Bis-choline tetrathiomolybdate for treating Wilson Disease
Inventors
BJARTMAR, CARL • Weiss, Karl-Heinz • SCHILSKY, MICHAEL • ASKARI, FREDERICK • CZLONKOWSKA, ANNA • Ferenci, Peter • HEDERA, PETER • ALA, AFTAB
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12233088-B2
Publication Date
2025-02-25
Expiration Date
Abstract
Methods for treating Wilson Disease with bis-choline tetrathiomolybdate therapy are provided. The methods may include administering 15 mg or between 30 and 90 mg of bis-choline tetrathiomolybdate once daily to a patient exhibiting NCCcorrected, alanine aminotransferase (ALT), hemoglobin, platelets, or neutrophils levels meeting specified criteria. The methods may include modifying treatment by decreasing or increasing the daily dose of bis-choline tetrathiomolybdate or discontinuing treatment for a period of time.
Core Innovation
The invention relates to a method of treating Wilson Disease in a patient by administering bis-choline tetrathiomolybdate in a fasted state. The disclosure includes embodiments in which administration is carried out with enterically coated formulations and delayed-release dosage forms.
The disclosure further describes dose regimens for bis-choline tetrathiomolybdate that can be administered in once-daily schedules and that include dose modification based on abnormal biomarkers. Biomarker criteria are based on NCC-corrected (NCCcorr) and hematology/liver tests including ALT, hemoglobin, platelets, and neutrophils, with dose reductions and increases carried out in defined increments and schedules.
In the described treatment framework, abnormal biomarker results can trigger temporary interruption and resumption of bis-choline tetrathiomolybdate dosing according to predefined schedules. The disclosure also includes long treatment duration embodiments and reports clinical and pharmacokinetic findings showing copper control with NCCcorr reduction and improved disability/neurological scores measured using UWDRS, together with a manageable safety profile and absence of paradoxical early neurological worsening in the reported examples.
Claims Coverage
The independent claim is directed to treating Wilson Disease by administering bis-choline tetrathiomolybdate in a fasted state. The dependent claims refine the method by defining dosing amounts and timing, and by modifying discontinuation or dosing based on abnormal test results using specific biomarker thresholds and schedules.
Fasted-state administration for Wilson Disease treatment
Administering bis-choline tetrathiomolybdate to the patient in need thereof in a fasted state.
Two-period dose-stepdown based on abnormal test result
If the patient exhibits an abnormal test result, administering a first dose level of about 15 to about 90 mg per day for a first time period, followed by a second dose level at least about 15 mg per day less for a second time period.
Abnormal biomarker criteria using baseline comparisons
Where the abnormal test result includes specified increases and decreases relative to baseline levels measured before bis-choline tetrathiomolybdate administration and/or defined normal thresholds, including ALT, hemoglobin, platelets, and neutrophils.
ALT-guided discontinuation until ALT normalization
Using alanine aminotransferase (ALT) test results relative to a baseline ALT taken before bis-choline tetrathiomolybdate administration to determine dose timing, including discontinuing treatment for a third period until ALT falls to less than two times the baseline.
Once-daily fixed-dose regimen
Administering 15 mg of bis-choline tetrathiomolybdate to the patient once daily.
Delayed-release dosage form administration
Administering bis-choline tetrathiomolybdate to the patient as a delayed-release dosage form.
Overall, the claim coverage centers on fasted-state administration of bis-choline tetrathiomolybdate for treating Wilson Disease, with refinements that define dose levels, dosing frequency and dose-stepdown schedules, and biomarker-guided discontinuation or adjustment based on NCCcorr and hematology/liver tests (including ALT, hemoglobin, platelets, and neutrophils) using baseline-relative criteria and predefined time periods.
Stated Advantages
Copper control, including reduction in NCC-corrected (NCCcorr).
Improved disability/neurological scores as measured by UWDRS.
Overall stable liver function.
Manageable safety profile, including reversible liver enzyme elevations.
Absence of paradoxical early neurological worsening in the reported study examples.
Documented Applications
Treating Wilson Disease in a patient by administering bis-choline tetrathiomolybdate in a fasted state, including embodiments with enterically coated and delayed-release dosage forms.
Use of biomarker-guided dosing and discontinuation based on abnormal ALT, hemoglobin, platelets, neutrophils, and NCCcorr, including long treatment duration in the disclosed examples.
Interested in licensing this patent?