Novel first-in-class agent shows promise in Wilson's disease

Last Updated: 2017-10-19

By Reuters Staff

NEW YORK (Reuters Health) - In patients with Wilson's disease, once-daily oral treatment with bis-choline tetrathiomolybdate rapidly lowered free copper levels, which correlated with reduced disability, improved neurological status, and stable liver function in an open-label phase 2 study.

Wilson's disease is a rare genetic disorder involving impaired copper transport that leads to copper accumulation in the liver, brain, and other tissues. The condition affects an estimated 1 in 30,000 people. Current therapies are limited by "efficacy, safety concerns, and multiple daily dosing," the study team notes.

Bis-choline tetrathiomolybdate (WTX101) is a stabilized form of tetrathiomolybdate being developed by Wilson Therapeutics AB, which funded the study published online October 5 in The Lancet Gastroenterology and Hepatology.

WTX101 is an oral "first-in-class copper-protein-binding molecule that targets hepatic intracellular copper and reduces plasma non-ceruloplasmin-bound copper (NCC) by forming tripartite complexes with albumin and increasing biliary copper excretion," Dr. Karl Heinz Weiss from University Hospital Heidelberg in Germany and colleagues explain in their article. WTX101 has orphan drug designation for the treatment of Wilson's disease in the United States and Europe.

Dr. Weiss and an international team enrolled 28 patients with Wilson's disease in the open-label phase 2 study. All patients were either untreated or had received no more than 24 months of treatment with chelators or zinc, and they had a Leipzig score of at least 4 and NCC concentrations above the lower limit of the normal reference range (0.8 micromole/liter).

Patients received WTX101 monotherapy once daily at a starting dose of 15 to 60 mg/day based on baseline NCC concentrations for the first 4 to 8 weeks, followed by individualized, response-guided dose adjustment for up to 24 weeks.

At 24 weeks, 20 of 28 (71%) patients met criteria for treatment success. That is, 16 (57%) patients treated with WTX101 either achieved or maintained corrected normalized NCC concentrations and 4 (14%) had at least a 25% reduction from baseline in corrected NCC. Average NCC corrected was reduced by 72% from baseline to week 24 (least-squares mean difference -2.4 micromoles/liter; P<0.0001).

According to the researchers, after 24 weeks, patients saw significant improvement in neurological symptoms, as measured by the Unified Wilson Disease Rating Scale part III (P<0.0001). The authors say no cases of "paradoxical drug-related neurological worsening were recorded." However, one patient had a decline in neurological functioning, which was "likely due to natural disease progression although causality could not be ruled out," they say.

Liver function remained stable in all patients, although reversible liver-enzyme elevations were seen in 11 patients (39%) treated with at least 30 mg/day. Eleven serious adverse events, reported in seven patients (25%), included psychiatric disorders, gait disturbance, and elevated liver aminotransferases.

"The seven serious adverse events categorized as psychiatric disorders and as gait disturbance were assessed as unlikely to be related to the study drug, whereas the remaining four events were possibly or probably related," the investigators conclude.

They say the "rapid biochemical and clinical improvements with WTX101 are possibly related to its novel, copper-specific, and direct hepatic mechanism of action of lowering concentrations of toxic free copper in plasma."

These phase 2 findings suggest that WTX101 "might be a promising new therapeutic approach for Wilson's disease, with a unique mode of action. In view of its once-daily dose and favorable safety profile, WTX101 could improve the treatment of patients with this debilitating condition," Dr. Weiss and colleagues conclude.

Dr. Roderick Houwen from University Medical Center Utrecht, Netherlands, agrees.

In a Comment published with the study, he notes that initial studies with tetrathiomolybdate showing a rapid reduction of free copper levels and less neurological deterioration compared to use of a chelating agent were a "substantial step forward," but that tetrathiomolybdate is too unstable for routine use.

The study by Dr. Weiss and colleagues using the more stable bis-choline tetrathiomolybdate provides a "much needed follow-up to these initial studies. The results hold promise for patients with Wilson's disease who cannot be adequately treated with chelators or zinc," Dr. Houwen writes.

He also notes that the dose of WTX101 used in the study was variable and needed to be individually titrated. "Before this drug can be used more generally, more specific guidelines are needed. Also needed are larger phase 3 trials, and data from the extension study that is announced in the discussion, to more fully address the side-effects that are described, notably leukopenia (two of 28 participants) and liver enzyme elevations (11 of 28 participants)," Dr. Houwen writes.

"The extension study should also clarify whether WTX101 should be primarily positioned for initial treatment, followed by a more conventional drug for maintenance treatment, or if WTX101 can be used in this phase, too. In view of its strong copper-binding properties, patients who are treated with this drug for months or years might be prone to copper deficiency, which should be avoided," Dr. Houwen adds.

Wilson Therapeutics AB, in addition to funding the study, was involved in various aspects of its design, data management, and manuscript preparation. Several of the authors have financial relationships with the company, and four are employed by it. Dr. Houwen reports no conflicts of interest.

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Lancet Gastroenterol Hepatol 2017.