present disclosure also provides a therapeutically effective amount of biscoline tetrathiomolybdate for use in treating a copper metabolism-related disease or disorder in a subject from about 3 years of age to less than about 18 years of age. For example, in certain embodiments, the subject is from about 3 years of age to less than about 12 years of age.

[0016] In one aspect, the disclosure provides a method for treating a copper metabolism-related disease or disorder in a subject aged from about 3 years to less than about 18 years, comprising administering to the subject a therapeutically effective amount of bischoline tetrathiomolybdate.

[0017] In some embodiments of the methods disclosed herein, the copper metabolism-related disease or disorder is Wilson's disease (WD).

[0018] In some embodiments of the methods disclosed herein, the subject is between about 3 years of age and less than about 12 years of age.

[0019] In some embodiments of the methods disclosed herein, the therapeutically effective amount of biscoline tetrathiomolybdate ranges from about 2.5 mg to about 15 mg per day. In certain embodiments, the therapeutically effective amount of biscoline tetrathiomolybdate is about 2.5 mg per day. In certain embodiments, the therapeutically effective amount of biscoline tetrathiomolybdate is about 5 mg per day. In certain embodiments, the therapeutically effective amount of biscoline tetrathiomolybdate ranges from about 5 mg to about 15 mg per day. In certain embodiments, the therapeutically effective amount of biscoline tetrathiomolybdate of about 2.5 mg per day is maintained for at least four weeks. In certain embodiments, after at least four weeks, the therapeutically effective amount of biscoline tetrathiomolybdate of about 2.5 mg per day is increased to a second therapeutically effective amount of biscoline tetrathiomolybdate. In certain embodiments, the increase to the second therapeutically effective amount of biscoline tetrathiomolybdate is one or more increments of 2.5 mg per day, with each increment being at least four weeks apart.

[0020] In some embodiments of the methods disclosed herein, the subject is less than about 12 years old to about 18 years old. In certain embodiments, the therapeutically effective amount of biscoline tetrathiomolybdate ranges from about 15 mg every other day to about 15 mg per day. In certain embodiments, the therapeutically effective amount of biscoline tetrathiomolybdate is about 15 mg every other day. In certain embodiments, the therapeutically effective amount of biscoline tetrathiomolybdate is about 15 mg per day. In certain embodiments, the therapeutically effective amount of biscoline tetrathiomolybdate of about 15 mg every other day is maintained for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 24 weeks, at least 48 weeks, at least 72 weeks, or at least 96 weeks, or for about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years or more. In certain embodiments, a therapeutically effective amount of about 15 mg per day of biscoline tetrathiomolybdate is maintained for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 24 weeks, at least 48 weeks, at least 72 weeks, or at least 96 weeks, or for about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years or more.

[0021] In some embodiments of the methods disclosed herein, the subject has not previously undergone treatment for a copper metabolism-related disease or disorder, such as for Wilson's disease (ie, a treatment-naive subject).

[0022] In some embodiments of the methods disclosed herein, the subject has previously received standard of care for a copper metabolism-related disease or disorder, such as Wilson's disease. In certain embodiments, the subject has previously received standard of care for less than 28 days. In certain embodiments, the subject has previously received standard of care for at least 28 days, at least 5 weeks, at least 6 weeks, at least 12 weeks, at least 24 weeks, or at least 48 weeks.

[0023] In some embodiments of the methods disclosed herein, the subject has not been previously treated, or the subject has previously received standard treatment for copper metabolism-related diseases or disorders, such as Wilson's disease, for less than 28 days. In certain embodiments, the standard treatment includes trientine, D-penicillamine, and / or zinc. In certain embodiments, the standard treatment includes trientine and / or D-penicillamine. In certain embodiments, the subject has received the last dose of standard treatment at least 2 weeks prior to administration of biscolin tetrathiomolybdate.

[0024] In some embodiments of the methods disclosed herein, the methods further include measuring a concentration of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper (such as calculated cNCC or directly measured dNCC), and labile bound copper (LBC) in the subject's plasma.

[0025] In some embodiments of the methods disclosed herein, the method comprises administering to a subject a subject, the subject being administered an NCC corrected or determining the daily average area under the effect time curve (AUEC) of directly measured non-ceruloplasmin bound copper (dNCC) (e.g., from baseline to week 48). In certain embodiments, the method further comprises measuring the concentration of NCC in the subject. corrected NCC corrected If the NCC is outside the reference range, the therapeutically effective amount of biscoline tetrathiomolybdate is adjusted. corrected The reference range for is 0.8 to 2.3 μM.

[0026] In some embodiments of the methods disclosed herein, the methods further comprise measuring the concentration of total molybdenum and / or plasma ultrafiltrate (PUF) molybdenum in the subject's plasma. In certain embodiments, the measurements are performed at baseline, at or after 6 weeks of administration, at or after 24 weeks of administration, and / or at or after 48 weeks of administration. In certain embodiments, the measurements are performed at baseline and up to 6 weeks of administration, or up to 24 weeks of administration, or up to 48 weeks of administration, or up to at least 48 weeks of administration.

[0027] In some embodiments of the methods disclosed herein, the methods further comprise assessing the patient 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.

[0028] In some embodiments of the methods disclosed herein, the methods further comprise evaluating the patient for improvement in disability status, psychiatric symptoms, clinical symptoms, treatment satisfaction, or a combination thereof.

[0029] In another aspect, the disclosure provides a composition comprising bischoline tetrathiomolybdate for use in treating a copper metabolism-related disease or disorder in a subject from about 3 years of age to less than about 18 years of age.

[0030] In some embodiments of the compositions disclosed herein, the copper metabolism-related disease or disorder is Wilson's disease (WD). In certain embodiments, the subject is about 3 years old to less than about 12 years old. In certain embodiments, about 2.5 mg to about 15 mg of bischoline tetrathiomolybdate is administered to the subject per day. In certain embodiments, about 2.5 mg of bischoline tetrathiomolybdate is administered to the subject per day. In certain embodiments, about 5 mg of bischoline tetrathiomolybdate is administered to the subject per day. In certain embodiments, about 5 mg to about 15 mg of bischoline tetrathiomolybdate is administered to the subject per day. In certain embodiments, about 2.5 mg of bischoline tetrathiomolybdate is administered to the subject per day for at least four weeks. In certain embodiments, the amount of bischoline tetrathiomolybdate administered to the subject is increased after at least four weeks. In certain embodiments, the amount of bischoline tetrathiomolybdate is increased by one or more increments of 2.5 mg per day. In certain embodiments, the subject is about 12 years old to less than about 18 years old. In certain embodiments, the subject is administered about 15 mg to about 15 mg of biscoline tetrathiomolybdate every other day. In certain embodiments, about 15 mg of biscoline tetrathiomolybdate every other day. In certain embodiments, the subject is administered about 15 mg of biscoline tetrathiomolybdate every other day. In certain embodiments, the subject is administered about 15 mg of biscoline tetrathiomolybdate every other day. In certain embodiments, about 15 mg of biscoline tetrathiomolybdate every other day is administered to the subject for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 24 weeks, at least 48 weeks, at least 72 weeks, or at least 96 weeks, or for about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years or more. In certain embodiments, about 15 mg of biscoline tetrathiomolybdate per day is administered to a subject for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 24 weeks, at least 48 weeks, at least 72 weeks, or at least 96 weeks, or for about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years or more.

[0031] In some embodiments of the compositions disclosed herein, the subject has not previously undergone treatment for a copper metabolism-related disease or disorder, such as for Wilson's disease (ie, a treatment-naive subject).

[0032] In some embodiments of the compositions disclosed herein, the subject has previously received standard treatment for a copper metabolism-related disease or disorder, such as Wilson's disease. In certain embodiments, the subject has previously received standard treatment for less than 28 days. In certain embodiments, the subject has previously received standard treatment for at least 28 days, at least 5 weeks, at least 6 weeks, at least 12 weeks, at least 24 weeks, or at least 48 weeks.

[0033] In some embodiments of the compositions disclosed herein, the subject has not previously been treated, or the subject has previously received standard treatment for copper metabolism-related diseases or disorders, such as Wilson's disease, for less than 28 days. In certain embodiments, the standard treatment includes trientine, D-penicillamine, and / or zinc. In certain embodiments, the standard treatment includes trientine and / or D-penicillamine. In certain embodiments, the subject received the last dose of standard treatment at least 2 weeks before taking biscolin tetrathiomolybdate.

[0034] In some embodiments of the compositions disclosed herein, the concentration of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper (such as calculated cNCC or directly measured dNCC), and labile bound copper (LBC) in the subject's plasma is measured.

[0035] In some embodiments of the compositions disclosed herein, NCC corrected The daily mean area under the effect time curve (AUEC) of the concentration or directly measured non-ceruloplasmin bound copper (dNCC) (e.g., from baseline to 48 weeks) is determined. In certain embodiments, the amount of biscoline tetrathiomolybdate is adjusted to a level that is in accordance with the subject's NCC. corrected NCC correctedIf the NCC is outside the reference range, it is adjusted. corrected The reference range for is 0.8 to 2.3 μM.

