Methods for Treating Copper Metabolism-Related Diseases or Disorders

Abstract

The present disclosure relates to methods of treating a copper metabolism-related disease or disorder, such as Wilson's Disease (WD). The present disclosure also relates to methods of sequestering copper in a subject or mobilizing copper to plasma in a subject.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is incorporated by reference in its entirety into U.S. Provisional Patent Applications Nos. 63 / 234,176, filed August 17, 2021, 63 / 235,098, filed August 19, 2021, 63 / 237,089, filed August 25, 2021, 63 / 237,120, filed August 25, 2021, 63 / 237,506, filed August 26, 2021, and 63 / 237,506, filed October 21, 2021. The present application claims benefit of priority to Specification No. 0,421, Specification No. 63 / 281,994 filed November 22, 2021, Specification No. 63 / 290,599 filed December 16, 2021, Specification No. 63 / 294,715 filed December 29, 2021, Specification No. 63 / 322,155 filed March 21, 2022, Specification No. 63 / 339,307 filed May 6, 2022, and Specification No. 63 / 353,790 filed June 20, 2022.

[0002] The present disclosure relates to methods of treating a copper metabolism-related disease or disorder, such as Wilson's Disease (WD). The present disclosure also relates to methods of sequestering copper in a subject or mobilizing copper to plasma in a subject. [Background technology]

[0003] 2. Description of Related Art 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 an identified mutation, disease manifestations are present in approximately 50%. The majority of patients are diagnosed before the age of 30. A recent nationwide population-based epidemiological study based in France found a diagnosed prevalence of WD of 1.5 per 100,000 population.

[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 of effective treatment of WD has been to excrete excess copper from tissues. 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 rate and plasma NCC concentration are highly variable, and neither is ideal for monitoring therapeutic copper control.

[0009] Disease control in patients with neurological symptoms at WD diagnosis is an area of ​​particular concern. Over one-third of patients with neurological symptoms do not show any improvement after 4 years of treatment with chelators. This failure to respond to chelation therapy in cases of neurological symptoms may reflect irreversible damage to the nervous system. Also, in a recent study, about 50% of patients had residual neurological symptoms despite treatment with copper modifiers for several years. A worsening of neurological symptoms at the onset of treatment has been reported in about 25% of patients started on penicillamine and trientine, and up to 50% of these patients never recover. The mechanism behind this deterioration is thought to be mobilization of copper from the liver, causing the elevation of brain copper associated with neurological progression. This theory is supported by non-clinical data. Copper accumulation in the central nervous system is an evolutionary long-term process. Excess copper in the body as a whole (not just from the liver) can gradually accumulate in the central nervous system over time.

[0010] 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.

[0011] 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]

[0012] BC-TTM improves Cu control through rapid and irreversible formation of the Cu-tetrathiomolybdate-albumin ternary complex (TPC), resulting in rapid mobilization and sequestration of excess copper without the release 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.

[0013] Effective treatment of WD is believed to involve establishing and maintaining a net negative balance between dietary copper absorption and copper excretion. Monitoring the effectiveness of copper control relies on regular measurement of biomarkers in blood and urine. While "free" copper levels may be a conceptual biomarker of disease burden in WD, copper present in blood and urine is thought to be associated with carriers of various affinities, including ceruloplasmin, metallothionein, albumin, transcuplain, and others. Copper control in patients with WD has been monitored through analysis of 24-hour urinary copper excretion. Following copper management, stabilization or improvement of hepatic, neurological, and psychiatric symptoms is expected, and these factors contribute to the clinician's interpretation of treatment response. In addition to monitoring 24-hour urinary copper excretion, circulating copper in serum or plasma has been assessed through estimation of non-ceruloplasmin-bound copper (NCC); however, these estimates of NCC (also called calculated values) (cNCC) are of limited value because they are indirect estimates and may produce negative NCC results that are physiologically and numerically impossible.

[0014] Furthermore, the results of recent studies using BC-TTM described herein suggest that effective treatment of WD can be achieved by mobilizing excess copper from tissues, sequestering it in the form of stable TPC, and further blocking further copper absorption, without necessarily requiring a net negative copper balance (or excretion of excess copper from the body). Without being bound by theory, it is believed that BC-TTM can achieve this effect, in part, by reducing excess Cu(II) ions to Cu(I) ions present in tissues or blood, followed by binding of Cu(I) ions to generate stable TPC. Because BC-TTM safely mobilizes and sequesters potentially toxic excess copper to form stable TPC, effective treatment of WD can be achieved, in part, by reducing the copper redox cycle, thereby reducing potential toxic threats to tissues, such as, but not limited to, the liver and / or brain. Furthermore, recent study results indicate that BC-TTM supports its sequestration effect by blocking further de novo absorption of copper into tissues such as those of the liver and / or gastrointestinal tract. Summary of the Invention [Problem to be solved by the invention]

[0015] Therefore, there remains a need to treat the underlying disease by mobilizing excess tissue copper, rapidly forming copper-protein complexes with high specificity for copper, and blocking copper absorption to reduce copper overload. [Means for solving the problem]

[0016] The present disclosure generally provides methods useful for treating a copper metabolism-related disease or disorder, such as Wilson's disease, in a subject.

[0017] One aspect of the present disclosure provides a method for reducing copper concentration in a tissue of a subject, comprising administering to the subject a therapeutically effective amount of biscoline tetrathiomolybdate.

[0018] The present disclosure also provides a therapeutically effective amount of bischoline tetrathiomolybdate for use in reducing copper concentrations in the tissue of a subject.

[0019] Another aspect of the present disclosure provides a method for treating a copper metabolism-related disease or disorder in a subject who is at least 12 years of age. Such a method comprises administering to the subject a therapeutically effective amount of bischoline tetrathiomolybdate.

[0020] Another aspect of the disclosure provides a method for treating a copper metabolism-related disease or disorder (such as Wilson's disease) in a subject, comprising: Measuring the concentration of total copper in the plasma; administering to a subject a therapeutically effective amount of biscoline tetrathiomolybdate; Includes.

[0021] Based on its mechanism of action, BC-TTM forms a stable TPC (tetrathiomolybdate-albumin-copper ternary complex) with copper in the body, thereby sequestering and mobilizing excess copper for transport and eventual excretion.

[0022] Thus, another aspect of the present disclosure provides a method for sequestering copper in a subject who is at least 12 years old. Such a method comprises administering to the subject a therapeutically effective amount of bischoline tetrathiomolybdate. In certain embodiments, the bischoline tetrathiomolybdate reduces the average daily AUEC for dNCC by 100% or more. 0-48W and compared to standard of care therapy, the subject sequesters copper by at least about 3.3-fold. In certain embodiments, the subject is treatment naive or has previously received 28 days or less of standard of care therapy, but biscoline tetrathiomolybdate sequesters copper by at least about 3.3-fold when compared to standard of care therapy. 0-48W and compared to standard of care therapy. In certain embodiments, the subject has previously received more than 28 days of standard of care therapy, but biscoline tetrathiomolybdate sequesters copper by at least about 4.9-fold.0-48W and when compared to standard of care therapy, sequesters copper in the subject by at least about 2.9 times.

[0023] Another aspect of the present disclosure provides a method for mobilizing copper in a subject who is at least 12 years old. Such a method comprises administering to the subject a therapeutically effective amount of bischoline tetrathiomolybdate. In certain embodiments, the bischoline tetrathiomolybdate reduces the average daily AUEC for dNCC by 100%. 0-48W and compared to standard of care therapy, the subject is treatment naive or has previously received 28 days or less of standard of care therapy, but biscoline tetrathiomolybdate mobilizes copper by at least about 3.3-fold. 0-48W and when compared to standard of care therapy. In certain embodiments, biscoline tetrathiomolybdate mobilizes copper in a subject at least about 4.9-fold higher than the mean daily AUEC for dNCCs, when measured by .times. ... 0-48W and when compared to standard of care therapy, mobilizes copper in the subject by at least about 2.9-fold.

[0024] Another aspect of the present disclosure provides a method for blocking copper absorption in tissue of a subject who is at least 12 years of age. Such a method includes administering to the subject a therapeutically effective amount of bischoline tetrathiomolybdate, the therapeutically effective amount of bischoline tetrathiomolybdate being sufficient to block copper absorption in tissue of the subject.

[0025] Another aspect of the present disclosure provides a method of treating a copper metabolism-related disease or disorder in a subject who is at least 12 years of age. Such a method comprises administering a therapeutically effective amount of biscoline tetrathiomolybdate to the subject for at least 48 weeks.

[0026] The present disclosure also provides a therapeutically effective amount of bischoline tetrathiomolybdate for use in treating a copper metabolism-related disease or disorder in a subject who is at least 12 years of age.

[0027] In certain embodiments of the disclosed methods or BC-TTM described herein, the subject is suffering from Wilson's disease. In certain embodiments, the subject has not been previously treated for Wilson's disease (i.e., a treatment-naive subject). In certain embodiments, the subject has previously been treated with standard of care (SoC) for Wilson's disease. In certain embodiments of the disclosed methods or BC-TTM, the subject has not been previously treated for Wilson's disease, or the subject has previously been treated with standard of care for Wilson's disease for 4 weeks or less.

[0028] 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.

[0029] The accompanying drawings are included to provide a further understanding of the disclosed compositions and methods, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiments of the present disclosure, and together with the description, serve to explain the principles and operation of the present disclosure. [Brief description of the drawings]

