Effect of tiomolibdate choline on copper balance in patients with Wilson disease: An open-label phase 2 trial

Background: Wilson disease (WD) is a rare disorder of copper (Cu) disposition. Tiomolibdate choline (TMC, bis-choline tetrathiomolybdate, ALXN1840), an oral Cu-binding agent, was investigated for the treatment of WD. The effect of repeat-dose TMC on Cu balance, serum Cu parameters, and safety was evaluated in an open-label, single-arm phase 2 study in 9 patients with WD. Methods: Enrolled patients with WD were admitted to a clinical research unit (CRU) and initiated on a Cu-controlled diet. Copper intake (food and drink) and output (feces and urine) were collected during a baseline period (days −4 through −1) and after initiation of daily TMC (days 1–8 and 25–39). Patients were allowed to leave the CRU during an interim period (days 9–24) but continued outpatient TMC treatment. Patients started on 15 mg/day TMC on day 1 with planned dose escalation to 30 mg/day TMC on day 29. Results: TMC showed a statistically significant reduction in daily Cu balance from baseline over the entire study period (days 1–39), attributed to increased fecal Cu excretion. The decrease in Cu balance was rapid, with a statistically significant decrease beginning on day 4. The cumulative mean decrease from baseline in Cu balance was −6.08 mg over 21 days. Plasma total Cu and directly measured non-ceruloplasmin-bound Cu levels increased immediately, consistent with Cu mobilization into blood and formation of stable tripartite complexes of Cu, TMC, and albumin. TMC was well tolerated. Alanine aminotransferase elevations that occurred were mild and reversible with dose modulation. Conclusion: TMC’s reduction in Cu balance in WD patients, along with strong mobilization of Cu, supports the therapeutic potential of TMC in WD.