[0036] In some embodiments of the compositions disclosed herein, the concentration of total molybdenum and / or plasma ultrafiltrate (PUF) molybdenum in the plasma of the subject is measured.In certain embodiments, the concentration of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper, and labile bound copper (LBC) in the plasma of the subject is measured at baseline, at or after 6 weeks of administration of biscoline tetrathiomolybdate, at or after 24 weeks of administration of biscoline tetrathiomolybdate, and / or at or after 48 weeks of administration of biscoline tetrathiomolybdate. In certain embodiments, concentrations of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper, and labile bound copper (LBC) in the subject's plasma are measured at baseline and up to 6 weeks of administration of bischoline tetrathiomolybdate, or up to 24 weeks of administration of bischoline tetrathiomolybdate, or up to 48 weeks of administration, or up to at least 48 weeks or more of administration of bischoline tetrathiomolybdate.

[0037] In some embodiments of the compositions disclosed herein, subjects are 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.

[0038] In some embodiments of the compositions disclosed herein, the subject is assessed for improvement in a disability condition, a psychiatric symptom, a clinical symptom, treatment satisfaction, or a combination thereof.

[0039] In another aspect, the disclosure provides a use of a composition comprising bischoline tetrathiomolybdate in the manufacture of a medicament for treating a copper metabolism-related disease or disorder in a subject aged from about 3 years to less than about 18 years.

[0040] In some embodiments of the use of the compositions disclosed herein, the copper metabolism-related disease or disorder is Wilson's disease (WD). In certain embodiments, the subject is about 3 years old to less than about 12 years old. In certain embodiments, about 2.5 mg to about 15 mg of bischoline tetrathiomolybdate is administered to the subject per day. In certain embodiments, about 2.5 mg of bischoline tetrathiomolybdate is administered to the subject per day. In certain embodiments, about 5 mg of bischoline tetrathiomolybdate is administered to the subject per day. In certain embodiments, about 5 mg to about 15 mg of bischoline tetrathiomolybdate is administered to the subject per day. In certain embodiments, about 2.5 mg of bischoline tetrathiomolybdate is administered to the subject per day for at least four weeks. In certain embodiments, the amount of bischoline tetrathiomolybdate administered to the subject is increased after at least four weeks. In certain embodiments, the amount of bischoline tetrathiomolybdate is increased in one or more increments of 2.5 mg per day. In certain embodiments, the subject is about 12 years old to less than about 18 years old. In certain embodiments, the subject is administered about 15 mg to about 15 mg of biscoline tetrathiomolybdate every other day. In certain embodiments, about 15 mg of biscoline tetrathiomolybdate every other day. In certain embodiments, the subject is administered about 15 mg of biscoline tetrathiomolybdate every other day. In certain embodiments, the subject is administered about 15 mg of biscoline tetrathiomolybdate every other day. In certain embodiments, about 15 mg of biscoline tetrathiomolybdate every other day is administered to the subject for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 24 weeks, at least 48 weeks, at least 72 weeks, or at least 96 weeks, or for about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years or more. In certain embodiments, about 15 mg of biscoline tetrathiomolybdate per day is administered to a subject for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 24 weeks, at least 48 weeks, at least 72 weeks, or at least 96 weeks, or for about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years or more.

[0041] In some embodiments of the use of the compositions disclosed herein, the subject has not previously undergone treatment for a copper metabolism related disease or disorder, such as for Wilson's disease (i.e., a treatment naive subject).

[0042] In some embodiments of the use of the compositions disclosed herein, the subject has previously received standard treatment for a copper metabolism-related disease or disorder, such as Wilson's disease. In certain embodiments, the subject has previously received standard treatment for less than 28 days. In certain embodiments, the subject has previously received standard treatment for at least 28 days, at least 5 weeks, at least 6 weeks, at least 12 weeks, at least 24 weeks, or at least 48 weeks.

[0043] In some embodiments of the use of the compositions disclosed herein, the subject has not been previously treated, or the subject has previously received standard treatment for copper metabolism-related diseases or disorders, for example, Wilson's disease, for less than 28 days. In certain embodiments, the standard treatment includes trientine, D-penicillamine, and / or zinc. In certain embodiments, the standard treatment includes trientine and / or D-penicillamine. In certain embodiments, the subject has received the last dose of standard treatment at least 2 weeks before taking biscolin tetrathiomolybdate.

[0044] In some embodiments of the use of the compositions disclosed herein, the concentration of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper (such as calculated cNCC or directly measured dNCC), and labile bound copper (LBC) in the plasma of a subject is measured.

[0045] In some embodiments of the uses of the compositions disclosed herein, NCC corrected The daily mean area under the effect time curve (AUEC) of the concentration or directly measured non-ceruloplasmin bound copper (dNCC) (e.g., from baseline to 48 weeks) is determined. In certain embodiments, the amount of biscoline tetrathiomolybdate is adjusted to a level that is in accordance with the subject's NCC. corrected NCCcorrected If the NCC is outside the reference range, it is adjusted. corrected The reference range in is 0.8 to 2.3 μM.

[0046] In some embodiments of the use of the compositions disclosed herein, the concentration of total molybdenum and / or plasma ultrafiltrate (PUF) molybdenum in the plasma of a subject is measured.In certain embodiments, the concentration of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper, and labile bound copper (LBC) in the plasma of a subject is measured at baseline, at or after 6 weeks of administration of biscoline tetrathiomolybdate, at or after 24 weeks of administration of biscoline tetrathiomolybdate, and / or at or after 48 weeks of administration of biscoline tetrathiomolybdate. In certain embodiments, concentrations of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper, and labile bound copper (LBC) in the subject's plasma are measured at baseline and up to 6 weeks of administration of bischoline tetrathiomolybdate, or up to 24 weeks of administration of bischoline tetrathiomolybdate, or up to 48 weeks of administration, or up to at least 48 weeks or more of administration of bischoline tetrathiomolybdate.

[0047] In some embodiments of the uses of the compositions disclosed herein, subjects are 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.

[0048] In some embodiments of the uses of the compositions disclosed herein, the subject is assessed for improvement in a disability condition, a psychiatric symptom, a clinical symptom, treatment satisfaction, or a combination thereof.

[0049] 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, with the understanding that the claims are defined by the detailed description therein, and not by the specific discussion of the features and advantages described herein. [Brief description of the drawings]

[0050] [Figure 1] Figure 1 provides a schematic diagram of the study design. [Diagram 2] Projected pharmacokinetic exposure range in participants aged 12 to <18 years. Simulations are based on a two-compartment population-PK model for pediatric participants, based on allometric scaling of the adult population-PK model currently under development, using day 1 PK data from Study 201 in participants with WD and relevant PK data from Study 102 in healthy volunteers. Simulation results will be updated once final data are available from Study 201. Abbreviations: hr = time; Mo = molybdenum; PK = pharmacokinetics; WD = Wilson's disease; yrs = years. [Figure 3-1] Projected pharmacokinetic exposure range in patients 3 to <12 years of age. Simulations are based on a two-compartment population-PK model for pediatric participants, based on allometric scaling of the adult population-PK model currently under development, using Day 1 PK data from Study 201 in participants with WD and relevant PK data from Study 102 in healthy volunteers. Simulation results will be updated once final data are available from Study 201. Abbreviations: hr = time; PK = pharmacokinetics; yrs = years; QD = once daily; QOD = every other day. [Figure 3-2] Same as above. [Figure 4] Planned pharmacokinetic exposure range in participants aged 3 to <6 years. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] Before describing the disclosed processes and materials, it is to be understood that the aspects described herein are not limited to particular 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.

[0052] Before describing the present disclosure in detail, certain terms are defined. Unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" and "an," as used herein, should be understood to refer to "one or more" of the listed components unless otherwise indicated or indicated by the context. The use of alternatives (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives, unless otherwise indicated.

[0053] In this disclosure, any concentration range, percentage range, ratio range, or integer range, unless otherwise indicated, should be understood to include any integer value within the recited range, and fractions thereof, where appropriate (such as tenths and percentiles of integers).

[0054] As used herein, the terms "about" and "approximately," when used to modify a numerical value or numerical range, indicate a reasonable deviation from the value or range, typically the upper 5% or 10% and the lower 5% or 10% of the value or range, that remains within the intended meaning of the recited value or range. In certain embodiments, when values ​​are expressed as approximations using the antecedent "about," it will be understood that the particular value forms one possible entity and that there may be a variation of the given value (e.g., about 80 may include 80±10%). Furthermore, it will be understood that each endpoint of the range is significant both in relation to the other endpoint and independently of the other endpoint.

[0055] It is noted that terms such as "preferably," "generally," and "typically" are not used herein to limit the scope of the claimed subject matter or to imply that a particular feature is critical, essential, or even critical to the structure or function of the claimed subject matter. Rather, these terms are not intended to merely highlight alternative or additional features that may or may not be used in a particular embodiment of the present disclosure.

[0056] As used herein, the terms "prevent," "preventing," and "prevention" in the context of administration of a therapeutic agent to a subject refer to the inhibition of the onset or recurrence of a disease or disorder in a subject.

[0057] As used herein, the terms "manage," "managing," and "management" in the context of administration of a therapeutic agent to a subject refer to the beneficial effects that a subject derives from a therapeutic agent that does not result in a cure of a disease or disorder. In certain embodiments, one or more therapeutic agents are administered to a subject to "manage" a disease or disorder to prevent the progression or worsening of symptoms associated with the disease or disorder.

[0058] For purposes of describing and defining this disclosure, the term "substantially" is used herein to express the inherent degree of uncertainty that may result from any quantitative comparison, value, measurement, or other representation. The term "substantially" is also used herein to express the extent to which a quantitative representation may vary from the stated reference without resulting in a change in the basic functionality of the unresolved subject matter.