[0030] [Figure 1A] Figure 1A is a schematic diagram of the study presented in Example 1. Abbreviations: SoC = standard of care. [Figure 1B] FIG. 1B is a schematic diagram of the enrollment and study design of the study presented in Example 1. [Diagram 2]Figure 2 shows plasma total copper, directly measured non-ceruloplasmin-bound copper (dNCC) values, and 24-hour urinary copper over time, means and 95% CIs for a cohort of BC-TTM-treated participants (full analysis set). The dashed red line is the lower limit of the normal reference range for plasma total copper: 11.3 μmol / L. [Diagram 3] Figure 3 shows plasma total copper, directly measured NCC and 24-h urinary copper over time, means and 95% CIs by cohort of SoC-treated participants (full analysis set). The dashed red line is the lower limit of the normal reference range for plasma total copper: 11.3 μmol / L. [Figure 4] Figure 4 shows plasma total copper, directly measured NCC, and 24-hour urinary copper over time, means and 95% CIs by cohort of zinc monotherapy-treated participants (full analysis set). The dashed red line is the lower limit of the normal reference range for plasma total copper: 11.3 μmol / L. Cohort 2 participants were not treated with zinc monotherapy. [Diagram 5] Figure 5 shows plasma total copper, directly measured NCC and 24-hour urinary copper over time, means and 95% CIs for a cohort of penicillamine (+ / - zinc) treated participants (full analysis set). The dashed red line is the lower limit of the normal reference range for plasma total copper: 11.3 μmol / L. [Figure 6] Figure 6 shows plasma total copper, directly measured NCC and 24-hour urinary copper over time, means and 95% CI for a cohort of trientine (+ / - zinc) treated participants (full analysis set). The dashed red line is the lower limit of the normal reference range for plasma total copper: 11.3 μmol / L. [Figure 7] FIG. 7 shows box plots of plasma CpC / Cp ratios by treatment (BC-TTM vs. SoC) in Study 301. [Figure 8] FIG. 8 shows box plots of calculated mean daily AUC(Weeks 0-48) values ​​for plasma total and ultrafiltrate molybdenum by age group (adult vs. adolescent) (PK analysis set). [Figure 9]FIG. 9 shows box plots of calculated mean daily AUEC (0-48 weeks) values ​​for plasma total copper (PTC), dNCC, and LBC by age group (adult vs. adolescent) (PD and biomarker analysis set). [Figure 10] FIG. 10 shows the increase from baseline in directly measured NCC (μmol / L) in plasma in each of the three patients in Study 204. [Figure 11] FIG. 11 shows the increase from baseline in daily fecal copper excretion (mg) in each of the three patients in Study 204. [Figure 12] FIG. 12 shows the decrease from baseline in mean daily net copper balance (mg) in each of the three patients in Study 204. [Figure 13] FIG. 13 shows the least squares means and standard errors of improvement from baseline in UWDRS Part II scores (range 0-40) over 5 years of BC-TTM (pooled full analysis set, Study 301 and Study 201). X-axis legend: Red = number of participants; Black = weeks since start of BC-TTM treatment. [Figure 14] Figure 14 shows the least squares means and standard errors of improvement from baseline in UWDRS Part III scores (range 0-175) over 5 years of BC-TTM (pooled full analysis set, Study 301 and Study 201). Note: X-axis legend: Red = number of participants; Black = weeks since start of BC-TTM treatment. [Figure 15] Figure 15 shows least squares means and standard errors of improvement from baseline in UWDRS Part III Functioning subscale scores (range 0-10) over 5 years of BC-TTM (pooled full analysis set, Study 301 and Study 201). Note: X-axis legend: Red = number of participants; Black = weeks since start of BC-TTM treatment. [Figure 16] FIG. 16 shows the mean over time with 95% CI for ALT (primary evaluation period-safety set). [Figure 17] FIG. 17 shows the mean over time with 95% CI for GGT (primary evaluation period - safety set). [Figure 18]Figure 18 shows the mean over time with 95% CI for Total Cholesterol (Primary Evaluation Period - Safety Set). Note: Upper limit of normal: 5.17 mmol / L = 200 mg / dL. [Figure 19] Figure 19 shows the mean over time with 95% CI for triglycerides (Primary Evaluation Period - Safety Set). Note: Upper limit of normal: 1.69 mmol / L = 150 mg / dL. [Figure 20] Figure 20 shows improvement in UWDRS part II score at week 24 in most groups. a Asymptomatic patients were those with a UWDRS part II score >0 at baseline; data for these subgroups are available from post-hoc analyses. [Figure 21] Figure 21 shows improvement in UWDRS part III score at week 24 in most groups. a Asymptomatic patients were those with a UWDRS part III score >0 at baseline; data for these subgroups are available from post-hoc analyses. [Figure 22] FIG. 22 shows improvement in CGI-I score in BC-TTM at week 48 versus SoC. [Diagram 23] Figure 23 shows 24-hour urinary copper concentrations (μmol / day, mean (SD)). P / T, penicillamine / trientine; Zn, zinc. [Figure 24] FIG. 24 is a schematic diagram of the study provided in Example 2. [Diagram 25] FIG. 25 shows the reduction in hepatic 64Cu uptake in a 1-hour scan of healthy subjects treated with BC-TTM, as provided in the study of Example 2. [Figure 26] Figure 26 shows the average standard uptake values ​​(SUV) of 64Cu in liver. Legend: Liver 1 is the average SUV 1 hour before treatment; Liver 2 is the average SUV 15 hours before treatment; Liver 1t is the average SUV 1 hour after treatment; Liver 2t is the average SUV 15 hours after treatment; Tetrathiomolybdic acid is BC-TTM. [Figure 27] FIG. 27 is a schematic diagram of the study provided in Example 3. [Figure 28]FIG. 28 shows the reduction in hepatic 64Cu uptake in subjects treated with BC-TTM, as provided in the study of Example 3. [Figure 29] FIG. 29 shows the reduction in hepatic copper uptake after treatment with BC-TTM in a gallbladder scan obtained 6 hours after intravenous administration of 64Cu. [Diagram 30] FIG. 30 shows the mean SUV of static PET-MR scans in four WD patients who received BC-TTM in various organs. [Diagram 31] FIG. 31 shows the median percent injected dose (ID) before and after treatment with BC-TTM in various organs. [Diagram 32] FIG. 32 shows the median percent ID before and after treatment with BC-TTM in venous blood. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] 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.

[0032] 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.

[0033] In certain embodiments of the disclosed methods or BC-TTM described herein, the copper metabolism related disease or disorder is Wilson's disease.

[0034] 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.

[0035] As used herein, the terms "treatment" and "treating" mean (i) to ameliorate the referenced disease state, medical condition or disorder (or a symptom thereof), e.g., to ameliorate the disease, medical condition or disorder (i.e., to reverse or ameliorate the medical condition and / or symptomatology) in an individual experiencing or exhibiting the medical condition or symptomatology of the disease, medical condition or disorder, e.g., to reduce the severity of the disease or a symptom thereof or to inhibit the progression of the disease, or (ii) to elicit the referenced biological effect.

[0036] As noted above, bischoline tetrathiomolybdate (also known as ALXN1840, BC-TTM, choline thiomolybdate, thiomolybdic acid, and WTX101) is administered in the methods of the disclosure.

[0037] BC-TTM is a first-in-class Cu protein-binding agent in development for the treatment of WD and is described in detail in WO 2019 / 110619, which is incorporated by reference in its entirety.

[0038] BC-TTM targets the following medical needs:

[0039] Rapid and sustained control of copper and clinical symptoms with low risk of neurological deterioration through rapid formation of irreversible copper-tetrathiomolybdate-protein complexes resulting in rapid copper mobilization and sequestration that may protect patients with WD from tissue toxicity, including neurological deterioration. Results from previous studies support the proposed mechanism of action of BC-TTM, whereby copper is mobilized to the bloodstream and sequestered through the formation of a stable ternary complex (TPC) containing TTM, copper, and albumin.

[0040] An effective, well-tolerated, and publicly available treatment option for all treatment-naive and treatment-experienced patients, e.g., those with neurological symptoms who are at greatest risk for neurological deterioration during the early stages of chelation therapy.

[0041] Improved adherence over chronic treatment through improved tolerability and convenience of a simplified dosing regimen (once daily [QD]) compared with current treatment options (multiple daily doses in the fasted state).

[0042] BC-TTM has been evaluated in patients with WD in Phase 2 Study 201 (registered at ClinicalTrials.gov, number NCT02273596; Weiss KH et al. Lancet Gastroenterol Hepatol. 2017 Dec;2(12):869-876, incorporated by reference in its entirety), which enrolled 28 patients with WD. Study 201 is described in Example 2 of U.S. Provisional Patent Application No. 63 / 339,307, filed May 6, 2022, and incorporated by reference herein. Final results from the pivotal 24-week study show that BC-TTM monotherapy significantly reduced mean serum cNCC at 24 weeks. corrected showed a 72% decrease compared to baseline, which was a significant decrease (p<0.0001). corrected The reduction in plasma copper was sustained through week 72 and beyond. There was an initial increase in plasma total copper, exchangeable copper, and labile bound copper (LBC, mostly bound to albumin), which then gradually decreased to baseline or even lower levels. These results suggest that BC-TTM mobilizes copper from tissues to the blood and forms the copper-albumin-tetrathiomolybdate complex, thereby fulfilling the therapeutic goal of therapy for WD, which is to excrete excess copper from tissues such as the liver.

[0043] BC-TTM treatment also resulted in significant improvements in neurological status (p<0.0001) and patient-reported disability (p<0.001), measured as change from baseline in the Unified WD Rating Scale (UWDRS) Part III and Part II, respectively. In the extension period of Study 201, 48-week follow-up data show that the global improvement in disability was maintained, as indicated by the mean reduction in UWDRS Part II scores, and the global improvement in neurological status was maintained, as indicated by the mean reduction in UWDRS Part III scores.

[0044] Furthermore, liver status stabilized or improved in the majority of patients as measured by the modified Nazer score. Treatment with BC-TTM was generally well tolerated, with mild (grade 1) to moderate (grade 2) AEs being the most commonly reported. The most frequently reported drug-related AEs were changes in hematological parameters, fatigue, sulfurous 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. All patients who completed the 24-week study period were enrolled in the 36-month extension period. Preliminary available follow-up data at 48 weeks from the ongoing 36-month study extension period were consistent with the 24-week study period results.

[0045] The primary objective of effective WD treatment has generally been to provide rapid copper control, i.e., copper mobilization and elimination. The current goal of WD treatment has been to establish and maintain a negative or neutral whole-body copper balance. As such, current clinical recommendations suggest that copper control is essential for stabilization or improvement of hepatic, neurological, or psychiatric symptoms of WD. Circulating plasma total copper concentrations are expected to be low in WD due to reduced levels of Cp. Consistent with the efficacy assessments relied upon for the approval of the copper chelators penicillamine and trientine, the primary endpoint measures in Study 201 and Study 203 (described in Example 3 of U.S. Provisional Patent Application No. 63 / 339,307, filed May 6, 2022, and incorporated herein by reference) were based on assessing the control of plasma exchangeable copper via a correction calculation of cNCC / NCC.

[0046] With copper concentrations consistently low at baseline in treatment-naive patients with WD, it is difficult to demonstrate the use of continuous copper-blood scales as an appropriate monitoring tool for treatment efficacy. With plasma total copper concentrations consistently low in WD, continuous measurement of total copper has not previously been considered beneficial for monitoring treatment. However, the temporal patterns in both plasma total copper and molybdenum observed in Study 201 support a mobilization and sequestration mechanism of action for BC-TTM. After an initial mobilization and sequestration period of approximately 24 weeks, it is clear that participants with WD entered a maintenance phase in which less tissue copper became available and therefore less TPC was formed, even though BC-TTM doses were generally maintained. Overall, BC-TTM PK (plasma total molybdenum) and PD (plasma total copper) profiles changed in a coordinated manner and were highly correlated, with both PK and PD clearly dependent on the formation of copper-albumin-TPC complexes. These observations support the ability of BC-TTM to reduce copper overload in patients with WD.

[0047] Approximately half of patients with newly diagnosed WD are under 18 years of age. Although standard treatments for WD are approved for use in children or adolescents, significant unmet needs remain regarding efficacy, safety, and simplicity of dosing regimens. All currently available WD treatments are associated with adverse effects (such as neurological deterioration) in a subset of patients, which may require treatment adjustment, substitution, or even interruption. These adverse effects may also reduce patient adherence to treatment and, as such, may cause clinical deterioration and even death. All require multiple daily doses to achieve adequate copper control. The burden of multiple daily doses in standard treatments may negatively affect medical adherence and clinical outcomes, especially among patients who discontinue treatment overall. The once-daily dosing and small tablet diameter (5 mm) of the 15 mg dose of BC-TTM may increase treatment adherence.

[0048] In patients with WD, the most commonly reported AEs associated with multiple doses of BC-TTM are reversible, dose-dependent, elevated liver tests (transaminases) observed after initiation of treatment at doses of 30 mg or more per day. In Phase 2 Study 201, reversible elevated liver tests were observed in 39% of patients. These elevations were generally mild to moderate, asymptomatic, and normalized with dose adjustment. No initial drug-induced neurological deterioration was observed at the initiation of treatment with BC-TTM. As tetrathiomolybdate is a copper-modifying agent, there is a risk of copper deficiency with extended dosing of BC-TTM. Changes in hematological parameters (thrombocytopenia and leukopenia) due to investigator overtreatment and resulting copper deficiency have been observed. Therefore, multiple dose WD studies such as Study 301 include frequent monitoring for these potential adverse hematological and hepatic effects of BC-TTM.

