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Investigational Drug May Effectively Treat Wilson’s Disease

WTX101 appears to normalize copper levels, provide neurologic improvement, and reduce disability.


VANCOUVER—The investigational agent bis-choline tetrathiomolybdate (WTX101) may help treat Wilson’s disease, according to a study presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders. The drug lowered circulating copper, and this effect was associated with reduced disability, improved neurologic status without initial paradoxical worsening, and stable liver function.

Danny Bega, MD

“With dose adjustments, WTX101 demonstrated a favorable safety profile, and with a simple regimen (once daily in most patients), WTX101 has the potential to address several unmet needs in Wilson’s disease,” said Danny Bega, MD, Assistant Professor of Neurology (Movement Disorders) at Northwestern University’s Feinberg School of Medicine in Chicago, and colleagues.

Wilson’s disease is a rare genetic disorder of impaired copper transport, in which copper accumulates pathologically in the CNS, liver, and other tissues. Current treatments for this disease, such as zinc and chelators (eg, D-penicillamine and trientine), require multiple doses and may be tolerated poorly. To address these challenges, Wilson Therapeutics developed WTX101, an oral first-in-class copper-modulating agent given once daily as monotherapy for Wilson’s disease.

Unlike other treatments for Wilson’s disease, WTX101 appears to have direct intracellular activity in hepatocytes, where it binds excess copper and promotes biliary copper excretion. In addition, WTX101 rapidly binds nonceruloplasmin-bound copper (NCC), thus creating a stable complex with albumin.

Eligible Participants

To evaluate the clinical efficacy and safety of WTX101, as well as the copper control that it enables, in patients with Wilson’s disease, Dr. Bega and colleagues conducted an open-label, single-arm, phase II study at 11 sites in the United States and Europe. Eligible participants were age 18 or older and had been diagnosed with Wilson’s disease based on a Leipzig score of 4. They also had had no prior treatment for Wilson’s disease or 24 months of chelation or zinc therapy. Finally, participants’ NCC levels were within or above the normal reference range (0.8 µM).

Patients received WTX101 for 24 weeks. Researchers used a response-guided dosing regimen with individualized doses of between 15 and 120 mg/day based on NCC levels and safety criteria. In most patients, dosing occurred once daily.

The primary end point was change from baseline to 24 weeks in NCC levels corrected for bound copper contained in tetrathiomolybdate-copper-albumin complexes. Secondary end points included clinical, neurologic, and hepatic assessments.

Of 28 participants involved in the study, 15 were women. The mean age was 34.1. Nine patients were treatment naïve, an additional nine patients had prior treatment for fewer than 28 days, and 10 patients had prior treatment for 28 days to two years. The mean Unified Wilson’s Disease Rating Scale (UWDRS) Part 3 score was 22.8. Three patients had no neurologic abnormalities.

In all, 22 patients completed the 24-week study. Three patients discontinued WTX101 due to liver-related adverse events. Investigators discontinued three patients because of neurologic or psychiatric manifestations. At the end of the study, daily dosages were 15 mg for six patients, 30 mg for 13 patients, and 60 mg for nine patients.

Benefits of Treatment and Adverse Events

WTX101 was associated with rapid improvements in NCC. Mean NCC levels were within the upper limit of normal by week 12. At 24 weeks, 71% of patients met the primary end point of achieving or maintaining normalized levels of NCC or a 25% reduction in NCC from baseline. The mean NCC at baseline was reduced by 72% at week 24.

At week 24, investigators observed significant improvements in trained-rater-assessed neurologic signs, as measured by UWDRS Part 3. The UWDRS Part 3 score improved by 4 points in 13 patients, stabilized in six patients, and deteriorated by 5 points in two patients.

No participants had early paradoxical neurologic worsening. Significant improvement in patient-reported disability was observed at week 24. In addition, the UWDRS Part 2 score improved by 1 point in 12 patients and was unchanged in nine patients. No patient reported deterioration.

The Model for End-Stage Liver Disease (MELD) score remained stable in patients throughout the study, and the mean MELD score was 7.7 ±1.9 at baseline and 7.2 ±1.8 at week 24.

Overall, WTX101 was generally well tolerated. Most adverse events were mild or moderate. Psychiatric and gait disturbance were most likely unrelated to the study treatment. Eleven patients who received 30 mg/day or more had elevated liver function tests. These elevations were mostly mild or moderate and normalized within two weeks after dose adjustments.

“Additional clinical evaluation of WTX101 in a larger controlled trial is warranted to further establish its safety and efficacy for the treatment of Wilson’s disease,” said Dr. Bega and colleagues.

This study was sponsored by Wilson Therapeutics, which is headquartered in Stockholm.

Erica Tricarico

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