[0059] Unless expressly specified otherwise, the term "comprising" is used in the context of this disclosure to indicate that, optionally, there may be further members in addition to the members of the list introduced by "comprising". However, it is contemplated as a specific embodiment of the present disclosure that the term "comprising" encompasses the possibility that there are no further members, i.e., for the purposes of this embodiment, "comprising" should be understood as having the meaning of "consisting of".

[0060] As used in accordance with the present disclosure, unless otherwise indicated, all technical and scientific terms shall be understood to have the same meaning as commonly understood by one of ordinary skill in the art.

[0061] In view of the present disclosure, the methods and compositions described herein can be adapted by one of skill in the art to meet a desired need. The present disclosure provides improvements in the treatment of copper metabolism-related diseases or disorders.

[0062] In certain embodiments of the disclosed methods or BC-TTM described herein, the copper metabolism related disease or disorder is Wilson's disease.

[0063] In certain embodiments, the copper metabolism-related disease or disorder is copper toxicity (e.g., due to high exposure to copper sulfate fungicides, ingesting copper-rich drinking water, overuse of copper supplements, etc.) In certain embodiments, the copper metabolism-related disease or disorder is copper deficiency, Menkes disease, or aceruloplasminemia. In certain embodiments, 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, liver cirrhosis, depression, elevated adrenergic activity, elevated copper protein, elevated norepinephrine activity, emotional meltdown fibromyalgia, frequent anger, senile copper excretion disorder, high anxiety, hair loss, liver disease, hyperactivity, hypothyroidism, intolerance to estrogen, intolerance to birth control pills, Kayser-Fleischer ring, learning disabilities, low dopamine activity, multiple sclerosis, neurological problems, oxidative stress, Parkinson's disease, poor concentration, poor concentration, focus), weakened immune system (tinnitus), allergies, sensitivity to food dyes, sensitivity to shellfish, skin metal intolerance, skin hypersensitivity, sleep disorder, and white spots on the nails.

[0064] As used herein, the terms "treatment" and "treating" refer to (i) improving a referenced disease state, medical condition or disorder (or a symptom thereof), e.g., ameliorating a disease, medical condition or disorder (i.e., reversing or ameliorating the pathology and / or symptomatology) in an individual experiencing or exhibiting the pathology or symptomatology of the disease, medical condition or disorder, e.g., reducing the severity of the disease or a symptom thereof or inhibiting the progression of the disease, or (ii) eliciting a referenced biological effect.

[0065] As described herein, bischoline tetrathiomolybdate (BC-TTM, also known as ALXN1840, choline thiomolybdate, thiomolybdic acid, and WTX101) is administered in the methods of the disclosure.

[0066] BC-TTM is a first-in-class Cu-protein binder in development for the treatment of WD and is described in detail in WO 2019 / 110619, which is incorporated herein by reference in its entirety. BC-TTM monotherapy has been evaluated in 28 patients with WD, where it was shown to reduce mean serum non-ceruloplasmin-bound Cu (NCC) by 72% compared to baseline at week 24. Treatment with BC-TTM was generally well tolerated, with most reported adverse events (AEs) being mild (grade 1) to moderate (grade 2). The most frequently reported drug-related AEs were changes in hematological parameters, fatigue, sulfur burps, and other gastrointestinal symptoms. Reversible liver function test elevations were observed in 39% of patients; these elevations were mild to moderate, asymptomatic, associated with unremarkable increases in bilirubin, and normalized with dose reduction or treatment interruption. No paradoxical neurological deterioration was observed at the start of treatment with BC-TTM.

[0067] In certain embodiments, for participants aged 12 to <18 years, a BC-TTM dose of 15 mg / day is administered and dose escalation is not permitted. In some embodiments, the BC-TTM dose may range from 15 mg to 15 mg / day every other day, and doses less than 15 mg every other day may be considered. In certain embodiments, BC-TTM may be administered as a 12 x 1.25 mg dose for a total dose of 15 mg. In some embodiments, BC-TTM may be administered as a 1 x 15 mg dose. In some embodiments, doses may be 1 mg, 1.25 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg administered daily or every other day. In certain embodiments, the maximum dose in participants aged 12 to <18 years is 15 mg / day. In certain embodiments, the BC-TTM dose can be modified, reduced, temporarily suspended, or, if necessary, limited in dose escalation following review of results from one or more laboratory tests. For example, the dose can be increased or decreased following one or more laboratory tests for ALT, triglycerides, cholesterol, hemoglobin, platelets, neutrophils, or bilirubin. Specific criteria for dose reduction, temporary suspension of administration, or limited in dose escalation of BC-TTM are detailed in Table 3.

[0068] In a specific embodiment, for participants aged 3 to <12 years, a BC-TTM dose of 2.5 mg / day is administered, and dose escalation is permitted but not required. The dose is adjusted based on the clinical status of the participant, NCC, under the approval of Alexion Medical Monitor. correctedDepending on concentration and safety test results, doses may be increased in increments of 2.5 mg per day. Dose escalations may be spaced at least 4 weeks apart and may occur only if no other criteria for dose modification (reduction or discontinuation) apply. In certain embodiments, BC-TTM may be administered as a 12×1.25 mg dose for a total dose of 15 mg. In some embodiments, BC-TTM may be administered as a 1×15 mg dose. In some embodiments, doses may be 1 mg, 1.25 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg administered daily or every other day. In certain embodiments, the maximum dose in participants aged 3 to <12 years is 15 mg / day. In certain embodiments, the BC-TTM dose can be modified, reduced, temporarily suspended, or, if necessary, limited in dose escalation following review of results from one or more laboratory tests. For example, the dose can be increased or decreased following one or more laboratory tests for ALT, triglycerides, cholesterol, hemoglobin, platelets, neutrophils, or bilirubin. Specific criteria for dose reduction, temporary suspension of administration, or limited in dose escalation of BC-TTM are detailed in Table 4.

[0069] In certain embodiments, a dose of BC-TTM can be administered in oral, parenteral, rectal or transdermal dosage form. For oral administration, the dose can be in the form of a solution, suspension, tablet, pill, capsule, powder, etc. For example, a tablet can contain a dose of 1 mg, 1.25 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg. In certain embodiments, multiple doses of BC-TTM can be administered, for example, daily, every other day, twice weekly, weekly, twice monthly, monthly, or more or less frequently, as needed, for a period of time sufficient to achieve a desired response. In certain embodiments, patients may be administered BC-TTM for about 4 weeks, about 8 weeks, about 12 weeks, about 24 weeks, about 48 weeks, about 72 weeks, about 96 weeks, or about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years or more. In certain embodiments, the maximum dose for all subjects is 15 mg / day. In some embodiments, the BC-TTM dose may be administered with a small amount of food (e.g., applesauce or yogurt). In certain embodiments, the dose may be in the form of an enteric coated tablet.

[0070] As used herein, the terms "individual", "participant" or "subject" are used interchangeably and refer to any animal, including mammals, and in at least one embodiment, humans. In certain embodiments, the subject is a healthy subject. In certain embodiments, the subject is afflicted with WD. In certain embodiments of the methods or BC-TTM of the present disclosure described herein, the subject has cirrhosis of the liver. In certain other embodiments, the subject does not have cirrhosis of the liver.

[0071] The disclosed method or BC-TTM is useful as a first-line treatment. Thus, in certain embodiments of the disclosed method or BC-TTM, the subject has not previously been treated for Wilson's disease (i.e., a treatment-naive subject).

[0072] The disclosed method or BC-TTM is also useful as a second-line treatment and / or a first-line maintenance treatment for WD. Thus, in certain embodiments of the disclosed method or BC-TTM, the subject has previously received standard of care (SoC) treatment for WD. For example, in certain embodiments, the subject has previously received trientine (also known as triethylenetatramine; N'-[2-(2-aminoethylamino)ethyl]ethane-1,2-diamine). Trientine is available under the name CUPRIOR® (GMP-Orphan United Kingdom Ltd), SYPRINE® (Aton Pharma, Inc.), or Cufence (Univar, Inc.). In certain other embodiments, the subject has previously received trientine and zinc. In certain embodiments, the subject has previously received D-penicillamine (also known as penicillamine; (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid). D-penicillamine is available under the name CUPRIMINE® (Valeant Pharmaceuticals) or DEPEN® (Meda Pharmaceuticals). In certain other embodiments, the subject has previously taken D-penicillamine and zinc. In certain embodiments, the subject has previously taken zinc. In certain embodiments, the subject has previously taken trientine, D-penicillamine, and / or zinc. In certain other embodiments, the subject has previously taken trientine and / or D-penicillamine.

[0073] In certain embodiments of the disclosed methods or BC-TTM, the subject has been receiving standard treatment for WD for 4 weeks or less.

[0074] In certain embodiments of the disclosed methods or BC-TTM, the subject has been on standard treatment for WD for at least 4 weeks. In certain embodiments, the standard treatment has been 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 in length. In certain embodiments, the standard treatment has been at least 41 months. In certain embodiments, the standard treatment has been from about 41 months to about 228 months. In certain embodiments, the standard treatment has been at least 116 months. In certain embodiments, the standard treatment has been at least 155 months.

[0075] Standard treatment does not have to be continuous. For example, the subject may receive intermittent treatment, in total, at least 4 weeks (e.g., 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 50 weeks, or at least 52 weeks, or at least 103 weeks, or at least 41 months, or about 41 months to about 228 months, or at least 116 months, or at least 155 months). However, in certain embodiments, standard treatment is continuous.