[0049] Based on the efficacy results from Study 201 (reduction in free copper, stabilization or improvement in liver status, and improvement in neurological symptoms) and the risk mitigation measures included in the protocol to account for the most common AEs reported in the study, BC-TTM is considered to have acceptable benefit / risk in adult patients. The pathophysiology of copper overload does not differ substantially between adolescents and adults with WD, and the approved treatment options and goals for copper control are also the same in adolescents and adults.

[0050] Therapeutically effective amounts of BC-TTM have been previously established. For example, in certain embodiments, BC-TTM may be administered in the range of about 7.5-60 mg per day, e.g., 15-60 mg per day. In certain embodiments, BC-TTM is administered in an amount of about 15 mg every other day (or alternatively 7.5 mg per day). In certain embodiments, BC-TTM is administered in an amount of about 15 mg per day. In certain embodiments, BC-TTM is administered in an amount of about 30 mg per day (e.g., about 15 mg taken twice per day or two 15 mg tablets taken once per day). In certain embodiments, BC-TTM is administered in an amount of about 45 mg per day (e.g., about 15 mg taken three times per day or three 15 mg tablets taken once per day). In certain embodiments, BC-TTM is administered in an amount of about 60 mg per day (eg, about 15 mg taken four times per day or four 15 mg tablets taken once per day).

[0051] In certain other embodiments, BC-TTM may be administered in the range of about 15-60 mg every other day. In certain embodiments, BC-TTM is administered in an amount of about 15 mg every other day. In certain embodiments, BC-TTM is administered in an amount of about 30 mg every other day. In certain embodiments, BC-TTM is administered in an amount of about 45 mg every other day. In certain embodiments, BC-TTM is administered in an amount of about 60 mg every other day.

[0052] In certain embodiments of the present disclosure, increasing the therapeutically effective amount of BC-TTM during treatment may provide additional benefits. Thus, in certain embodiments, the therapeutically effective amount of BC-TTM is increased after 6 weeks of treatment (i.e., after 42 days). For example, in certain embodiments, the initial therapeutically effective amount of BC-TTM (i.e., days 1-42) is about 15 mg per day. Subsequent increases in the therapeutically effective amount of BC-TTM (i.e., after day 42, such as day 43) are, in certain embodiments, about 30 mg per day. In certain embodiments, the subsequent increases in the therapeutically effective amount of BC-TTM are about 45 mg per day. In certain embodiments, the subsequent increases in the therapeutically effective amount of BC-TTM are about 60 mg per day. For example, in certain other embodiments, the initial therapeutically effective amount of BC-TTM is about 30 mg per day. In certain embodiments, the subsequent increases in the therapeutically effective amount of BC-TTM are about 45 mg per day. In certain embodiments, the subsequent increases in the therapeutically effective amount of BC-TTM are about 60 mg per day. For example, in certain embodiments, the initial therapeutically effective amount of BC-TTM is about 15 mg every other day. In certain embodiments, the increased subsequent therapeutically effective amount of BC-TTM is about 15 mg daily.

[0053] In certain embodiments of the present disclosure, further benefits may be provided by reducing the therapeutically effective amount of BC-TTM during treatment. Thus, in certain embodiments, the therapeutically effective amount of BC-TTM is reduced after 6 weeks of treatment (i.e., after 42 days). For example, in certain embodiments, the initial therapeutically effective amount of BC-TTM (i.e., days 1-42) is about 60 mg per day. Subsequent reductions in the therapeutically effective amount of BC-TTM (i.e., after day 42, such as day 43), in certain embodiments, are about 45 mg per day. In certain embodiments, the subsequent reductions in the therapeutically effective amount of BC-TTM are about 30 mg per day. In certain embodiments, the subsequent reductions in the therapeutically effective amount of BC-TTM are about 15 mg per day. For example, in certain other embodiments, the initial therapeutically effective amount of BC-TTM is about 30 mg per day. In certain embodiments, the subsequent reductions in the therapeutically effective amount of BC-TTM are about 15 mg per day. For example, in certain other embodiments, the initial therapeutically effective amount of BC-TTM is about 15 mg per day. In certain embodiments, the increased subsequent therapeutically effective amount of BC-TTM is about 15 mg every other day.

[0054] As used herein, the terms "individual", "patient" 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.

[0055] 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).

[0056] 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.

[0057] In certain embodiments of the disclosed methods or BC-TTM, the subject has been receiving standard treatment for WD for 4 weeks or less.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] In certain embodiments, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms one possible embodiment, and that variation of the given value is possible (e.g., about 80 can include 80±10%). It will further be understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0063] 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).

[0064] 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:

number

[0065] The term "cNCC" refers to the NCC calculated using this formula. 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.

[0066] In subjects treated with BC-TTM, non-ceruloplasmin-bound copper includes the fraction of total copper bound to albumin, transcupulin, and other minor plasma proteins (collectively referred to as LBC) or 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.

[0067] "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.

[0068] 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.

[0069] 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.

[0070] 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

[0071] Example 1: Overall design We conducted Study 301 (registered with ClinicalTrials.gov, number NCT03403205) to evaluate the efficacy and safety of BC-TTM, a novel, first-in-class copper-protein binder, against standard of care (SoC) in patients with Wilson's disease (WD) aged 12 years or older, or aged 18 years or older. Currently available drugs have a high rate of treatment discontinuation due to tolerability and efficacy challenges. They also need to be administered 2-4 times daily and must be taken in the fasting state. Their AE profile and complex dosing regimen result in poor treatment adherence and high rates of treatment failure, which are major concerns in WD, a disease requiring lifelong treatment.

[0072] Unlike currently available treatments for WD, BC-TTM provides an alternative copper-protein transporter that is designed to rapidly form copper-protein complexes with extremely high specificity for copper and rapidly treat the underlying disease by mobilizing excess tissue copper.

[0073] [Table 27-1]

[0074] [Table 27-2]

[0075] [Table 27-3]

[0076] Figure 1 presents a schematic of the study design. This was a randomized, assessor-blinded, multicenter study evaluating the efficacy and safety of BC-TTM versus standard of care (SoC). This study is referred to throughout as Study 301. The primary evaluation period evaluated the efficacy and safety of an individualized BC-TTM dosing regimen compared to SoC administered for 48 weeks in patients with WD who were 12 years of age or older, or 18 years of age or older.

[0077] Patients who met all inclusion and no exclusion criteria were enrolled in the study and examined as outpatients. Eligible patients with WD were enrolled in one of two cohorts. Cohort 1: Patients who received SoC therapy (i.e., chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc therapy) for more than 28 days Cohort 2: Patients who were treatment-naïve or had received SoC therapy for 28 days or less All patients were enrolled in a 3:1 ratio by cohort and randomized within cohorts in a 2:1 ratio to treatment with BC-TTM or SoC (as either continuation therapy in cohort 1 or continuation or initial therapy in cohort 2). An interactive voice / web response system was used to randomly assign treatment and stratify by cohort (Figure 1B).

[0078] Patients randomized to receive BC-TTM were asked to withhold treatment with SoC for at least 48 hours immediately prior to the first study evaluation on Day 1. Patients randomized to BC-TTM received BC-TTM at doses ranging from 15 mg QOD to 60 mg QD every other day as delayed-release tablets for oral administration. Efficacy and safety assessments were performed at scheduled visits, while AEs and concomitant medications were continuously monitored throughout the study. Patients randomized to SoC were initiated or continued treatment on their current regimen, if possible, if individual patient safety was not compromised.

[0079] The primary evaluation period consisted of a screening period of up to 28 days, a 1-day enrollment visit, a 48-week treatment period, and a follow-up visit 4 weeks after the last dose for patients who did not elect to continue in the extension period.

[0080] Patients in Study 301 who completed the 48-week treatment period were offered the opportunity to participate in an extension period of up to 60 months to evaluate the long-term safety and efficacy of BC-TTM.

[0081] Control of exchangeable copper is important for the management of hepatic and neuropsychiatric symptoms in patients with WD. Results from related studies support the proposed mechanism of action of BC-TTM, in which copper is mobilized into the bloodstream and sequestered through the formation of stable TPC, resulting in copper exchange from chelators with lower affinity for copper, with a lower risk of neurological deterioration. Study 301 is the first prospective randomized study to compare tetrathiomolybdate with penicillamine, trientine, or zinc in WD.

[0082] The primary endpoint incorporated copper mobilization and sequestration (i.e., copper control) throughout the 48-week main treatment period by assessment of the daily mean area under the effect time curve (AUEC) of directly measured non-ceruloplasmin-bound copper (dNCC) concentrations. AUEC characterizes and evaluates the cumulative effect of BC-TTM. Measurement of dNCC in plasma is highly sensitive and accurate and does not require special formulas or assumptions. As proposed, dNCC AUEC 0-48Wis an indirect measure of copper mobilization and sequestration. Results from companion study 201 strongly suggest a rapid onset of TPC formation within hours of administration of BC-TTM and a robust mobilization of excess copper from tissues to plasma, which continued through week 12 and appeared nearly complete by week 24. Over the 24-48 week period of treatment with BC-TTM in study 201, plasma dNCC concentrations continued to taper off to baseline. The sustained time-dependent decline in plasma dNCC concentrations indicates that copper mobilized by BC-TTM is not simply being redeposited in tissues, as both plasma concentrations of tetrathiomolybdate (from a daily weighted average dose of 30 mg BC-TTM) and plasma concentrations of circulating albumin (the other two components of TPC) remained essentially constant and adequately available for TPC formation throughout the study. Thus, the daily average dNCC AUEC 0-48W is suitable as a quantitative measure of the therapeutic effect of BC-TTM on WD based on its mechanism of action.

[0083] Measurement of AUEC for dNCC as a primary endpoint overcomes many of the limitations of the estimated cNCC approach. The calculated estimate of NCC relies on separate measurements of plasma total copper and ceruloplasmin protein. The amount of copper in Cp is further estimated based on an estimated ratio of 6 copper atoms per molecule of Cp, which may be an overestimation in WD. Overestimation of ceruloplasmin-bound copper (CpC) results in approximately 20% of samples with physiologically impossible negative values ​​for cNCC. In patients treated with BC-TTM, the estimation of cNCC requires additional correction for the presence of copper in TPC. Copper in TPC cannot be measured directly, but instead needs to be estimated based on the plasma concentration of molybdenum.

[0084] For the primary efficacy and safety endpoints, a 1-year treatment period was chosen to allow sufficient time for evaluation of changes in copper biochemical measures, and changes in hepatic and neurological dysfunction, and for an adequate evaluation of safety and tolerability.

[0085] Following the primary period, patients randomized to SoC during the primary period will be switched to treatment with BC-TTM in the extension period, providing further evaluation of changes in copper, liver function, and neurological dysfunction. A further extension period of up to 5 years will allow further evaluation of long-term efficacy, safety, tolerability, and clinical outcomes in patients treated with BC-TTM.

[0086] The UWDRS scoring system was developed specifically for kinesia and movement disorders associated with chronic copper neurotoxicity in WD. The entire UWDRS Parts I, II, and III, as well as several individual items / subscales of UWDRS Part III (arising from chair, walking, handwriting, and speech) were assessed to further define the range of burdensome signs and symptoms of WD and thus gain further understanding for the assessment of treatment efficacy in patients with WD. UWDRS scores for consciousness (Part I) and abnormal neurological examination findings (Part III) are determined by trained neurological assessors blinded to study treatment randomization. These scores were used to provide a rigorous data set for evaluating change from baseline.

