Bis-Choline Tetrathiomolybdate for Treating Wilson Disease

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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation of U.S. application Ser. No. 16 / 770,022, filed Jun. 4, 2020, which is a national stage application under 35 U. S.C. § 371 of International Application No. PCT / EP2018 / 083551, filed Dec. 4, 2018, which claims priority to U.S. Provisional Application No. 62 / 594,184, filed Dec. 4, 2017; U.S. Provisional Application No. 62 / 646,553, filed Mar. 22, 2018; U.S. Provisional Application No. 62 / 655,568, filed Apr. 10, 2018; U.S. Provisional Application No. 62 / 669,095, filed May 9, 2018; U.S. Provisional Application No. 62 / 741,313, filed Oct. 4, 2018; and U.S. Provisional Application No. 62 / 750,595, filed Oct. 25, 2018, each of which is incorporated herein by reference in its entirety for all purposes.BACKGROUND[0002]Wilson Disease (WD) is an autosomal recessive disorder of impaired copper (Cu) metabolism. Mutations in the ATP7B gene result in deficient production of the Cu-transporter ATPase2, leading to impa...

AI Technical Summary

Benefits of technology

[0017]In one aspect, the present disclosure further provides methods for decreasing or increasing the daily dose of bis-choline tetrathiomolybdate in a patient exhibiting an abnormal test result, including optionally discontinuing treatment for a period of time.

Problems solved by technology

Mutations in the ATP7B gene result in deficient production of the Cu-transporter ATPase2, leading to impaired incorporation of Cu into ceruloplasmin, impaired biliary excretion of Cu, increased free and albumin-bound Cu, and Cu accumulation in liver, brain, and other tissues, with resulting organ damage and dysfunction.

Untreated or inadequately treated patients have progressive morbidity, and mortality is usually secondary to decompensated hepatic cirrhosis and liver failure.

However, beyond the Cu buffering capacity of MT, free Cu ions appear and this excessive amount of free intracellular Cu triggers pro-oxidant properties, leading to an increased risk of tissue / organ damages with clinical manifestations as a result.

This failure to respond to chelation therapy with neurological presentation may reflect irreversible damage to the nervous system.

Currently available drugs for treating WD have high rates of treatment discontinuation due to adverse events and treatment failure.

Their adverse event profiles and complicated dosing regimens lead to poor treatment compliance and high rates of treatment failure, a major concern in a disease such as WD that requires life-long treatment.

Nonetheless, it is difficult to predict, de novo, whether or not a particular active agent or pharmaceutical formulation will exhibit a food effect.

Furthermore, even if present, the food effect for an active agent or pharmaceutical formulation may result in an increase or a decrease in bioavailability in the fed conditions compared to the administration of an equivalent dose under fasted conditions.

For example, administering a pharmaceutical composition with food may provide dangerously high drug blood plasma levels of the active agent resulting clinical adverse effects.

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