[0076] In certain embodiments of the methods or BC-TTM of the present disclosure, the subject has not been previously treated for a copper metabolism related disease or disorder, such as Wilson's disease, or has received standard treatment for no more than four weeks.

[0077] In the disclosed method or BC-TTM described herein, the subject has completed standard treatment at least 2 weeks prior to administration of biscoline tetrathiomolybdate. In certain embodiments, the subject has completed standard treatment at least 3 weeks, at least 4 weeks, or at least 6 weeks prior to administration of biscoline tetrathiomolybdate.

[0078] 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 non-ceruloplasmin-bound copper species. In general, total copper can be measured directly with high sensitivity and specificity by mass spectrometry, such as inductively coupled plasma mass spectrometry (ICP-MS).

[0079] The term "NCC" refers to the percentage 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 (Formula I):

number

[0080] The term "cNCC" refers to the NCC calculated using formula I above. The calculation is premised on the assumption that six copper atoms are always bound to a single Cp molecule, and that NCC and ceruloplasmin concentrations are directly correlated. In reality, Cp can show significant 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 changes with pathology. In fact, six to eight copper atoms can actually be bound to Cp, and in WD, typically fewer than six copper atoms are associated per Cp molecule.

[0081] In subjects treated with BC-TTM, non-ceruloplasmin-bound copper includes the fraction of total copper that is bound to albumin, transcupulin, and other low abundance plasma proteins (collectively referred to as labile-bound copper, or LBC) or is in the tetrathiomolybdate-Cu-albumin ternary complex (TPC). The concentration of TPC cannot be measured directly, but in certain embodiments, molybdenum concentration can be used as a surrogate to estimate the concentration of TPC.

[0082] "N.C.C.corrected The term "NCC" refers to the fraction of total copper (i.e., LBC) that is not bound to ceruloplasmin or in the TPC, and is calculated by subtracting a direct measurement of molybdenum in blood (e.g., serum or plasma) from the estimated NCC (or cNCC). corrected " is the correction of the cNCC value taking into account the presence of the molybdenum-copper-albumin ternary complex in the blood of subjects treated with BC-TTM.

[0083] The term "dNCC" refers to NCC calculated directly using NCC assay. For example, in certain embodiments, dNCC is measured directly using the NCC assay disclosed in PCT Patent Application Publication No. WO2021 / 050850, filed September 11, 2020, which is incorporated herein by reference in its entirety.

[0084] The term "LBC" or "labile bound copper" refers to the fraction of total copper bound to albumin, transcuplain, and other less abundant plasma proteins. Thus, LBC includes the fraction of total copper that is not bound to either ceruloplasmin or TPC. In certain embodiments, the LBC fraction is measured directly using an LBC assay. For example, in certain embodiments, the LBC assay is as disclosed in PCT Patent Application Publication No. WO 2021 / 050850, filed September 11, 2020, which is incorporated herein by reference in its entirety. In biological samples in the absence of TPC, the NCC and LBC fractions are the same.

[0085] The methods and uses of the present disclosure are further illustrated by the following examples, which are not to be construed as limiting the disclosure either in scope or spirit to the specific procedures and compounds described therein. EXAMPLES

[0086] Example 1: A multicenter, randomized, controlled, open-label, assessor-blinded study to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of biscoline tetrathiomolybdate (BC-TTM) versus standard of care (SoC) in pediatric participants with Wilson's disease (WD). Overall design This is a randomized, controlled, open-label, assessor-blinded study designed to evaluate the efficacy, safety, PK, and PD of BC-TTM versus SoC in pediatric participants aged 3-<18 years with a confirmed diagnosis of WD and without decompensated cirrhosis, meeting pre-specified laboratory parameters. We will determine the PK of BC-TTM in plasma as measured by total molybdenum and plasma ultrafiltrate (PUF) molybdenum, and the PD as measured by plasma total copper and LBC. Figure 1 presents a schematic of the study design.

[0087] The study will include two periods; 48-week Period 1 will serve to evaluate efficacy, safety, and the effect of BC-TTM versus SoC on PD. Participants who complete 48-week Period 1 will be offered the opportunity to participate in a 24-week open-label Period 2 (i.e., up to 72 weeks in total) to evaluate the safety and efficacy of BC-TTM.

[0088] Approximately 48 participants will be randomized 1:1 to either BC-TTM or SoC treatment, with the goal of having 40 evaluable participants at week 48. Participants in the primary evaluation period will be stratified by age group (3 to <12 years, 12 to <18 years) into one of two cohorts: Cohort 1: Patients who had received SoC therapy (i.e., chelation therapy with penicillamine or trientine, treatment with zinc, or a combination of both chelation and zinc therapy) for more than 28 days prior to study enrollment. Cohort 2: Patients who were treatment-naïve or had received SoC therapy for 28 days or less prior to study enrollment

[0089] The primary enrollment and randomization objectives are to have at least 12 participants in each age group and to achieve balanced treatment assignment both overall and within each age group. A secondary objective is to have at least 3 participants assigned to each treatment within each cohort of each age group.

[0090] To achieve this goal, participants will be randomized to treatment within one of the following four age groups per cohort: Stratum 1: Randomized and cohort 1 (previous SoC treatment >28 days) aged 3 to <12 years (minimum 6 participants) Stratum 2: Randomized and cohort 2 (previous SoC treatment ≤ 28 days) aged 3 to < 12 years (minimum 6 participants) Stratum 3: Randomized and cohort 1 (previous SoC treatment >28 days) aged 12 to <18 years (minimum 6 participants) Stratum 4: Randomized and cohort 2 (previous SoC treatment ≤ 28 days) aged 12 to < 18 years (minimum 6 participants)

[0091] Throughout Period 1, participants randomized to receive BC-TTM will receive BC-TTM orally daily at the following doses: Participants aged 12 to <18 years will follow the same dosing paradigm as in the ongoing Phase 3 study 301 conducted in adults and adolescents. BC-TTM will be administered at a starting dose of 15 mg / day. Dose escalation will not be permitted. Individualized dosing ranging from 15 mg / day to 15 mg / day every other day will be permitted. Doses less than 15 mg every other day may be considered with approval of an Alexion medical monitor. For participants aged 3 to <12 years, a lower starting dose of 2.5 mg / day will be administered for at least 4 weeks, based on the scaling of the starting dose of 15 mg / day in the ongoing Study 301. Dose escalation is permitted but not required. Dose will be determined based on the clinical status of the participant, NCC, correctedDepending on concentration and safety test results, doses may be increased in increments of 2.5 mg per day with approval from the Alexion Medical Monitor. Dose increases must be separated by at least 4 weeks and may only be made if no other criteria for dose changes (reduction or discontinuation) apply. Participants requiring a dose of 15 mg per day may use the 15 mg adult tablet. The maximum dose in children under 12 years of age is 15 mg / day.

[0092] Individualized BC-TTM dosing will be utilized throughout the study based on the following parameters: Clinical criteria: Dose titration based on hepatic and neurological status · N.C.C. corrected :NCC corrected Concentration-based dose titration. NCC corrected The reference range for is 0.8 to 2.3 μM. · Safety monitoring: Dose modification criteria are based on regularly scheduled evaluations of the perceived hematological effects of copper reduction, liver tests, and neurological tests.

[0093] Participants randomized to receive SoC treatment will continue their current therapy or, if they are not currently receiving SoC at the start of the study, will start an SoC, i.e., chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc therapy.

[0094] The study objectives and endpoints are presented in Table 1.

[0095] [Table 1-1]

[0096] [Table 1-2]

[0097] [Table 1-3]

[0098] [Table 1-4]

[0099] Scientific basis for study design The study will be designed as a randomized, open-label, exploratory study. The dosing regimen will be similar to that used in the current Phase 3 study 301, with adjustments to the pediatric dose based on population PK simulations.

[0100] After BC-TTM administration, the active drug moiety, i.e., tetrathiomolybdate anion, rapidly binds to copper, mostly in the liver and blood, to form TPC, which remains intact in the systemic circulation. If TPC is not rapidly formed, tetrathiomolybdate spontaneously undergoes continuous hydrolysis to form molybdate, the most common form of nutrient molybdenum, which is excreted in urine. The concentration of endogenous molybdenum in plasma is very low, so background subtraction is not necessary, and plasma molybdenum can be entirely attributed to BC-TTM. Total molybdenum concentration cannot distinguish whether the molybdenum is protein-bound (mostly as TPC), free active drug as BC-TTM, intermediate hydrolysis products, or molybdate. To more fully characterize the amount of non-TPC-bound drug and its unbound degradation products, plasma PUF molybdenum, which represents the free parent drug (BC-TTM), short-lived intermediate hydrolysis products, and molybdate that may be derived from dietary intake as tetrathiomolybdate or micronutrients, is also measured. To more fully characterize the absorption, distribution, metabolism, and excretion of BC-TTM, the PK of both total and PUF molybdenum is characterized and described.

[0101] In this study, we evaluate the PK and PD of BC-TTM in children and adolescents with WD. The PD of SoC is evaluated in children and adolescents. The PK and PD parameters of BC-TTM are expected to adjust with body weight according to the relative rule, since the higher blood flow rate in children may have an effect on drug clearance. In addition, the copper content in the liver of participants, and therefore liver volume, may have an effect on the extent of drug binding in the liver and clearance. Based on the mechanism of action of BC-TTM, after considering the factors of body weight and liver volume, it is predicted that drug-copper binding and chemical degradation will not be different in the pediatric population compared to adults.