[0087] The inclusion of adolescents aged 12 years and older in this protocol is justified by the natural history of WD. In a large European cohort of 1357 patients, the mean age at diagnosis of WD was 19.8 years, with half of all patients diagnosed before the age of 18 years. Compared to adults, children and adolescents are more likely to present with hepatic rather than neuropsychiatric symptoms. The goal of treatment in adolescents is the same as in adults, i.e., rapid and effective excretion of excess copper from tissues.

[0088] Drug administration The daily dose of BC-TTM intended for use in this study was based on doses established as safe and effective in previous WD studies conducted with BC-TTM. Daily doses of 30-60 mg have been shown to be effective in decopperizing patients newly diagnosed with WD or maintaining normal copper levels in patients with WD previously treated with SoC. In patients with WD treated with BC-TTM, asymptomatic elevations of hepatic transaminases and / or gamma glutamyl transferase were observed in 39% of patients. Elevations in hepatic enzymes were dose-dependent and reversible with interruption or dose reduction of BC-TTM. Therefore, the dose of BC-TTM in this study was limited to a maximum of 60 mg per day, the highest dose studied and considered to have a good safety profile in healthy volunteers. The intent was to individually titrate the dose of BC-TTM to an appropriate dose based on cNCC levels adjusted for molybdenum plasma concentrations, hematology values, and liver function tests, as is done with currently available chelators. Thus, the dosing regimen of BC-TTM included the following features: initial administration of QD as described below; and uptitration design and individualized dosing as indicated by neurological and liver function tests.

[0089] Consistent with currently available WD treatments, the dose of BC-TTM in individual patients was adjusted based on protocol-defined guidelines, as appropriate, depending on clinical response and safety. A detailed dosing guide for BC-TTM dose modifications is outlined below and in Table 1.

[0090] The type and dose of SoC medication was not changed throughout the 48-week study period to the extent possible without compromising individual patient safety.

[0091] BC-TTM was provided as a white round delayed release tablet for oral administration. Each tablet contained 15 mg of bischoline salt of tetrathiomolybdic acid, bis[2-hydroxyethyl)trimethyl-ammonium]tetrathiomolybdic acid, and the following excipients: tribasic calcium phosphate, sodium carbonate, sodium starch glycolate, and magnesium stearate. The tablets were coated with an internal precoat (Opadry 03K19229 clear) and an external enteric coating (Acryl-EZE white). The tablets were debossed on one side with a hexagonal shape.

[0092] BC-TTM was provided in a treatment kit containing 28 tablets, which consisted of a heat-formed blister strip contained in a cardboard medicine box.

[0093] BC-TTM was administered on day 1. BC-TTM was administered orally at doses ranging from 15 mg QOD to 60 mg QD. BC-TTM was administered QD or QOD in the fasted state (1 hour before or 2 hours after a meal).

[0094] Individualized BC-TTM dosing was used throughout the study based on the following parameters: · Clinical criteria: Dose titration based on hepatic and neurological status; · N.C.C. corrected : Dose titration specified based on cNCC levels adjusted for the amount of copper bound to BC-TTM TPC; Safety monitoring: Dose modification criteria were based on regularly scheduled evaluations of the perceived hematological effect of Cu reduction, liver tests, and neurological tests.

[0095] In all patients, BC-TTM was administered at a starting dose of 15 mg QD on day 1 and continued for 4 weeks from the beginning. After 4 weeks, uptitration to 30 mg QD could be performed at the investigator's discretion, but if the disease was not adequately controlled, cNCC / cNCC correctedNo dose modification criteria were applied, taking into account the patient's clinical status and free blood copper levels, as measured by . Further dose escalation was allowed at the investigator's discretion, according to the same criteria above, in 15 mg increments spaced at least 4 weeks apart. If any of the relevant dose modification criteria were met, the dose should have been reduced or discontinued.

[0096] cNCC corrected If levels have fallen within the normal range (<2.3 μmol / L) and / or the patient's clinical condition has stabilized or improved at two consecutive study visits, the BC-TTM dose may be maintained or reduced at the investigator's discretion. To avoid overtreatment, the dose may be reduced if the patient's clinical condition indicates possible overtreatment and / or if cNCC / cNCC corrected The dose was guided by values ​​below the normal range and could be reduced at any time at the investigator's discretion. Specific criteria for dose modifications of BC-TTM are detailed in Table 1.

[0097] The type of SoC medication should not be changed to the extent possible throughout the 48-week study period unless required as part of treatment (e.g., if a patient initiates an SoC at study initiation) if it does not compromise individual patient safety. Similarly, the administration of SoC medication should remain consistent to the extent possible throughout the 48-week study period unless required as part of treatment (e.g., titration of SoC initiated at study initiation) if it does not compromise individual patient safety.

[0098] [Table 1-1]

[0099] [Table 1-2]

[0100] [Table 1-3]

[0101] All patients were treated with BC-TTM in the extension period. Patients who received BC-TTM in the primary evaluation period of Study 301 continued to receive the same dose that they received at the final study visit in the primary evaluation period; individualized dosing was subsequently managed as described herein. Patients who transitioned from SoC in the extension period were administered BC-TTM as described herein. Dose modifications, if necessary, were made as described herein.

[0102] Efficacy evaluation The Week 48 visit marked the end of the primary evaluation period and the start of the extension period (i.e., the Week 48 visit and the Extension Day 1 visit occurred on the same day). All assessments at the Week 48 visit were performed prior to administration of BC-TTM. Administration of BC-TTM on Extension Day 1 marked the start of the extension period. Patients who did not enter the extension period discontinued treatment at Week 48 and had a final study visit for safety follow-up at Week 52.

[0103] Copper assessment: Measurement of plasma dNCC concentration was the primary assessment of the efficacy of BC-TTM treatment of WD. AUEC in plasma dNCC concentration over time aims to quantify the dynamic tissue Cu mobilization and Cu sequestration effect of BC-TTM. This assessment is also applicable to SoC treatment. In addition, plasma Cp, CpC, plasma total copper, and LBC were measured, and AUEC was calculated for plasma total copper and LBC.

[0104] The LBC method measures exchangeable plasma copper that is not bound to either Cp or TPC.

[0105] Unified Wilson's Disease Rating Scale (Parts I, II, and III): The UWDRS is a clinical rating scale designed to assess the neurological signs of WD, which can be generally divided into three movement disorder syndromes: dystonia, ataxia, and parkinsonism. The UWDRS includes three parts: UWDRS Part I (Level of consciousness, item 1), UWDRS Part II (Patient-reported review of daily activity items [disability], items 2-11), and UWDRS Part III (Detailed neurological examination, items 12-34).

[0106] UWDRS Parts I and III were assessed by a neurologist blinded to treatment randomization, while UWDRS Part II could be reported by the patient, family member, or caregiver to an unblinded member of the study team. The UWDRS was not formally assessed in adolescents. However, components of Parts I (level of consciousness), II (patient- or caregiver-reported disability), and III (neurological examination findings) did not fundamentally differ between adults and adolescents. Patients aged 12 years or older were expected to be able to comply with the UWDRS assessment.

[0107] Clinical Global Impression-Severity of Improvement Scale and Clinical Global Impression-Severity of Improvement Scale: The Clinical Global Impression (CGI) rating scale has been a commonly used measure of symptom severity, treatment response, and treatment effectiveness in treatment studies of adult and pediatric patients with psychiatric disorders.

[0108] The Clinical Global Impression-Severity scale (CGI-S) is a 7-point scale that requires clinicians to rate the severity of the patient's illness at the time of evaluation in comparison with the clinician's previous experience with patients with the same diagnosis. Considering the entire clinical experience, patients were assessed at the point where they rated the severity of their illness as 1, normal, no illness; 2, borderline illness; 3, mild illness; 4, moderate illness; 5, marked illness; 6, severe illness; or 7, extreme illness.

[0109] The Clinical Global Impression-Improvement scale (CGI-I) is a 7-point scale required for clinicians to rate how much a patient's disease has improved or worsened compared to the baseline state at the start of an 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.

[0110] Adverse events and serious adverse events An AE is any adverse medical occurrence in a participant administered a medicinal product or participating in a clinical investigation, which does not necessarily have a causal relationship to this treatment (ICH E2A).

[0111] An SAE is defined as any adverse medical event, at any dose, that results in death; is life-threatening; requires inpatient hospitalization or an extension of a previous hospitalization; results in persistent disability / incapacity; is a congenital anomaly / birth defect; or other situation that results in, for example, invasive or malignant cancer, allergic bronchospasm that does not result in hospitalization, intensive care in the emergency room or at home for blood disorders or seizures, or the development of drug dependence or abuse.

[0112] Adverse events were reported by the patient (or, where appropriate, by the caregiver, surrogate, or legally authorized representative of the patient). The investigator and any authorized designee were involved in detecting, documenting, and recording events that met the definition of an AE or SAE, and would maintain involvement in the follow-up of AEs that were deemed to be serious, related to the study intervention or procedures, or that caused the patient to discontinue the study.

[0113] Adverse events of special interest: Any new neurological symptom or clinically significant worsening of an ongoing neurological symptom after initiation of study drug (BC-TTM or SoC), whether serious or non-serious, was termed an AESI.

[0114] If a patient has an AESI, in addition to the evaluations deemed clinically relevant by the Investigator, the following evaluations should be performed to the extent that they may be useful in evaluating the AE and patient status: UWDRS Part III, Nonverbal Stroop Interference Test, Digit Span Test, and CGI-I and CGI-S. The Investigator or subinvestigator may perform additional evaluations or clinical tests at their discretion.

[0115] Pharmacokinetics, Pharmacodynamics, and Biomarkers Pre-dose whole blood samples were collected at each designated visit for measurement of the following BC-TTM PK, PD, and biomarker analyses:

[0116] Pharmacokinetics: Blood samples were collected for PK analysis to measure plasma total molybdenum and plasma ultrafiltrate (PUF) molybdenum.

[0117] Pharmacodynamics: Blood samples were collected and plasma total copper, PUF copper, dNCC, and LBC were directly measured. corrected (the latter being non-ceruloplasmin bound copper and non-molybdenum-albumin bound copper) calculations can be performed.

[0118] Biomarkers and Biobank Samples: Blood samples were collected to measure plasma Cp and CpC. Urine samples were collected for urinary copper and molybdenum analysis. Additional biomarker or biobank samples were collected for analysis of treatment-related molybdenum and / or copper species.

[0119] Statistical considerations A general description of the statistical methods used to analyze the efficacy and safety data is outlined below.

[0120] Statistical analyses were performed using SAS®, version 9.3 or later, SAS Institute, Cary, North Carolina, USA. Baseline for all assessments was defined as the last assessment resulting in a valid, non-missing value obtained before the first dose of study medication (BC-TTM or SoC). Analysis populations included:

[0121] The full analysis set included all randomized patients who received at least one dose of randomized treatment. Patients were analyzed as randomized.

[0122] Safety analyses were performed on the safety analysis set, which included all patients who received at least one dose of randomized treatment. Patients were summarized according to the treatment actually received.

[0123] The per-protocol set included all patients who were randomized and had at least baseline and week 48 efficacy assessments for dNCC in the primary evaluation period. Patients with major protocol deviations that were likely to affect the primary efficacy analysis were excluded from the per-protocol set.

