Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study

Weiss, Karl Heinz; Askari, Frederick K.; Członkowska, Anna; Ferenci, Péter; Bronstein, Jeff M.; Bega, Danny; Ala, Aftab; Nicholl, David; Flint, Susan; Olsson, Lars; Plitz, Thomas; Bjartmar, Carl; Schilsky, Michael L.

doi:10.1016/s2468-1253(17)30293-5

Cited by 132 publications

(123 citation statements)

References 29 publications

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“…In the present trial, a bis‐choline TTM (WTX101) was examined . The complex is more stable than TTM and has a better bioavailability.…”

mentioning

confidence: 99%

“…The primary endpoint was defined as achieving or maintaining normal NCC levels less than or equal to 2.3 µM or a reduction of 25% or more in NCC levels from baseline. The calculated NCC levels (total serum copper minus ceruloplasmin‐bound copper) were corrected for the amount of copper bound in tripartite TTM‐copper‐albumin complexes in blood (NCC corrected ), which was determined using the relationship between NCC and plasma molybdenum concentrations …”

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confidence: 99%

“…Clinical outcomes were assessed as secondary endpoints and included neurological disability and status (measured as UWDRS [Unified Wilson’s Disease Rating Scale] parts II and III), liver function (modified Nazer score and MELD [Model for End‐Stage Liver Disease] score), and quality of life (EQ‐VAS [EuroQol‐visual analog scale]) …”

mentioning

confidence: 99%

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Bis‐choline Tetrathiomolybdate as Old Drug in a New Design for Wilson’s Disease: Good for Brain and Liver?

Stremmel

2018

Hepatology

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The article reported by Weiss et al. describes in a phase II trial showing the efficacy of bis-choline tetrathiomolybdate (TTM) in 28 patients with Wilson disease (WD) (1). After 24 weeks of treatment, 71% of patients met the primary endpoint of normalized non-ceruloplasmin-bound copper (NCC) (57%) or a ≥ 25% reduction of NCC (14%). This was accompanied by an improvement of neurological status. A reversible increase of transaminases and gamma-glutamyltransferase occurred in 39% of patients who received at least 30 mg/day. In 25% of patients, 11 serious adverse events were reported of which 7 were unlikely to be related to the study drug. This article is protected by copyright. All rights reserved.

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“…In the present trial, a bis‐choline TTM (WTX101) was examined . The complex is more stable than TTM and has a better bioavailability.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Bis‐choline Tetrathiomolybdate as Old Drug in a New Design for Wilson’s Disease: Good for Brain and Liver?

Stremmel

2018

Hepatology

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“…Alternate dosing strategies might lessen compliance concerns and still result in efficacy. Indeed, an experimental formulation of tetrathiomolybdate that requires once daily dosing is currently in development for humans with Wilson's disease …”

Section: Discussionmentioning

confidence: 99%

Ammonium tetrathiomolybdate treatment of copper‐associated hepatopathy in dogs

Langlois

Querubin

Schall

et al. 2019

Veterinary Internal Medicne

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Background Copper‐associated hepatopathy (CAH) is a common cause of liver disease in dogs. Although d ‐penicillamine can be an effective treatment, some dogs fail treatment or develop adverse effects. Ammonium tetrathiomolybdate (TTM) has been used to treat pathologic copper accumulation in other species, but its therapeutic potential for CAH is unknown. Objectives To investigate short‐term safety and efficacy of TTM for treatment of CAH. Animals Ten dogs with CAH. Methods Prospective study. All dogs were treated with TTM PO for 6 weeks, and hepatic biopsies were performed after the treatment course. Dog experiencing initial decreases in hepatic copper concentrations ([Cu] H ) received 6 additional weeks of TTM treatment and underwent 1 additional biopsy. Physical and laboratory examinations were performed every 2 weeks for study duration. Results Eight of 10 dogs had decreases in [Cu] H . Compared to baseline (median, 1606 μg/g; range, 572‐5158 μg/g), [Cu] H were decreased at 6 weeks (1033 μg/g, 450‐2975 μg/g; P = .04) and 12 weeks (931 μg/g, 218‐1677 μg/g; P = .02). Hepatic molybdenum concentrations increased >50‐fold ( P < 0.001). Changes in histologic scores and hematologic and biochemical test results were variable and not significantly different from baseline. One dog developed presumed immune‐mediated anemia and thrombocytopenia, but it was unclear if this was related to TTM administration. Conclusions and Clinical Importance Results suggest that TTM can effectively decrease [Cu] H in some dogs with CAH. Larger studies are needed to determine the overall safety and efficacy of TTM for treating CAH and how it compares with current treatments.

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“…Tetrathiomolybdate is an investigational product with strong decoppering properties 22. Potential adverse effects include bone marrow depression, hepatotoxicity and overly aggressive copper removal, which causes neurological dysfunction.…”

Section: Treatmentmentioning

confidence: 99%

Wilson disease: more than meets the eye

Kelly

Pericleous

2018

Postgraduate Medical Journal

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Wilson disease is a rare but important disorder of copper metabolism, with a failure to excrete copper appropriately into bile. It is a multisystem condition with presentations across all branches of medicine. Diagnosis can be difficult and requires a high index of suspicion. It should be considered in unexplained liver disease particularly where neuropsychiatric features are also present. Treatments are available for all stages of disease. A particularly important presentation not to overlook is acute liver failure which carries a high mortality risk and may require urgent liver transplantation. Here, we provide an overview of this complex condition.

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Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study

Cited by 132 publications

References 29 publications

Bis‐choline Tetrathiomolybdate as Old Drug in a New Design for Wilson’s Disease: Good for Brain and Liver?

Bis‐choline Tetrathiomolybdate as Old Drug in a New Design for Wilson’s Disease: Good for Brain and Liver?

Ammonium tetrathiomolybdate treatment of copper‐associated hepatopathy in dogs

Wilson disease: more than meets the eye

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