[0102] Participants will be randomized provided they meet all inclusion and none of the exclusion criteria. Participants will be randomized and stratified in a 1:1 ratio by cohort to treatment with BC-TTM or continuation treatment with SoC in cohort 1, or as continuation or initial therapy in cohort 2, via an automated voice / web response system.

[0103] This study is rater blinded for the UWDRS assessments only. Raters will be blinded, will not be aware of the participants' treatment assignment, and will have no access to the system that could result in potential unblinding of treatment assignment. Both raters and participants will be instructed to avoid a series of interviews, questions, and responses that could potentially result in their unblinding. Raters' assessments will be strictly limited to the performance of the devices and assessments specified in the protocol.

[0104] Drug administration Results from studies 101, 102, 104, 106, 107, 108, 109, 201, and ongoing study 301 indicate that there are no significant covariates of age, sex, or weight that may affect the PK of BC-TTM in adults and adolescents.

[0105] In the ongoing Phase 3 Study 301, participants were initially administered BC-TTM at a dose of 15 mg / day. Titration dose escalation is permitted but not required up to 60 mg / day. In the completed 48-week primary evaluation period of Study 301, the overall mean daily dose of BC-TTM was 15.6 mg, with a minimum daily dose of 12.6 mg and a maximum daily dose of 19.8 mg. Results from the primary evaluation period showed that during treatment with BC-TTM, mobilization of copper from tissues to blood was approximately three-fold greater compared to SoC, as measured by mean daily dNCC AUEC weeks 0-48 (μmol / L).

[0106] Although single or repeated daily doses of 15-60 mg / day have been shown to have an acceptable safety profile and are generally well tolerated throughout Phase 1-3 clinical studies in both healthy adult and adult participants with WD, approximately 15% of participants in Study 301 experienced Grade 2 or higher ALT elevations during treatment with BC-TTM. In summary, the maximum daily dose tolerated in this study (Study 302) is set at 15 mg / day.

[0107] Selection of the starting and maximum doses in Study 302 in the pediatric population aged 3 to <12 years was based on a combination of relative weight-based rules and an approach to account for potential changes in hepatic copper content in pediatric participants driven by age-based changes in liver volume.

[0108] Participants taking the 1.25 mg mini-tablets who require a 15 mg dose may change to the 15 mg tablet formulation. Participants may be titrated down to 15 mg every other day, or a lower or less frequent dose, as appropriate.

[0109] To support dose selection, a population PK model for BC-TTM was developed based on data from healthy volunteers and patients with WD. For model building for adult dosing, single-dose PK data from 18 healthy volunteers (Study 102) and 27 patients (Study 201) were utilized. For pediatrics, simulations were based on typical parameter estimates without including variable components. In each simulation, the starting dose and concentration range were derived from typical participants within the studied age cohort at the extremes of the weight range.

[0110] Based on the modeling results, additional pediatric PK / PD studies were deemed unnecessary as recommended in the agreed pediatric investigation plan (PIP) according to EMA decision P / 0234 / 2020. The general approach for dose selection for pediatric studies used here is consistent with EMA guidance (ICH E11(R1), 2017).

[0111] The starting and maximum doses were selected using a conservative approach that included consideration of the low end of the range obtained from the scaling method and further downward adjustment to lower doses to ensure safety in the pediatric population aged 3 to < 12 years. This conservative approach to the selection of the starting and maximum doses for participants aged 3 to < 12 years (i.e., downward adjustment to the low end of the planned dose range) is supported by the fact that BC-TTM has a greater binding affinity for copper compared to other treatments.

[0112] The PK and PD processes of BC-TTM are expected to be adjusted by body weight per relative order, since the higher blood flow rate in children may have an effect on drug clearance. In addition, the copper content in the liver of participants, and therefore liver volume, may have an effect on the extent of drug binding and clearance in the liver. Based on the mechanism of action of BC-TTM, after taking into account the factors of body weight and liver volume, it is expected that drug-copper binding and chemical degradation will not be different in the pediatric population compared to adults.

[0113] BC-TTM is administered in the fasted state (1 hour before or 2 hours after a meal) and taken with approximately 240 mL of water.

[0114] Population inclusion criteria Participants must be aged 3-<18 years at the time of signing the informed consent / assent. Additionally, participants must have an established diagnosis of WD with a Leipzig score of 4 or greater (documented by testing as outlined in the 2012 European Association for the Study of Liver WD Clinical Practice Guidelines). Note: If deemed appropriate, historical test results for WD, including any or all of the following: presence of KF ring, neurological symptoms, serum ceruloplasmin below the reference range, Coombs-negative hemolytic anemia, elevated hepatic or urinary copper, presence of a mutation in the ATP7B gene, or others, may be used instead to confirm the diagnosis of Wilson's disease. The participant's parent / surrogate must be willing and able to provide written informed consent, and the participant must be willing and able to provide informed assent (if applicable as determined by the central or local Institutional Review Board [IRB] / Institutional [or Independent] Ethics Committee [IEC]). If permissible according to local regulations, the participant's legally authorized representative (LAR) may provide informed consent, in case the participant is unable to do so. In addition, participants must have adequate venous access to allow the collection of necessary blood samples and be able to swallow intact BC-TTM tablets or mini-tablets. Participants who require a gastrostomy device for feeding or medication can be enrolled if the inner diameter of the tube can accommodate the intact tablets or mini-tablets without passage obstruction. In addition, patients must be willing to avoid the intake of foods and beverages with high copper content throughout the study period. Female participants and male participants of childbearing potential must follow the contraceptive guidance stipulated in the protocol. They may submit a signed informed consent or assent, including the informed consent or assent form and compliance with the requirements and restrictions listed in this protocol.

[0115] Participants will be excluded from the study if any of the following criteria apply: 1. Decompensated cirrhosis 2. MELD score > 13 (ages 12 to < 18) or PELD score > 13 (ages 3 to < 12) 3. Modified Nazer score >7 4. Clinically significant gastrointestinal (GI) bleeding within the past 3 months 5. Alanine aminotransferase (ALT) >2× upper limit of normal (ULN) in participants treated with WD therapy for >28 days (Cohort 1) 6. ALT >5×ULN in treatment-naive participants or participants receiving treatment for ≤28 days (Cohort 2) 7. Significant neurological illness requiring either a nasogastric feeding tube or inpatient intensive care 8. Hemoglobin below the lower limit of the reference range for age and gender 9. History of epileptic seizure activity within 6 months prior to informed consent / assent 10. Previous use of BC-TTM or ammonium tetrathiomolybdate 11. Use of an investigational drug within 30 days prior to initiation of first dose of study intervention 12.Participants with end-stage renal disease (chronic kidney disease stage 5 [CKD5]) on dialysis or renal failure defined as estimated glomerular filtration rate < 30 mL / min / 1.73 m2 13. Active infection with hepatitis B virus (positive hepatitis B surface antigen) or hepatitis C virus (participants with positive hepatitis C antibody results will require confirmation of active disease with a positive hepatitis C polymerase chain reaction test), or HIV seropositivity 14. Any disability resulting from trauma or another illness that, in the opinion of the investigator, may interfere with the assessment of disability due to WD. 15. Any systemic or other illness, or deviations in clinical laboratory values, that are confirmed to be clinically significant by the Investigator upon rechecking, that in the Investigator's opinion would compromise the Participant's safety or interfere with the collection or interpretation of study results. 16. Pregnant women (or women planning to become pregnant) or breastfeeding women 17. Known sensitivity to BC-TTM, BC-TTM excipients (anhydrous calcium dibasic phosphate, anhydrous sodium carbonate), or any of the ingredients contained in BC-TTM or related compounds. 18. Regular alcohol consumption within 6 months prior to the study, defined as more than 14 units in men or more than 7 units in women per week. One unit is equal to 14 grams of alcohol: half a pint (approximately 240 mL) of beer, one glass (125 mL) of wine, or one (25 mL) measure of spirits. 19. Abuse of illegal or prescription drugs 20. In the opinion of the Investigator, the participant and / or their parent / surrogate is likely to be uncooperative or uncooperative during the study.

[0116] research intervention A study intervention is defined as any investigational intervention, marketed product, placebo, or medical device intended to be administered to study participants according to the study protocol.

[0117] Participants randomized to receive SoC treatment will continue their current therapy if they are not currently receiving SoC at the start of the study, or will start chelation therapy with penicillamine or trientine, zinc, or a combination of both chelation and zinc therapy.

[0118] Standard of care medications should be stored according to the details on the package label.

[0119] Details of the BC-TTM administered in the study are presented in Table 2 .

[0120] [Table 2]

[0121] Previous combination therapy Any medications (including over-the-counter or prescription drugs, vitamins, and / or herbal supplements, or vaccines, or other specific category of interest) that a participant has taken within 30 days prior to enrollment or will take during the study must be recorded along with the reason for use, dates of administration including start and end dates, and dosage information including dose and frequency.

[0122] Medications specific for copper control in WD (ie, any penicillamine, trientine or zinc ever taken for WD) taken ad libitum prior to the study will be recorded on the specific CRF for previous WD treatment.

[0123] Acceptable Drugs and Treatments Investigators should exercise caution in coadministering medications known to be substrates of cytochromes 2C9 and 2B6 (CYP2C9 and CYP2B6).