[0124] The extension analysis set included all patients who entered the extension period and received at least one dose of BC-TTM in the extension period.

[0125] Primary efficacy analysis The primary estimand was the difference in mean daily dNCC AUEC from weeks 0 to 48 between BC-TTM and SoC in patients with WD, independent of less than perfect adherence or use of another drug that affects plasma dNCC and derives no benefit from treatment after death.

[0126] The AUEC for dNCC concentrations was calculated using the trapezoidal rule and then divided by the number of days to obtain the mean daily AUEC plasma dNCC concentrations from baseline to week 48 (expressed as μmol / L, AUEC 0-48W (Written as ).

[0127] AUEC 0-48W were compared between BC-TTM and SoC using an analysis of covariance (ANCOVA) statistical model; treatment arm, baseline plasma dNCC concentration, and cohort were included in the model. The study was performed at a significance level of 0.05 (two-sided).

[0128] AUEC 0-48W Model-based estimates of the difference between randomized treatments (BC-TTM vs. SoC) in were provided with two-sided 95% CIs and P values. Superiority was concluded when the lower two-sided 95% CI was above 0 μM.

[0129] Cohort 1: Patients previously treated for >28 days. The supportive analysis of the primary endpoint within Cohort 1 mirrored the description for the full population analysis except for the exclusion of Cohort 2 from the model.

[0130] Cohort 2: Patients who were treatment naïve or had received prior treatment for 28 days or less. 0-48W were analysed descriptively; no formal statistical comparisons were made between randomised treatment arms. 0-48W was estimated using the same model terms as described for the analysis of Cohort 1 patients.

[0131] Patient population Patients were eligible for inclusion in the study only if all of the following criteria applied: 1. Established diagnosis of WD with a Leipzig score of 4 or greater, documented by testing as outlined in the 2012 European Association for the Study of Liver WD Clinical Practice Guidelines. 2. Age 12 years or older (18 years or older in Germany) at the time of informed consent / assent. 3. Willingly withhold treatment with SoC for at least 48 hours immediately prior to the first study evaluation on Day 1. 4. Willing to avoid vitamins and / or minerals containing copper, zinc, or molybdenum throughout the study period. 5. Willingly avoid intake of foods and beverages with high copper content throughout the study period.

[0132] Patients were excluded from the study if any of the following criteria applied: 1. Decompensated cirrhosis 2. MELD (Model for End-Stage Liver Disease) score > 13 3. Modified Nazer score >7 4. Clinically significant GI bleeding within the past 3 months 5. Alanine aminotransferase >2× upper limit of normal (ULN) in patients treated with WD therapy for >28 days (cohort 1) 6. Alanine aminotransferase >5×ULN in treatment-naive patients or patients on treatment for 28 days or less (Cohort 2) 7. Significant neurological illness requiring either nasal feeding or inpatient intensive care 8. Hemoglobin < 9g / dL 9. Participation in a clinical study of an experimental or unapproved / unlicensed therapy during the screening period or within 4 weeks prior to informed consent 10. History of seizure activity within 6 months prior to informed consent 11. Pregnant (or planning to become pregnant) or breastfeeding women 12. Known sensitivity to BC-TTM, BC-TTM excipients (anhydrous calcium dibasic phosphate, anhydrous sodium carbonate), or any of the ingredients contained in BC-TTM or related compounds. 13. Active infection with hepatitis B virus (positive hepatitis B surface antigen) or hepatitis C virus (patients with positive hepatitis C antibody results require confirmation of active disease with a positive hepatitis C polymerase chain reaction test), or seropositive human immunodeficiency virus (HIV) 14. Previous treatment with tetrathiomolybdic acid 15. Any illness, disability, disease, or abnormal laboratory findings that, in the opinion of the Investigator, may compromise patient safety or interfere with the collection or interpretation of study results. 16. Patients with end-stage renal disease on dialysis (chronic kidney disease stage 5 [CKD5]) or creatinine clearance less than 30 mL / min.

[0133] Patients in the primary evaluation period were randomized to either BC-TTM or SoC treatment and enrolled in one of two cohorts as described above. All patients in the extension period will receive treatment with BC-TTM.

[0134] Approximately 180 eligible patients with WD aged ≥12 years (≥18 years in Germany) were enrolled in the study. The allocation per cohort and treatment is presented in Table 2.

[0135] [Table 2]

[0136] Ultimately, 214 patients were enrolled; all had preserved liver function and 79% had neurological symptoms. Of the 214 patients, 207 were randomized: 137 to BC-TTM (104 in cohort 1 and 33 in cohort 2) and 70 to SoC (56 in cohort 1 and 14 in cohort 2). All patient demographics are presented in Tables 3-1 and 3-2, and previous treatment history for WD is presented in Table 4.

[0137] [Table 3-1]

[0138] [Table 3-2]

[0139] [Table 4]

[0140] Finally, 184 patients completed the 48-week treatment period: 119 for BC-TTM (91 for cohort 1 and 28 for cohort 2) and 65 for SoC (52 for cohort 1 and 13 for cohort 2); and 178 patients entered the extension period: 117 for BC-TTM (89 for cohort 1 and 28 for cohort 2) and 61 for SoC (49 for cohort 1 and 12 for cohort 2).

[0141] The numbers of patients in the SoC groups who received each treatment were as follows: zinc monotherapy: cohort 1, n=23 (41%), cohort 2, n=0 (0%), overall, n=23 (33%); penicillamine (± zinc): cohort 1, n=19 (39%), cohort 2, n=10 (71%), overall, n=29 (41%); trientine (± zinc): cohort 1, n=14 (25%), cohort 2, n=4 (29%), overall, n=18 (26%).

[0142] Copper Mobilization and Sequestration The primary objective of the study was to evaluate the efficacy of BC-TTM administered for 48 weeks compared with standard of care (SoC) for copper control in WD patients aged 12 years and older (or 18 years and older in Germany). The primary endpoint was the daily mean AUEC of dNCC in the primary evaluation period. 0-48W Results from the study are presented in Table 4. These results were consistent with the primary efficacy endpoint of mean daily dNCC AUEC 0-48wks As shown by the ΔC, there is a superiority of BC-TTM over SoC in copper mobilization; the value for BC-TTM is 3.18 (standard error [SE] = 0.167) and for SoC is 1.00 (SE = 0.219), with a difference of p < 0.0001.

[0143] [Table 5]

[0144] The study results showed that BC-TTM was statistically superior to SoC in mobilizing copper from tissues (Figure 2). Overall, the daily mean dNCC AUEC 0-48W (μmol) was 3.2-fold higher in patients treated with BC-TTM versus SoC. The overall results and the results in each cohort were statistically significant (P<0.00001). The mean values ​​in patients treated with BC-TTM were 2.9-fold higher in treatment-experienced (cohort 1) and 4.9-fold higher in treatment-naive patients (cohort 2). While more copper was mobilized in treatment-naive patients (cohort 2) than in treatment-experienced (cohort 1), these results indicate that tissue-bound copper remains stored in tissues even in patients who have been on SoC therapy for many years, for example, an average of 10 years or more. As can be seen from the results in Table 4, the duration of previous treatment does not meaningfully affect the magnitude of benefit, even if the magnitude of effect differs between cohorts. BC-TMM, in contrast to SoC, has a significant effect on mobilizing and safely sequestering copper from tissues.

[0145] BC-TTM mobilized copper even in cohort 1 participants who had been on SoC therapy for an average of just over 10 years. As shown in Table 5, the mean daily dNCC AUECs of SoC assessed at time points equivalent to BC-TTM 0-48週 is measurable but low (<1.0) regardless of previous treatment status.

[0146] A plot of plasma dNCC over time in participants treated with BC-TTM shows an immediate rise, a peak at weeks 4-6, and a slow return to baseline by week 48 (Figure 2). Mobilization of tissue copper is observed in both cohorts, even in participants in Cohort 1 who had been treated with SoC for an average of 10 years. Furthermore, Figure 2 also shows that the time to return of dNCC to baseline was greater (longer) in Cohort 2 compared to Cohort 1; this reflects a greater mobilization of larger excess tissue copper stores in participants with little or no prior treatment.

[0147] For participants treated with SoC, plots of plasma dNCC at equal time points (when available) were essentially flat (Figures 3, 4, 5, and 6), indicating minimal changes in circulating non-ceruloplasmin-bound copper. Figure 23 shows that 24-hour urinary copper was lower with BC-TTM than with SoC chelator therapy. Overall, little change was observed in either plasma total copper or non-ceruloplasmin-bound copper levels during SoC treatment. The superiority of BC-TTM over SoC in mobilizing copper from tissues is demonstrated.

[0148] To assess whether tissue copper mobilization from BC-TTM treatment has any effect on the most important plasma copper carrier ceruloplasmin (Cp) and the number of copper atoms carried per molecule of ceruloplasmin (CpC), Table 6 summarizes the plasma CpC / Cp ratios. At pre-dose baseline, an average of 3-4 copper molecules were bound per molecule of ceruloplasmin. The data are also presented in Figure 7 as a visual inspection. The average CpC / Cp values ​​after dosing during the entire 48-week treatment period remained relatively stable for BC-TTM, while they declined somewhat for SoC. This means that both BC-TTM and SoC have limited impact on the CpC / Cp ratio over the 48 weeks of treatment. This observation is likely due to either a much higher binding affinity of ceruloplasmin to copper or limited, if any, impact of BC-TTM and SoC on the formation of holoceruloplasmin by the liver.

[0149] [Table 6]

[0150] Preliminary population PK analyses including data from healthy participants (Study 104, Study 106, Study 107, Study 108, and Study 109) and participants with WD (Study 201 and Study 301) indicate that age is not a significant covariate for plasma total molybdenum clearance. Elimination half-life was also similar across age subgroups. Study 106 is a Phase 1 study evaluating the pharmacokinetics (PK), pharmacodynamics (PD), biomarkers, and safety of BC-TTM in healthy Japanese and non-Japanese subjects, and is described in Example 1 of U.S. Provisional Patent Application No. 63 / 339,307, filed May 6, 2022, and incorporated herein by reference. Study 104 is registered with EudraCT under study number 2019-000516-28; study 107 is registered with ClinicalTrials.gov, number NCT04560816; study 108 is registered with ClinicalTrials.gov, number NCT04594252; and study 109 is registered with ClinicalTrials.gov, number NCT04610580.

[0151] Calculated AUC of plasma total molybdenum after 48 weeks of treatment with BC-TTM in Study 301 (0-48週) (Table 7 and Figure 8) and plasma total copper, dNCC, and LBC AUEC () The values ​​(Table 8 and Figure 9) show similar median values ​​for adults and adolescents.

[0152] [Table 7]

[0153] [Table 8]

[0154] Study 204 is an exploratory study designed to investigate the effect of BC-TTM on Cu balance in participants with WD. Study 204 is registered at ClinicalTrials.gov, number NCT04573309, and described in Example 1 of U.S. Provisional Patent Application No. 63 / 237,120, filed August 25, 2021, and incorporated herein by reference. Study 204 specifically evaluates the effect of 15 mg and 30 mg doses of BC-TTM and duration of treatment on Cu balance. Participants continued on a Cu-controlled diet and Cu and Mo balance was measured at all intakes (i.e., study drug, food, and fluids) and all excretions (urine and stool). The Cu and Mo concentrations of each sample were measured by inductively coupled plasma mass spectrometry (ICP-MS). The copper and Mo content of all intakes and excretions was calculated based on the volume or weight of intakes and excretions and the concentrations of representative samples.