[0124] Unacceptable Drugs and Treatments Concomitant use of penicillamine, trientine, or zinc is prohibited for participants treated with BC-TTM during the randomized primary evaluation period (Period 1) or the open-label extension period (Period 2). Standard of care medications may be taken only for participants randomized to SoC during Period 1. Use of non-prescription / over-the-counter medications, including herbal remedies, nutritional supplements, or mineral supplements containing copper, zinc, iron, or molybdenum after Day 1-End of Study dosing is also not permitted. Vitamin E and estrogen should not be initiated during the study, but may be continued if already taken.

[0125] Dose Modification The BC-TTM dose should be reduced or discontinued if any of the relevant dose modification criteria are met. Deviations from dose modification guidelines must be concurred with by an Alexion Medical Monitor.

[0126] youth participants Adolescent participants (12 years to <18 years) randomized to BC-TTM in Period 1 will be initiated at 15 mg / day for BC-TTM. Specific criteria for dose reduction or temporary interruption of administration of BC-TTM are detailed in Table 3. Repeat testing of laboratory parameters resulting in dose modification criteria should follow the indications in Table 3. Clinical testing should be performed through a central laboratory, if possible. Results from unscheduled safety laboratory evaluations performed in local laboratories must be recorded on the CRF.

[0127] Pediatric participants Pediatric participants (ages 3 to <12 years) will be initiated with 2.5 mg / day of BC-TTM. After the first 4 weeks, the dose may be increased in 2.5 mg increments to a maximum of 15 mg / day, with at least 4 weeks between dose increases, with the consent of the Alexion medical monitor. Titration dose escalation is permitted but not required. Specific criteria for dose reduction, temporary interruption of administration, or restriction of dose increase of BC-TTM are detailed in Table 4. Repeat testing of laboratory parameters resulting in dose modification criteria should follow the indications in Table 4. Clinical testing should be performed through a central laboratory, if possible. Results from unscheduled safety laboratory evaluations performed by local laboratories must be recorded on the CRF.

[0128] [Table 3-1]

[0129] [Table 3-2]

[0130] [Table 3-3]

[0131] [Table 4-1]

[0132] [Table 4-2]

[0133] [Table 4-3]

[0134] [Table 4-4]

[0135] Intervention after End of Study: After completion of Period 2 of the study, participants may transition to the treatment that was discontinued prior to enrollment, or participants who have satisfactorily completed all study assessments and have not prematurely discontinued may be eligible for post-study access if they are deemed by the treating physician to be of highest interest. Participants will take the study drug for up to 2 years or until the earlier of 1) the study drug is registered or approved and available by prescription, or 2) the study drug can be made available through the Alexion Post-Study / Early Access Program as permitted by local laws and regulations. Only investigational drug will be available for post-study / early access. All participants will be required to return to the site of the EOS visit on Day 197 (+ / - 7 days) of Period 2.

[0136] Discontinuation of study intervention In rare cases, it may be necessary for a participant to permanently discontinue the study intervention (definitive discontinuation). If the study intervention is definitively discontinued, the participant will be required to have an early termination visit and return within 4 weeks to be assessed for safety follow-up.

[0137] Participants must consider discontinuing from the study intervention if any of the following occur during the study: -Occurrence of decompensated cirrhosis events that do not respond to treatment A decompensated cirrhosis event was defined as acute esophageal or gastric variceal bleeding, new development of overt hepatic encephalopathy, or substantial new ascites formation. Serious hypersensitivity reactions Severe and uncontrollable infection Unacceptable drug use pregnancy or planned pregnancy; or Alexion or the Investigator deems it necessary for the participant

[0138] Study Assessment and Procedures Copper assessment: As a measure of non-ceruloplasmin-bound copper regulation in blood is the primary assessment of the efficacy of BC-TTM treatment, plasma samples are collected to measure total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), NCC, and LBC in blood. In BC-TTM-treated patients, an additional calculation is performed to correct NCC levels for the amount of copper bound to the BC-TTM ternary complex (NCC corrected ) will be implemented.

[0139] The AUEC of plasma total copper concentration over time aims to quantify the dynamic tissue mobilization and decopperization effects of BC-TTM. This assessment is also applicable to SoC treatment. The AUEC is calculated for direct NCC and plasma total copper.

[0140] Ongoing bioanalytical method development with new techniques for directly measuring TPC copper may make additional analysis of copper control feasible. Direct NCC and LBC assays are being developed because methods for indirectly estimating NCC concentrations yield physiologically impossible negative values ​​for NCC, with approximately 20% of samples obtained from healthy participants. The LBC method measures exchangeable plasma copper that is not bound to either ceruloplasmin or BC-TTM TPC.

[0141] Model for End-Stage Liver Disease and Pediatric End-Stage Liver Disease score: The Model for End-Stage Liver Disease (MELD) is a scoring system for assessing the severity of chronic liver disease in adults and adolescents aged 12 years and older. The MELD score (ranges from 6 to 40, with higher values ​​indicating more advanced disease) uses participants' values ​​for serum bilirubin, serum creatinine, and the international normalized ratio (INR) for prothrombin time to predict survival. In participants with a MELD score >11, serum sodium is also taken into account.

[0142] The Pediatric End-Stage Liver Disease (PELD) score is used to estimate 90-day survival in the absence of liver transplantation. The components of the PELD score are total bilirubin, INR, albumin, age, and growth failure. A PELD cutoff of >13 was chosen to exclude participants with advanced liver failure, equivalent to a MELD score >13 or a modified Nazer score >7.

[0143]

[0144] UWDRS Parts I and III are assessed by a neurologist blinded to treatment randomization, while UWDRS Part II may be reported by the participant, family member, or caregiver to an unblinded member of the study team. The UWDRS has not been formally assessed in children. However, the components of Parts I (level of consciousness), II (participant or caregiver-reported impairments), and III (neurological examination findings) do not fundamentally differ between adults and children. Participants aged 12 years or older are expected to be able to follow the unmodified UWDRS assessment. The UWDRS assessment should be performed to the maximum extent feasible in children under 12 years of age.

[0145] Clinical Global Impression-Severity Scale and Clinical Global Impression-Improvement Scale: The Clinical Global Impression (CGI) rating scales are commonly used measures of symptom severity, treatment response, and treatment effectiveness in treatment studies of adult and pediatric participants with psychiatric disorders.

[0146] Clinical Global Impression-Severity Scale: The Clinical Global Impression-Severity Scale (CGI-S) is a 7-point scale that requires clinicians to rate the severity of the participant's illness at the time of evaluation in comparison to the clinician's previous experience with participants with the same diagnosis. Taking into account the entire clinical experience, participants are rated at this point for the severity of their illness as follows: 1, normal, no illness; 2, borderline illness; 3, mild illness; 4, moderate illness; 5, significant illness; 6, severe illness; or 7, extreme illness.

[0147] Clinical Global Impression-Improvement Scale: The Clinical Global Impression-Improvement Scale (CGI-I) is a 7-point scale required for clinicians to rate how much a participant's disease has improved or worsened compared to the baseline state at the start of the intervention and is rated as 1, very improved; 2, very improved; 3, minimally improved; 4, no change; 5, minimally worsened; 6, very worsened; or 7, very worse.

[0148] Fibrosis-4 Index and Transient Elastography: The FIB-4 index is a formula used to predict liver fibrosis based on standard biochemistry values ​​(ALT, AST, and platelet count) and age. The FIB-4 index is calculated by a central laboratory. Transient elastography is a non-invasive imaging method that assesses the degree of hepatic fibrosis or fatty deposits in the liver by utilizing ultrasound imaging to measure the speed of sound waves through the liver.

[0149] Modified Nazer Score: The modified Nazer score is an assessment of liver status and consists of a composite of five laboratory parameters: AST, INR, bilirubin, albumin, and white blood cell count. The score has a total range of 0 to 20, with lower values ​​indicating a healthier liver status.

[0150] Brief Psychiatric Rating Scale 24: The Brief Psychiatric Rating Scale 24 (BPRS-24) is a 24-item instrument for adolescents aged 12 to <18 years that allows raters to measure psychopathology severity. The presence and severity of psychiatric symptoms are rated on a Likert scale ranging from 1 (not present) to 7 (extremely severe). The BPRS-24 can be administered by qualified personnel (e.g., neurologists, psychiatrists, psychologists, licensed mental health practitioners, social workers, etc.) who have completed the training required to administer the instrument. The BPRS-C9 is a 9-item instrument for children aged 3 to <12 years. The presence and severity of symptoms are rated on a scale ranging from 1 (not present) to 6 (extremely severe). Like the BPRS-24, the BPRS-C9 can be administered by qualified personnel who have been appropriately trained.

[0151] EuroQoL 5 dimensions: The EuroQoL 5 dimensions (EQ-5D) consists of two different assessments - the EQ-5D-5L descriptive system and the EQ visual analogue scale (VAS). The descriptive system includes measures of health-related quality of life status and consists of five dimensions: movement, self-care, daily activities, pain / discomfort, and anxiety / depression. Each dimension consists of five severity levels: no problems, slight problems, moderate problems, severe problems, or extreme problems. The EQ VAS records the participant's self-rated health on a vertical VAS. Taken together, it can be used as a quantitative measure of health outcomes that reflects the participant's own judgment. It should be noted that although the EQ-5D is designed for use in participants aged 16 years and older, the EQ-5D can also be used in participants aged 12-15 years, which is appropriate assuming that these participants will follow the study for several years.