[0155] Fecal and urinary collection periods varied in duration from 3 to 15 days to support the assessment of both pre- and steady-state Cu and Mo balance at both 15 and 30 mg. The equilibration period for the Cu / Mo control diet was a minimum of 48 h. Copper balance was calculated as the mean daily Cu balance for each of the four collection periods. Interpretation of Cu balance was based on criteria established previously when performing Cu balance studies with zinc treatment. For the assessment of BC-TTM effects on Cu balance, the period for analysis took into account a mean intestinal transit of approximately 40 h (males: 33 h; females: 47 h).

[0156] Preliminary results from Study 204 showed a net increase in daily fecal copper excretion following exposure to BC-TTM in participants with WD. Results are available for the first three participants enrolled in this open-label copper balance / molybdenum mass balance study. These participants had all intakes (food and drink) and excretion (urine and feces) collected on days -4 to -1 (baseline), days 1 to 8, and days 25 to 39. They were scheduled to receive BC-TTM at 15 mg / day for 28 days (period 1) and then 30 mg / day for 11 days (period 2), but only one participant was able to increase to a higher dose, while the other two had their dose reduced to 15 mg QOD due to elevated alanine aminotransferase (ALT).

[0157] Patient information for Study 204 is presented in Table 9. Results from the primary endpoint of Study 204, mean daily Cu balance, are presented in Table 10. As described above, mean daily Cu balance is measured by accumulation of BC-TTM at each dose and the calculated difference between Cu intake (in food and drink) and Cu excretion (in feces and urine) during the steady-state period.

[0158] [Table 9]

[0159] [Table 10]

[0160] Based on preliminary results from three participants with WD in Study 204, copper mobilization following treatment with 15 mg / day (or every other day) or 30 mg / day for a total duration of 39 days was significant compared to pre-treatment baseline. Consistent results among the three participants who have completed the study to date indicate that BC-TTM results in rapid and sustained mobilization of copper from tissues to the blood where it is safely sequestered in the tripartite complex. This is evidenced by the rapid and sustained increase from baseline in dNCC displayed in Table 11 and Figure 10, as well as the increase from baseline in fecal copper excretion displayed in Table 12 and Figure 11.

[0161] [Table 11-1]

[0162] [Table 11-2]

[0163] [Table 12]

[0164] [Table 12-1]

[0165] The dose of BC-TTM per protocol was planned to increase from 15 mg daily (days 1–28) to 30 mg daily on days 29–39. In two participants, this dose escalation was not performed due to elevated liver enzymes (maximum grade 2 on the Common Terminology Criteria for Adverse Events [CTCAE] toxicity scale). Participant 0344–1001 received 15 mg daily on days 1–31, followed by 15 mg QOD on days 32–39. Participant 0344–1003 received 15 mg daily on days 1–24, followed by 15 mg QOD on days 25–39. The lower daily dose of BC-TTM in period 2 could explain the smaller changes in dNCC on days 31–35 and 36–39.

[0166] The increased copper mobilization by BC-TTM is evidenced by the decrease from baseline in net copper balance (where net balance = copper import - copper export) displayed in Table 13 and FIG.

[0167] [Table 13]

[0168] Key secondary endpoints of Study 301 The key secondary endpoints of Study 301, intended to provide evidence of direct clinical benefit, were: Change from baseline in UWDRS Part II total score (activities of daily living) Change from baseline in the functioning subscale of the UWDRS Part III Change from baseline in individual function items of UWDRS Part III: chair, gait, speech, and handwriting attributable After adjusting for multiplicity using hierarchical testing, none of the key secondary efficacy endpoints were statistically significantly different between BC-TTM and SoC, as shown in Table 14. A trend toward stability / improvement was observed in both treatment groups. A possible explanation for the relative lack of improvement in neurological scores is the good baseline status of the majority of patients, as shown by the data in Table 15. Approximately 50% of patients had a baseline UWDRS score of 0, and patients with scores above 0 were relatively low within each UWDRS part II (score range: 0-40) and UWDRS part III (score range: 0-175) scale range, indicating little room for improvement. Further UWDRS scores by cohort were observed in Figures 20 and 21.

[0169] While the transformed CGI-I (TCGI-I) evaluates how the pathology of WD patients has changed compared to baseline, the CGI-I can show the total clinical benefit of patients in the study for each treatment arm compared to baseline. Out-of-sequence analysis of multiplicity tests showed significant improvement in transformed CGI-I scores at week 48 in cohort 1 and overall, as illustrated in Figure 22.

[0170] [Table 14-1]

[0171] [Table 14-2]

[0172] Another possible explanation for the relative lack of significant change in neurological scores is the low total baseline UWDRS scores in the entire population (data in Table 15). Overall, 55.9% and 51.4% of BC-TTM and SoC participants, respectively, had a baseline UWDRS part II total score of 0, and 21.3% and 18.6% of BC-TTM and SoC participants, respectively, had a baseline UWDRS part III total score of 0. Combined, 19.4% (40 / 206) of participants had a baseline total UWDRS score of 0 in both part II and part III. This impacts the low overall population means in part II (3.5-4.0 on a 40-point scale) and part III (6.50-15.97 on a 175-point scale). At the population comparison level, little room for overall improvement was observed, but at the individual participant level, the changes in scores for individual items could potentially provide meaningful clinical change in individual participants over time.

[0173] [Table 15]

[0174] For symptomatic patients, a moderate decline from baseline was observed in UWDRS scores 0-48W: Part II score change (mean) was -1.7 BC-TTM and -0.8 SoC; Part III score change (mean [95% CI]) was -2.91 [-4.74, -1.09] BC-TTM and -1.17 [-3.20, 0.86] SoC. Table 15-1 summarizes the UWDRS Part III score change at 48W for patients who were symptomatic at baseline.

[0175] [Table 15-1]

[0176] The symptoms and associated impacts of WD generally fall into neurological, psychiatric, and hepatic categories. Previous studies involving concept elicitation interviews with WD patients have provided insight into the complexity and heterogeneity among patients. Consistent with this, participants enrolled in Study 301 presented with a variety of symptoms, which have different types of impacts on their lives.

[0177] Exit interviews were conducted with a sample of participants (n=10) to understand their experience with BC-TTM treatment. These exit interviews demonstrate the diversity of neurological dysfunction and the need to better understand treatment experiences with participant-level data review. Overall, qualitative information suggests that participants who were symptomatic at the start of treatment with BC-TTM experienced improvement or maintenance across several neurological symptoms (including walking, balance, speech, and tremor) that were deemed significant. Conversely, participants who did not report experiencing any symptoms at the start of the study did not develop any symptoms during treatment and any worsening (experiencing symptoms or deterioration) was deemed significant. Exit interview insights provide deeper insight into the experiences of the interviewed participants and add to such observations that there is little room for overall improvement at the group comparison level.

[0178] Data from participants taking BC-TTM for more than 48 weeks are being analyzed to evaluate the longer-term safety and efficacy of this treatment (continuous copper control and clinical benefit). This includes 19 participants from Phase 2 Study 201 who have been transferred to Study 301 extension and have been treated with BC-TTM for more than 5 years, as well as participants who were enrolled in Study 301, randomized, and treated with BC-TTM in either the primary evaluation period or the open-label extension. Pooled results from all these participants will be combined together into one schedule to allow for analysis of UWDRS changes, long-term copper control, and long-term safety laboratory measures.

[0179] The UWDRS Part II total score results for this pooled population are presented in Table 16 and Figure 13, and the UWDRS Part III total score results are presented in Table 17 and Figure 14. The UWDRS Part III functional subscale (consisting of items originating from chair, walking, handwriting, and speech) results for this pooled population are presented in Table 18 and Figure 15. In all tabular documents, the mean and least squares mean (LSM) values ​​decrease over time, generally with greater decreases at subsequent time points. This indicates improvement in the entire population, since lower scores mean improvement in signs and symptoms. After 36 weeks of exposure to BC-TTM, significance in the mean and LSM is achieved (0 is excluded from the mean and LSM 95% CI) and is maintained in virtually all cases. The graphical representation shows that the line slopes downward over time, indicating a slow but steady improvement during treatment with BC-TTM. These results show that participant reported UWDRS Part II scores and clinical / neurologist reported UWDRS Part III and Part III functional subscale scores all continue to improve with up to 5 years of BC-TTM treatment, as evidenced by a statistically significant reduction from baseline.

[0180] [Table 16]

[0181] [Table 17]

[0182] [Table 18-1]

[0183] Table 18-1 provides some interim long-term safety and efficacy results throughout the extension period of Study 301. These results represent the pooled data set of 301 study participants who either started on BC-TTM or transitioned to BC-TTM after the 48-week main period. They demonstrate statistically significant improvements from baseline in key secondary endpoints, such as UWDRS and CGI, in patients treated with BC-TTM. In addition, these results show that the level of improvement increases over time with continued BC-TTM treatment.

[0184] [Table 18-2]

[0185] [Table 18-3]

[0186] [Table 18-4]

[0187] Adverse Events of Special Interest (AESI): Neurological events Acute worsening of neurological symptoms, typically within 6 months of treatment initiation, is a known complication associated with chelation therapy for WD. The presumed mechanism is rapid mobilization of unbound copper resulting in higher blood NCC and inducing cytotoxic effects in nervous tissue with consequent neurological deterioration in treated patients. Neurological AESIs in Study 301 were considered all AEs in the Medical Dictionary of Drugs and Regulation of Treatment (MedDRA) System Organ Class (SOC) "Nervous System Disorders" or any other AE adjudicated by the investigator as an AESI.

[0188] Overall, neurological AESIs were reported under the SOCs "Nervous system disorders" and "Psychiatric disorders" in 47 (34.3%) and 5 (3.6%) participants, respectively. Adverse events reported as AESIs in both of these SOCs are described below.

[0189] Nervous System Disorders (SOC) The incidence of AEs reported in the SOC "nervous system disorders" was higher in the BC-TTM treatment group compared to the SoC group (34.3% vs. 21.4%). Commonly reported AEs in both groups were headache (8.0% vs. 8.6%) and tremor (7.3% vs. 2.9%). Among neurological AEs, a significant difference between treatment groups (BC-TTM and SoC) was noted in the case of tremor events. Twelve tremor events occurred in 10 (7.3%) participants. All events were non-serious and low grade (grade 1 and grade 2). Of the 10 (7.3%) participants, six participants reported the events as "worsening" or "increased tremor." Treatment was discontinued due to three tremor events; in two events the outcome was "recovered" and in one event it was "not recovered." For the remaining 9 events, dosing was not modified and outcomes were "not recovered" for 3 events, "recovered" for 4 events, and "recovering" for 2 events.

[0190] The incidence of participants with the highest grade of severity AEs was similar in both treatment groups for grade 1 AEs (24.1% vs. 21.4%) and higher in the BC-TTM group for grade 2 AEs (13.9% vs. 4.3%). No grade 3 AEs were observed in either treatment group, and grade 4 and grade 5 AEs were observed in one participant each in the BC-TTM group. One AE (preferred term "neurological deterioration") led to treatment withdrawal.

[0191] The incidence of SAEs, as well as total AEs, was higher in the BC-TTM arm compared to the SoC arm [6 (4.4%) vs. 1 (1.4%)]. Seven SAEs were reported in 6 participants. In the BC-TTM arm, SAE severity was reported as grade 1 in 1 participant, grade 2 in 4 participants, no grade 3 events, grade 4 in 1 participant (the same participant also experienced a grade 2 SAE), and grade 5 in 1 participant with an SAE of "hepatic encephalopathy." All SAEs in both arms were assessed as unrelated.