[0152] EQ-5D Youth: A pediatric version of the EQ-5D (EQ-5D-Y) was introduced as a more understandable instrument suitable for children and adolescents. The wording was changed to be more suitable for children and adolescents, the indication of the most severe condition for the motor dimension was changed from "confined to bed" to "has a lot of trouble walking around" to increase the applicability and sensitivity of the motor dimension, and the instructions for the EQ VAS task were simplified to make the task easier to complete and score (https: / / euroqol.org / eq-5d-instruments / eq-5d-y-about / ).

[0153] The Treatment Satisfaction with Medication Questionnaire-9 (TSQM-9) was used to assess participants' overall level of satisfaction or dissatisfaction with the medications they were taking. This composite scale consists of three items for the TSQM-9 survey: Overall, how confident are you that taking this drug is good for you? · How satisfied are you that the good things about this drug outweigh the bad? All things considered, how satisfied or dissatisfied are you with this medication?

[0154] The TSQM-9 is expected to be completed by adolescent participants and by parents or caregivers for younger participants.

[0155] The Pediatric Quality of Life Inventory (PedsQL™) measurement model is a modular approach to measuring health-related quality of life in healthy children and adolescents and those with acute and chronic health conditions. The 23-item PedsQL™ Generic Core Scales were designed to measure the core dimensions of health as delineated by the World Health Organization (WHO), as well as role (school) functioning. The four multidimensional scales and three summary scores are: scale ·Physical function (8 items) ·Emotional function (5 items) ·Social function (5 items) ·School functions (5 items) Summary score Total scale score (23 items) Physical health summary score (8 items) Psychosocial health summary score (15 items)

[0156] Urinary and fecal copper excretion: 24-hour urinary copper excretion will be assessed in all participants at baseline, and at weeks 6, 24, and 48. 24-hour fecal copper excretion will be assessed in all participants at baseline and at week 6. This assessment is optional.

[0157] Physical Examination: A complete physical examination will include, at a minimum, cardiovascular, respiratory, GI, and neurological system evaluations. An abbreviated physical examination will consist of body system-related examinations based on the investigator's judgment and the participant's symptoms. At least one body system must be examined for the abbreviated physical examination. Symptom-triggered physical examinations may be performed at other times at the discretion of the principal investigator.

[0158] Adverse Events of Particular Interest: Any new neurological symptoms or clinically significant worsening of ongoing neurological symptoms after the start of the study intervention (BC-TTM or SoC), whether serious or non-serious, will be termed an Adverse Event of Particular Interest (AESI). If a participant has an AESI, in addition to the assessments deemed clinically relevant by the investigator, the following assessments should be performed to the extent that they may be useful in the assessment of the AE and participant status: UWDRS Part III, and CGI-I and CGI-S. The investigator or sub-investigator may perform additional assessments or clinical tests at their discretion. SAEs of particular interest will be evaluated by a panel of three independent neurologists who will not participate in the study. The panel will assess the probability that the clinically significant worsening or new clinically significant neurological symptoms are related to disease progression or caused by the study intervention (BC-TTM or SoC). They will be blinded to the treatment given to the participant. Providing this panel with all available relevant participant information will aid in their assessment.

[0159] Pharmacokinetics: · Whole blood samples will be collected for analysis of plasma concentrations of total and PUF molybdenum as specified in the Schedule of Activities (SoA). Instructions for collection and handling of biological samples will be provided by Alexion. Record the actual date and time (24-hour clock) of each sample. · Extra / additional samples may be stored for up to 5 years and used for PD and / or diagnostic biomarker development and research to understand pathways related to the mechanism of action of BC-TTM. These samples will not be used for genetic analysis (i.e., RNA or DNA analysis). · Genetic analysis will not be performed on whole blood samples collected for PK / PD analysis.

[0160] Pharmacodynamics: · Whole blood will be collected for measurement of plasma total and PUF copper, NCC, and LBC as specified in the SoA. Instructions for collection and handling of biological samples will be provided by Alexion. Record the actual date and time (24-hour clock) of each sample. Plasma samples are used to assess PD of BC-TTM or SoC through measurement of total copper, and copper measured as NCC and PUF copper, and / or LBC, or NCC / NCC corrected The samples collected for the BC-TTM and SoC PD measurements may also be used to evaluate aspects of safety or efficacy for concerns that arise during or after the study. · Extra / additional samples may be stored for up to 5 years and used for PD and / or diagnostic biomarker development and research to understand pathways related to the mechanism of action of BC-TTM. These samples will not be used for genetic analysis (i.e., RNA or DNA analysis).

[0161] Genetics: Blood samples for DNA isolation will be collected from participants who consent to take part in the genetic analysis component of the study. Participation is voluntary. Participants who do not wish to take part in genetic research may still participate in the study. Genetic variations in the ATP7B gene may affect patient response to and susceptibility to study interventions, as well as disease severity and progression. Therefore, where local regulations and IRB / IEC permit, blood samples for DNA analysis will be collected from consenting patients. Use DNA samples for research into WD, which may also be used to develop tests / assays, including diagnostic tests, for BC-TTM and WD. DNA samples will be analyzed for variants in the coding and regulatory sequences of the ATP7B gene and other genes (if suspected for WD). Additional analyses, such as identifying genetic mutations that may affect the metabolism of BC-TTM, can be performed if it is assumed that this may help further understanding of the clinical data. Samples may be analyzed as part of a multiplexed study evaluation of genetic factors involved in BC-TTM or response to this class of study intervention to understand the study disease or related pathology.

[0162] Efficacy analysis The primary endpoint was NCC / NCC corrected Percentage changes in concentrations from baseline to week 48 will be analyzed by treatment group within each cohort and overall treatment group using descriptive summary statistics. Analyses will be based on the per protocol set and the full analysis set. BC-TTM biomarkers such as ceruloplasmin and CpC will be measured in plasma / serum samples.

[0163] Analyses of secondary efficacy endpoints are based on the full analysis set. All secondary efficacy endpoints will be summarized by treatment group within each cohort and overall using descriptive statistics.

[0164] All exploratory endpoints will be summarized by treatment group within each cohort and overall using descriptive statistics using the full analysis set.

[0165] All safety analyses will be performed on the safety set. Safety analyses will include all AEs, ECG, clinical laboratory data, physical examination, and vital sign measurements using descriptive statistics. An AE is any adverse medical event in a patient or clinical study participant administered a medicinal product, not necessarily having a causal relationship to this treatment (ICH E2A). Note: An AE can therefore be any untoward, unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) temporarily associated with the use of the study intervention.

[0166] If an event is not an AE according to the above definition, it cannot be an SAE even if the serious condition is met (e.g., hospitalization for signs / symptoms of the disease under study, death due to disease progression). An SAE is defined as any adverse medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or extension of previous hospitalization; results in persistent disability / incapacity; is a congenital anomaly / birth defect; and other conditions.

[0167] A treatment-emergent adverse event (TEAE) is defined as an AE that begins after the first dose of randomized treatment or a pre-existing event that worsens in severity after the first dose of randomized treatment. Events reported with a partial start date (e.g., month and year reported but the day missing) will be considered treatment-emergent based on available date inputs if it cannot be confirmed that the event onset was before the first dose of study drug.

[0168] In addition, for patients randomized to SoC in Period 1 and switched to BC-TTM in Period 2, any AE that begins after the switch or worsens in severity of a pre-existing event will be attributed to BC-TTM.

[0169] The frequency (n) and relative frequency (n / N * An overall summary of TEAEs by treatment will be presented, including N = 100, where N is the number of patients in the safety set for each treatment group. The summary will include categories indicating the number of events that were TEAEs, treatment-emergent SAEs, and treatment-emergent non-SAEs. Within TEAEs, the following subcategories will also be summarized: Severity of TEAEs (Grade 1 to Grade 5) Related TEAEs (unrelated, related) TEAEs causing study drug deviation TEAEs causing death

[0170] The occurrence of AEs and SAEs will be summarized by system organ class and preferred term for each treatment and overall, and by relationship to the study intervention. Adverse events will also be summarized by treatment and overall by severity. Serious AEs and AEs resulting in withdrawal from the study will be listed. Participants with multiple AEs within a category (e.g., overall, system organ class, preferred term) will be counted once within that category. For severity tables, the participant's most severe event within the category will be counted.

[0171] Changes from baseline in vital sign measurements and laboratory assessments (e.g., chemistry, hematology, coagulation, and urinalysis) will be summarized by treatment. Laboratory parameter values ​​will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). Shift by treatment tables will be generated for these laboratory parameters. These tables will summarize the number of participants with each baseline grade compared to the reference range and the change to the worst and best grades assessed after dosing during the study.

[0172] Electrocardiogram parameters including heart rate, PR, RR, QRS, QT, and QT interval corrected for heart rate using the Fridericia formula (QTcF interval) are measured at specific time points according to the SoA. The mean of the triplicate ECG readings at the time of collection is calculated and changes from baseline values ​​are assessed with each treatment.

[0173] Pharmacokinetic (PK), pharmacodynamic (PD), and biomarker analysis For PK, PD, and biomarker endpoints, analyses will be performed using the PK / PD analysis set.

[0174] The following plasma PK parameters for total molybdenum and PUF molybdenum (if measured) will be calculated using non-compartmental methods with Phoenix® WinNonlin® (Certara USA Inc., Princeton, New Jersey) version 8.0 or later or SAS version 9.3 or later (SAS Institute Inc., Cary, North Carolina), as applicable. Calculations are based on actual sampling times recorded during the study. Maximum observed concentration (C max ) Time to maximum concentration (T max ) Observed trough (predose) concentrations at the beginning of the dosing interval (C trough ) Area under the plasma concentration versus time curve (AUC) over the dosing interval (AUC tau )

[0175] Additional plasma PK parameters may be calculated if deemed appropriate. Population PK analyses may be generated using pooled data from other clinical studies if deemed appropriate. For purposes of additive modeling and simulation, parameters such as, but not limited to, apparent total body clearance (CL / F) and apparent volume of distribution (V d Population PK parameters such as PK / F will be evaluated.

[0176] Plasma concentration versus time data for total molybdenum and PUF molybdenum (where measured) are presented in the data listing by participant. Plasma concentration data are summarized by analyte and time point for each treatment per day separately with the following descriptive statistics: number of participants, arithmetic mean, geometric mean (GM), SD, coefficient of variation (CV), GMCV, median, minimum, and maximum. Mean plasma concentration versus planned time profiles are presented on both linear and semi-log scales in the figures. Individual plasma concentration versus actual time profiles are presented similarly.

[0177] Pharmacokinetic parameters derived from plasma concentrations of total molybdenum and PUF molybdenum (if measured) will be presented in the data listing and summarized separately using the following descriptive statistics: number of participants, arithmetic mean, GM, SD, arithmetic CV, GMCV, median, minimum, and maximum.

[0178] PD (total and PUF (if measured) Cu, NCC, LBC and NCC / NCC over time corrected ) and biomarker endpoint (ceruloplasmin, CpC) concentration data are listed, summarized using descriptive statistics, and plotted. The same analysis is performed on the data for absolute and percent change from baseline in these concentrations over time.

[0179] When data permit, the following plasma PD parameters for total copper, NCC, and LBC will be calculated using non-compartmental methods with Phoenix® WinNonlin® version 8.0 or later or SAS version 9.4 or later, as applicable. Maximum observed effect after administration (CE max ) Time after administration at which maximum effect was observed (TE max ) Area under the effect versus time curve (AUEC) from the start of dose administration to the last observed quantifiable concentration (AUEC t )

[0180] Pharmacodynamic parameters derived from plasma concentrations of total copper, NCC, and LBC are presented and summarized by analyte and day similar to the PK parameters.

[0181] Additionally, the interim efficacy data will be used in efficacy extrapolation to generate evidence of efficacy of BC-TTM on copper control in pediatric participants (ages 3 to <18 years) using adult / adolescent participant data from this study and other Phase 3 studies.

[0182] Population PK simulation and dose selection in pediatric participants with WD Participants aged 12 to <18 years: Simulations showed that the planned PK exposure range in participants aged 12 to <18 years (Figure 2) was expected to overlap with the exposure range in adults at the proposed dose of 15 mg in this and other Phase 3 studies.

[0183] The 15 mg EC tablet formulation is the current formulation being used for administration at that dose, as well as subsequent individualized dose modifications in the ongoing Phase 3 study 301 involving participants aged 12 years and older, following protocol amendment 1. The 15 mg / day daily dose has been shown to have a favorable safety profile and to be well tolerated throughout Phase 1-3 clinical studies in both healthy adults and adult participants with WD.

[0184] Of note, the ongoing Phase 3 study 301 has enrolled 17 participants aged 12-<18 years, including one participant weighing 39.5 kg, receiving BC-TTM at a starting dose of 15 mg once daily, and has demonstrated a tolerable safety profile. To date, TEAEs observed in adolescent participants have been similar to those reported in the overall study.

[0185] Participants 3 to <12 years of age: The planned PK exposure at a starting dose of 5 mg every other day is lower than in adults receiving a starting dose of 15 mg, a more conservative dosing approach in the youngest age group, 3 to <12 years of age. The planned exposure at the original maximum dose tolerated in participants 3 to <12 years of age in Study 302 (i.e., 30 mg once daily) is similar to that at the highest dose tolerated in the ongoing Phase 3 Study 301 in adults and adolescents (i.e., 60 mg once daily) (Figure 3).

[0186] Looking more closely at participants aged 3 to <6 years, modeling results showed that the 5 mg dose had a similar exposure to the 15 mg administered to adult participants, and the 15 mg dose had a higher exposure than the 30 mg, but lower exposure than the 60 mg administered to adult participants (Figure 4). Therefore, the predicted dose range for participants aged 3 to <6 years is 5 mg to 15 mg, which is expected to provide similar safety and efficacy outcomes as in adolescent and adult participants over 12 years with the dose range of 15 mg to 60 mg allowed in the ongoing Phase 3 study 301.

[0187] A more conservative starting dose of 2.5 mg will be used in this study 302 for participants aged 3 to <12 years.

[0188] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes thereto will be suggested to those skilled in the art and should be incorporated within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A pharmaceutical composition for use in treating a copper metabolism-related disease or disorder in a subject from about 3 years of age to less than about 18 years of age, the pharmaceutical composition comprising biscoline tetrathiomolybdate.

2. 2. The pharmaceutical composition of claim 1, wherein the copper metabolism-related disease or disorder is Wilson's disease (WD).

3. 10. The pharmaceutical composition of claim 1, wherein the subject is between about 3 years old and less than about 12 years old.

4. 4. The pharmaceutical composition of claim 3, wherein about 2.5 mg to about 15 mg per day, or about 5 mg to about 15 mg per day, or about 2.5 mg per day, or about 5 mg per day of biscoline tetrathiomolybdate is administered to the subject.

5. about 2.5 mg of biscoline tetrathiomolybdate per day is administered to the subject for at least four weeks; or the amount of bischoline tetrathiomolybdate administered to the subject is increased after at least four weeks; or The amount of biscoline tetrathiomolybdate is increased by one or more increments of 2.5 mg per day. The pharmaceutical composition according to claim 4.

6. 10. The pharmaceutical composition of claim 1, wherein the subject is between about 12 and about 18 years of age.

7. The pharmaceutical composition described in claim 2, wherein the subject is between about 12 and about 18 years of age.

8. 7. The pharmaceutical composition of claim 6, wherein the subject is administered about 15 mg every other day to about 15 mg per day of biscoline tetrathiomolybdate.

9. about 15 mg of biscoline tetrathiomolybdate is administered to the subject every other day for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 24 weeks, at least 48 weeks, at least 72 weeks, or at least 96 weeks, or for about 2 years, or about 3 years, or about 4 years, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years, or about 10 years or more; or about 15 mg of biscoline tetrathiomolybdate per day is administered to the subject for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 24 weeks, at least 48 weeks, at least 72 weeks, or at least 96 weeks, or for about 2 years, or about 3 years, or about 4 years, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years, or about 10 years or more; The pharmaceutical composition according to claim 8.

10. the subject has not previously been treated for the copper metabolism-related disease or disorder; or the subject has previously received standard treatment for the copper metabolism-related disease or disorder, e.g., Wilson's disease; The pharmaceutical composition of claim 1.

11. 11. The pharmaceutical composition of claim 10, wherein the subject has previously received standard of care for less than 28 days, or for at least 28 days, at least 5 weeks, at least 6 weeks, at least 12 weeks, at least 24 weeks, or at least 48 weeks.

12. 12. The pharmaceutical composition of claim 11, wherein the standard of care comprises trientine, D-penicillamine, and / or zinc, or comprises trientine and / or D-penicillamine.

13. 13. The pharmaceutical composition of claim 12, wherein the subject received the last dose of the standard of care at least two weeks prior to taking biscoline tetrathiomolybdate.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the concentration of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper (such as calculated cNCC or directly measured dNCC), and labile bound copper (LBC) in the subject's plasma is measured.

15. NCC ｃｏｒｒｅｃｔｅｄ or wherein the daily mean (e.g., from baseline to 48 weeks) area under the effect-time curve (AUEC) of directly measured non-ceruloplasmin-bound copper (dNCC) is determined; or The amount of biscoline tetrathiomolybdate is adjusted if the subject's NCC corrected is outside the reference range for NCC corrected. The pharmaceutical composition according to any one of claims 1 to 13.

16. The pharmaceutical composition described in claim 15, wherein the reference range of NCC is 0.8 to 2.3 μM.

17. The pharmaceutical composition of any one of claims 1 to 13, wherein the concentration of total molybdenum and / or plasma ultrafiltrate (PUF) molybdenum in the subject's plasma is measured.

18. or wherein the concentration of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper, and labile-bound copper (LBC) in the subject's plasma is measured at baseline, at or after 6 weeks of administration of biscoline tetrathiomolybdate, at or after 24 weeks of administration of biscoline tetrathiomolybdate, and / or at or after 48 weeks of administration of biscoline tetrathiomolybdate; The concentration of one or more of total copper, ceruloplasmin, ceruloplasmin-bound copper (CpC), non-ceruloplasmin-bound copper, and labile-bound copper (LBC) in the subject's plasma is measured at baseline and up to 6 weeks of administration of biscoline tetrathiomolybdate, or up to 24 weeks of administration of biscoline tetrathiomolybdate, or up to 48 weeks of administration, or up to at least 48 weeks or more of administration of biscoline tetrathiomolybdate.

15. The pharmaceutical composition of claim 14.

19. The subject is characterized by an improvement in disability and neurological symptoms as measured according to the Unified Wilson's Disease Rating Scale (UWDRS), Part II and / or Part III; and / or The improvement in disability status, psychiatric symptoms, clinical symptoms, treatment satisfaction, or a combination thereof is evaluated. The pharmaceutical composition according to any one of claims 1 to 13.

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