[0192] The most common system organ class SAEs for BC-TTM were nervous system disorders (n=6 [4.4%]), and SoC were gastrointestinal disorders and musculoskeletal and connective tissue disorders (n=2 [2.9%] each).

[0193] Psychiatric Disorders (SOC) Neurological AESIs in SOC "Psychiatric Disorders" were observed only in the BC-TTM treatment group. Seven events were reported in five (3.6%) participants: depression, enuresis, insomnia, delusional disorder, sleep disorder, and blunted affect and irritability (each in one participant). All but one event was non-serious and low grade (grade 1 and grade 2). Of the seven events, only two led to dose modification (one dose reduction and one dose increase). Outcome for three events was "recovered" and for four events was "ongoing." Only one SAE was reported ("delusional disorder worsened"). No grade 4 or 5 events were reported, and no events led to study drug discontinuation.

[0194] Other significant events and laboratory findings Hepatic effects (increased hepatic transaminase levels) Overall, in Study 301, a higher percentage of participants treated with BC-TTM reported elevated liver enzymes (ALT, aspartate aminotransferase [AST], and / or GGT) compared to SoC (see Table 19). The most commonly reported event in the BC-TTM group was elevated ALT (14.6% vs. 2.9% in SoC), accounting for 4.3% (25 / 577) of treatment-emergent adverse events (TEAEs) in the BC-TTM group. These events typically occurred within the first 4-12 weeks and were generally mild to moderate in severity, asymptomatic, reversible, and normalized with dose adjustment and / or discontinuation. AEs of elevated liver enzymes are summarized in Table 19.

[0195] Based on laboratory values, 29 BC-TTM-treated participants had post-baseline ALT elevations of ≥3× upper limit of normal (ULN): Fourteen (10.2%) participants had ALT >3xULN but ≤5xULN Ten (7.3%) participants had ALT >5xULN but ≤10xULN One (0.7%) participant had an ALT >10xULN but ≤20xULN Four participants (2.9%) had ALT elevations >20×ULN

[0196] In participants treated with SoC, six had post-baseline ALT elevations of ≥3×ULN: three (4.3%) participants each had an ALT in the range of >3×ULN but ≤5×ULN and >5×ULN but ≤10×ULN.

[0197] One BC-TTM-treated participant experienced an ALT >3×ULN with concomitant total bilirubin >2×ULN. The participant's underlying liver disease was a confounding factor, determined in this case by an independent liver adjudication panel to be unlikely to be related to BC-TTM. Treatment with BC-TTM was restarted, and liver tests remained normal.

[0198] The mean values ​​and 95%CI of ALT and GGT values ​​over time are presented in Figures 16 and 17, respectively. In the BC-TTM group, ALT levels increased from baseline, peaked at week 6, then trended toward baseline by week 24. GGT levels increased from baseline to week 6, stabilized by week 12, then trended toward baseline by week 36 in the BC-TTM group. Overall, there were no clinically significant changes from baseline in ALT and GGT in the SoC group.

[0199] [Table 19]

[0200] Dyslipidemia: Routine lipid monitoring was not originally included in the clinical study. Through review of medical monitoring and available local laboratory values, three 301 participants were identified as experiencing elevated cholesterol and TGs concomitantly with liver enzyme elevations. Review of data from study 201 showed that seven participants experienced elevations above the ULN in total cholesterol, and all seven had concomitant ALT elevations. Consequently, routine lipid monitoring was added to study 301, and a retrospective analysis was performed using available retained samples for all participants.

[0201] In retrospective analysis, disparities in lipid outcomes were identified at baseline between the BC-TTM and SoC groups. Elevated cholesterol at baseline was found in 19% of BC-TTM cases and 10% of SoC cases; 13 (9.5%) of BC-TTM cases and 5 (7.1%) of SoC cases had reduced high-density lipoprotein (HDL); 10.9% of BC-TTM cases and 7.1% of SoC cases had elevated low-density lipoprotein (LDL). The proportion of elevated TGs was similar at baseline in both groups (16.8% of BC-TTM cases and 17.1% of SoC cases).

[0202] A baseline-to-worst change analysis was performed for cholesterol and TG. The results showed that a higher percentage of participants in the BC-TTM group compared to the SoC group experienced grade 1 (43.8% vs. 32.9%), grade 2 (5.1% vs. 0), and grade 3 (3.6% vs. 0) cholesterol elevations. The worst values ​​during the study were higher in the BC-TTM group compared to the SoC group, as were grade 2 (12.4% vs. 2.9%), grade 3 (5.1% vs. 1.4%), and grade 4 (2.9% vs. 0) TGs. The baseline-to-worst change during the study for cholesterol and triglycerides is presented in Table 20.

[0203] [Table 20]

[0204] The mean values ​​and 95%CI for total cholesterol over time are presented in Figure 18, with increases above baseline seen in the SoC group but not in the BC-TTM group throughout the primary study analysis period. In the BC-TTM group, cholesterol levels increased from baseline, peaked around week 6, then tended to decline toward baseline until week 24, and eventually stabilized at a level slightly higher than baseline. In Figure 19, changes in TG were primarily confined to the early portion of the treatment period, increasing from baseline at week 6, then gradually returning to baseline by week 36.

[0205] Analysis of lipid profiles was performed retrospectively using frozen plasma biomarker samples collected at scheduled study visits.Events under cardiac disorders SOC were reviewed to identify only AEs potentially correlated with dyslipidemia.

[0206] Events under the SOC for gastrointestinal disorders were also reviewed, and no events (e.g., pancreatitis) were identified that were potentially correlated with dyslipidemia. As noted above, lipid abnormalities and liver enzyme elevations were reported during the primary analysis period of Study 301, and these elevations were more frequent in the BC-TTM group than in the SoC. In general, lipid abnormalities were asymptomatic, transient, and not associated with any significant clinical outcomes.

[0207] Cytopenias: Copper is an essential micronutrient involved in the catalytic function of several key enzymes involved in a variety of processes throughout the body, including those in the bone marrow and central nervous system. Acquired or inherited copper deficiency can manifest in multiple organ systems, but hematological abnormalities are the most common. Copper deficiency occurs with anemia, neutropenia, and less frequently thrombocytopenia.

[0208] Hematological AEs were observed in the clinical program for BC-TTM and are presented in Table 21. The majority of hematological events were non-serious, low grade, and resolved with dose modification. Treatment with BC-TTM was discontinued due to AEs of neutropenia (grade 2) and anemia (grade 1) in one participant each. Overall, the incidence of hematological AEs was similar in the BC-TTM and SoC treatment groups.

[0209] [Table 21]

[0210] At baseline, the decline in neutrophil levels (0.7% vs. 1.4%) was similar between the BC-TTM and SoC groups, the decline in platelet levels (21.9% vs. 28.6%) was higher in the SoC group compared with the BC-TTM group, and the decline in hemoglobin levels (17.5% vs. 14.3%) was slightly higher in the BC-TTM group compared with the SoC group.

[0211] Changes from baseline to worst during the study for neutrophils, platelets, and hemoglobin are presented in Table 22. Overall, results showed similar percentages of change from baseline to worst for neutrophils, platelets, and hemoglobin; with the exception of grade 1 hemoglobin (41.6% vs. 24.3%), grade 1 platelets (24.1% vs. 17.1%), and grade 3 neutrophils (6.6% vs. 2.9%), which were higher in the BC-TTM group than in the SoC group.

[0212] [Table 22]

[0213] Safety findings in participants who switched from SoC to BC-TTM in the extension period Analyses were performed on preliminary data to compare AEs from study 301 participants receiving SoC during the primary evaluation period (48 weeks) and from the subset of participants who switched to BC-TTM during the extension period. Analyses were performed to identify imbalances in AEs reported after switching from SoC to BC-TTM and to compare results against the imbalances observed in events with SoC during the primary evaluation period [BC-TTM vs. SoC].

[0214] During the primary evaluation period in Study 301, disproportionate SoC (>5% difference) between BC-TTM and SoC included ear and labyrinth disorders (5.1% vs. 0%), systemic disorders and administration site conditions (21.2% vs. 10.0%), hepatobiliary disorders (6.6% vs. 1.4%), investigations (33.6% vs. 2.9%), nervous system disorders (34.3% vs. 21.4%), psychiatric disorders (19.0% vs. 4.3%), and skin and subcutaneous tissue disorders (21.9% vs. 5.7%). These are presented in Table 23.

[0215] Among participants who switched from SoC to BC-TTM, four SoCs were identified for participants experiencing a higher percentage of AEs (defined as a difference of >5%), including: general disorders and administration site conditions [10% vs. 18%], investigations [2.9% vs. 29.5%], metabolism and nutrition disorders [4.3% vs. 11.5%], and skin and subcutaneous tissue disorders [5.7% vs. 13.1%]. The imbalances observed within each SoC were driven by events of fatigue, ALT elevation, lipid elevation (i.e., hyperlipidemia, hypertriglyceridemia, and dyslipidemia), and pruritus, as shown in Table 24.

[0216] No imbalances were observed in AEs reported to be identified from any other SoC (see Table 24-1). Notably, and in contrast to the imbalances observed within the primary evaluation period, the switch analyses showed no imbalances in the SoCs of nervous system or psychiatric disorders.

[0217] [Table 23]

[0218] [Table 24]

[0219] [Table 24-1]

[0220] Overall, most AEs observed in Study 301 were non-serious, mild or moderate, manageable, and did not lead to treatment discontinuation. Commonly observed (>10%) AEs included ALT elevation and nasopharyngitis. Risks observed in participants treated with BC-TTM, including hepatic effects (elevated hepatic transaminase levels), dyslipidemia, and cytopenias, were generally asymptomatic, reversible with dose modification, and not associated with any clinical outcome.

[0221] Consistent with the above, analysis of data in participants switched from SoC treatment to BC-TTM showed an increased incidence of laboratory abnormalities (elevated ALT, elevated cholesterol and TG, neutropenia), further supporting an association with BC-TTM.

[0222] Deterioration of neurological symptoms is a known concern with SoC; this is primarily associated with penicillamine, but has also been seen with trientine and zinc. The mechanism of neurological deterioration is unknown, but an association with unbound copper has previously been hypothesized. Data from the primary evaluation period in Study 301 showed disparities in neurological and psychiatric events with a higher incidence in participants treated with BC-TTM versus SoC; however, these disparities were not observed in participants who switched from SoC treatment to BC-TTM during the extension period. Given that Study 301 is an open-label study, reporting may be biased by participants knowing they are taking the investigational drug. The findings mentioned suggest a lack of association between BC-TTM and neurological and psychiatric AEs.

[0223] Overall, BC-TTM has an acceptable safety profile and is generally well tolerated in participants with WD.

[0224] Cirrhosis and Albumin Levels at Baseline During BC-TTM Treatment: Across the 301, 201, and 205 studies, 102 participants had cirrhosis at baseline. Study 205 is registered with ClinicalTrials.gov under number NCT04422431 and is incorporated by reference in its entirety. Of the total 102, 13 participants experienced changes in albumin levels (indicating changes in composite liver function) over the course of treatment with BC-TTM. Albumin levels in the other 89 participants remained stable (indicating stable liver function) throughout the study. The changes in albumin levels in these 13 participants are listed below in Table 25 (units shown are mg / dL throughout).

[0225] [Table 25-1]

[0226] [Table 25-2]

[0227] These results indicate that of 102 participants with cirrhosis at baseline, 87% maintained their liver function (as measured by albumin levels) during BC-TTM treatment. Of 13 cirrhotic participants who experienced changes in liver function, seven participants receiving BC-TTM experienced improvement such that albumin levels that had fallen outside the normal range returned to the normal range during BC-TTM treatment.

[0228] Example 2: In this copper absorption study, the primary objective was to investigate the effect of BC-TTM on intestinal absorption and hepatic copper uptake in healthy subjects, compared with the effects of penicillamine, trientine, and placebo. Secondary objectives were to investigate the effect of BC-TTM on copper uptake in the gallbladder, pancreas, kidney, heart, and small and large intestine, compared with the effects of penicillamine, trientine, and placebo. Blood was collected at several time points to assess plasma copper kinetics.

[0229] The study was conducted as a randomized, placebo-controlled interventional study. Positron emission tomography-computed tomography (PET-CT) scans were performed with an orally administered radioactive copper isotope tracer in 32 healthy subjects. 64 CuCl2( 64 This enabled monitoring and evaluation of Cu) (Figure 24). 64 Cu uptake and tissue distribution were assessed by PET-CT scans before copper reduction treatment.

[0230] Subjects were then randomized to one of four anti-copper treatments (eight in each arm; penicillamine 600 mg twice daily, trientine 300 mg in the morning and 225 mg at night, BC-TTM 15 mg, or matching placebo) to be taken orally once daily for 7 days. Day 8, oral 64 CuCl2 was administered and PET-CT imaging was repeated to assess changes from baseline in copper absorption and tissue distribution.

[0231] In the study, the effects of previously listed organs and anti-copper treatments were evaluated by comparing the mean standard uptake values ​​(SUV) in the organs of interest. SUV allows for a semi-quantitative assessment of copper in the desired volume of interest of each organ by measuring the ratio of observed copper activity to the total dose of copper administered. Dynamic baseline scans and subsequent static scans were compared across all treatments. Preliminary results of the effect of each treatment on copper absorption are reported below.

[0232] After treatment with BC-TTM in healthy subjects 64 A visual indication of the significant decrease in Cu absorption is illustrated in Figure 25. It can be seen that prior to anti-copper treatment, the majority of copper was distributed between the liver and the gastrointestinal tract. This reflects the normal physiology of copper absorption from the intestine and transport to the liver via the portal vein. 3 After treatment with BC-TTM, 64 One hour after oral administration of the Cu tracer, virtually no copper uptake was observed in the liver. 64 The Cu tracer remained in the gastrointestinal tract.

[0233] Therefore, hepatic copper uptake was used to assess gastrointestinal 64 The effect of anti-copper treatment on Cu absorption was quantified. Before treatment, mean SUV 64 No significant difference was observed for Cu. Next, all subjects were 64 Patients were treated with anti-copper therapy or placebo for 7 days prior to the Cu absorption study. As presented in Figure 26, after treatment with BC-TTM, the mean liver SUV was significantly reduced compared to baseline or placebo.64 At 1 and 15 hours after oral administration of Cu, the mean hepatic SUV was significantly reduced in healthy subjects receiving BC-TTM compared with penicillamine or trientine. Hepatic uptake of labeled copper after treatment with trientine was significantly reduced compared with penicillamine at 1 and 15 hours. The effect of penicillamine was not different from placebo.

[0234] Mean SUV in liver after BC-TTM treatment 64 The reduction in Cu persisted through the 13-hour scan, with a somewhat more widespread reduction in hepatic copper uptake (60%-90%) observed in healthy subjects undergoing BC-TTM. 64 These results indicate a potent effect of BC-TTM in reducing the absorption of orally administered copper.

[0235] Compared with penicillamine or trientine, BC-TTM caused a greater reduction in hepatic copper uptake. At the 1-hour post-treatment scan, mean hepatic copper uptake was reduced by approximately 25% in those taking penicillamine, 50% in those taking trientine, and 90% in those taking BC-TTM in healthy subjects. No changes were observed in healthy subjects taking placebo.

[0236] In healthy subjects who took BC-TTM, 64 The decrease in blood levels of Cu was consistent with the observed decrease in hepatic copper uptake. 64 The decrease in Cu levels is the result of decreased intestinal absorption of copper. Mean SUV 64 Cu was significantly different after treatment compared with the other treatment groups and placebo in the following other organs: Gallbladder: after 15 hours, lower than penicillamine, trientine and placebo; Colon: after 15 hours, higher than penicillamine and placebo; Bladder: lower than penicillamine, trientine and placebo at 1 hour; Pancreas: After 1 hour, lower than penicillamine, trientine and placebo Absorption of orally administered copper was significantly reduced in healthy subjects treated with BC-TTM compared with penicillamine, trientine, or placebo.

[0237] Example 3: A copper excretion study (Figure 27) was conducted to investigate the effect of BC-TTM on biliary copper excretion and plasma copper kinetics in patients with WD. 64 This was a single-arm study in which Cu distribution was examined in four patients with WD using positron emission tomography-magnetic resonance (PET-MR) scans before and after treatment with BC-TTM. 64 Dynamic PET-MR scans were performed 15 min after intravenous administration of Cu, followed by further scans at 1, 2, 6, 20, 48, 54, and 68 h. Venous blood samples were collected at multiple time points for quantification of radioactivity.

[0238] Before treatment 64 After completion of the Cu PET-MR study, subjects received 15 mg of BC-TTM once daily for a total of 11 days. 64 Cu PET-MR studies were started on day 7 and serial PET-MR imaging was performed. 64 The tests were performed 1, 2, 6, 20, 48, 54, and 68 hours after intravenous administration of Cu.

[0239] In the study, 64 The kinetics of Cu and its distribution within the organs of interest were assessed. SUV allows a semi-quantitative assessment of copper within a desired volume of interest by measuring the ratio of observed copper activity to the total dose administered.

[0240] PET scans at 2 and 48 hours showed a significant decrease in hepatic copper uptake after treatment with BC-TTM. The scans also showed that copper was distributed to the kidneys.64 An increase in Cu was also observed (Figure 28, arrow). The decrease in hepatic copper uptake after treatment with BC-TTM was 64 This can be seen in a scan obtained 6 hours after intravenous administration of Cu. 64 No increase in Cu was observed, indicating that BC-TTM does not promote biliary copper excretion (Figure 29).

[0241] The mean SUV on static PET-MR scans in four WD patients receiving BC-TTM was plotted against time for various organs (Figure 30). After treatment with BC-TTM, the mean SUV of the liver decreased, the mean SUV of the kidneys increased, and the mean SUV of the gallbladder remained unchanged. After treatment with BC-TTM, the mean SUV of the other organs did not change.

[0242] Before and after treatment with BC-TTM, 64 Cu concentrations were measured as the median percent of injected dose (ID) (Figure 31). Before treatment with BC-TTM, 64 Cu was rapidly excreted from the blood (diamonds, solid line) to the liver (circles, solid line). After BC-TTM treatment, 64 Cu reached a higher peak in the blood and its clearance from the blood was delayed (diamonds, dashed line). 64 Hepatic Cu uptake was decreased by treatment with BC-TTM (circles, dashed line). 64 Cu uptake increased after treatment with BC-TTM (triangles, dashed line), even though the absolute changes (as % of injected dose) were relatively small.

[0243] Intravenously injected 64 Cu was rapidly distributed in the blood, reaching a peak after about 1 minute (Table 26, Figures 31 and 32). 64 Cu concentrations were not significantly different before and after treatment with BC-TTM during the first 10 min after intravenous injection. This observation supports the idea that Cu is present throughout the circulation before uptake into organs. 64 This is consistent with the immediate distribution of Cu from the blood prior to treatment with BC-TTM. 64A rapid disappearance of Cu was observed, which was consistent with normal hepatic uptake of copper from the blood, but corresponds to the PET-MR scans. After treatment with BC-TTM, significantly more copper was present in the blood between 1 and 48 hours. 64 After BC-TTM treatment, blood levels of Cu were significantly increased. 64 The mean Cu concentrations are consistent with reduced hepatic uptake of copper.

[0244] [Table 26]

[0245] WD patients treated with BC-TTM showed increased blood 64 There was a significant decrease in hepatic copper uptake, corresponding to a delayed clearance of Cu. A moderate increase in renal copper uptake was observed after treatment with BC-TTM. Biliary copper excretion was not detected before or after BC-TTM treatment.

[0246] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are incorporated within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

1. 1. A pharmaceutical composition for reducing copper concentrations in tissues of a subject, comprising an effective amount of bischoline tetrathiomolybdate, wherein the subject is at least 12 years old, and the bischoline tetrathiomolybdate is administered for at least 48 weeks.

2. 10. The pharmaceutical composition of claim 1, wherein the subject is at least 18 years old.

3. 1. A pharmaceutical composition for treating a copper metabolism-related disease or disorder in a subject, comprising an effective amount of bischoline tetrathiomolybdate, wherein the bischoline tetrathiomolybdate is administered for at least 48 weeks, and wherein the subject is at least 12 years of age.

4. The pharmaceutical composition of claim 3, wherein the subject is at least 18 years of age.

5. The pharmaceutical composition of claim 3 , wherein the copper metabolism-related disease or disorder is Wilson's disease.

6. 4. The pharmaceutical composition of claim 3, wherein the subject has not previously received treatment for the copper metabolism-related disease or disorder, e.g., Wilson's disease.

7. 4. The pharmaceutical composition of claim 3, wherein the subject has previously received standard treatment for the copper metabolism-related disease or disorder, e.g., Wilson's disease.

8. i) the subject has previously received standard therapy for 4 weeks or less, or 2 weeks or less; ii) the subject has previously received standard of care for at least 4 weeks, or at least 6 weeks, or at least 12 weeks, or at least 24 weeks, or at least 48 weeks; or iii) The pharmaceutical composition of claim 7, wherein the subject has previously received standard of care for at least 41 months, or from about 41 months to about 228 months, or at least 116 months, or at least 155 months.

9. 9. The pharmaceutical composition of claim 8, wherein the standard of care comprises trientine, D-penicillamine, and / or zinc.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the amount of bischoline tetrathiomolybdate ranges from about 15 mg to about 60 mg per day, or wherein the amount of bischoline tetrathiomolybdate is about 15 mg per day or about 15 mg every other day.

11. 10. The pharmaceutical composition according to any one of claims 1 to 9, 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 plasma of the subject is measured.

12. 10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that the daily mean area under the effect-time curve (AUEC) of directly measured non-ceruloplasmin-bound copper (dNCC) (e.g., from baseline to 48 weeks) is measured.

13. The subject's average daily AUEC for dNCC ０－４８Ｗ is the average daily AUEC for dNCC ０－４８Ｗ 13. The pharmaceutical composition according to claim 12, characterized in that if the reference range of biscoline tetrathiomolybdate is outside the reference range, the amount of biscoline tetrathiomolybdate is adjusted.

14. 10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that the concentration of total molybdenum and / or plasma ultrafiltrate (PUF) molybdenum in the plasma of the subject is measured.

15. 12. The pharmaceutical composition of claim 11, wherein 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.

16. 12. The pharmaceutical composition of claim 11, wherein the measurement is performed at baseline, at week 6 of administration, at week 24 of administration, at week 48 of administration, or at least 48 weeks or more of administration.

17. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the patient is 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.

Images