Tiomolibdate choline in neurologic Wilson disease: Insights from the Phase 3 FoCus trial

Prof. Peter Hedera discusses the potential of tiomolibdate choline to improve neurologic outcomes and reduce deterioration risk in Wilson disease.

Neurologic worsening remains one of the greatest treatment challenges in Wilson disease, where delayed diagnosis and paradoxical deterioration during therapy can result in irreversible disability.

At American Academy of Neurology 2026, Prof. Peter Hedera (Raymond Lee Lebby Endowed Chair of Parkinson’s Disease Research and Director of the Movement Disorders Program, University of Louisville, Louisville, KY, USA), joined us to discuss findings from the Phase 3 FoCus trial evaluating tiomolibdate choline (TMC) and its potential role as a first-line treatment option for neurologically affected patients living with Wilson disease.

Presented at AAN 2026: Greater Clinical Benefit with Tiomolibdate Choline Versus Standard-of-care in Neurologic WD Patients in the Phase 3 FoCus Trial. LS1: Late-breaking Science 1. April 18-22, Chicago, USA.

Could you briefly outline the current treatment challenges in Wilson disease, particularly for patients presenting with neurologic symptoms?

Wilson disease is a chronic copper overload disorder caused by mutations in the ATP7B gene, one of the main copper transporters in the body. It is an autosomal recessive disorder, meaning both gene copies have loss-of-function mutations, leading to chronic copper accumulation and subsequent copper toxicity.

Presentation can vary between neurologic and hepatic disease, although the overall principles of treatment are relatively similar in both groups. However, there are some specific challenges in neurologically affected patients.

Current standard-of-care treatment includes copper-chelating agents. Two FDA-approved agents are currently available: penicillamine and trientine. There are different formulations of trientine, including tetrahydrochloride trientine, which is a more recent addition with some practical advantages over classic trientine preparations.

Chelating agents work by binding excess copper, particularly non-ceruloplasmin-bound copper, sometimes referred to as free copper, which is biologically available and potentially toxic. The chelated copper is then excreted through the urine. These medications can be very effective and have saved many lives. However, some patients still do not achieve ideal outcomes.

One major challenge is that both hepatic and neurologic presentations are often nonspecific, which can delay diagnosis. The longer the delay, the less favorable the outcomes may be.

A particularly important issue in neurologically affected patients is paradoxical neurologic worsening during treatment. Patients may initially present with tremor, dystonia or parkinsonism and, despite appropriate therapy, can experience further deterioration that may become irreversible. This can be devastating and is estimated to occur in around one-fifth to one-quarter of patients. The risk appears somewhat higher with penicillamine, although it can occur with both chelating agents.

One leading mechanistic explanation is that treatment can transiently increase non-ceruloplasmin-bound copper levels, potentially increasing copper-related neurotoxicity during the early treatment period.

What makes tiomolibdate choline’s mechanism of action different from existing copper-lowering therapies, and why might that matter clinically?

Tiomolibdate choline is a first-in-class investigational therapy that works by forming stable tripartite complexes between copper, the medication itself and albumin.

These complexes tightly bind and sequester toxic non-ceruloplasmin-bound copper. One of the major potential advantages of TMC is its ability to rapidly normalize toxic copper levels while tightly controlling free copper exposure.

Unlike traditional chelators, which can transiently increase free copper levels, TMC may reduce the risk of paradoxical neurologic worsening through more stable copper sequestration. It is also a once-daily oral medication, which could provide practical advantages for patients.

Could you explain the design of the Phase 3 FoCus trial and the key findings?

Because Wilson disease is a treatable condition, a placebo-controlled design was not appropriate. The FoCus trial therefore compared TMC against standard-of-care treatment.

A total of 207 patients were enrolled. Of these, 137 were randomized to TMC and 70 received standard-of-care therapy with chelating agents. Treatment duration was 48 weeks, with an optional 5-year extension phase for patients receiving TMC.

The primary focus of the study was copper homeostasis, assessed through measures such as urinary copper excretion and non-ceruloplasmin-bound copper levels. The study included both treatment-naive patients and treatment-experienced patients who were already receiving standard therapies.

In addition to copper control, there were important neurologic findings. Patients were evaluated using the Unified Wilson’s Disease Rating Scale, a structured neurologic assessment tool similar in concept to the Unified Parkinson’s Disease Rating Scale.

At 48 weeks, among neurologically affected patients receiving standard of care, 32% improved and 25% worsened. In contrast, among patients receiving TMC, 45% improved and only 10% worsened.

There was also evidence of continued improvement over time in the TMC-treated group, suggesting that neurologic recovery may continue with ongoing therapy. This is particularly important because many patients present after symptoms have already been present for several years, raising questions about how much neurologic dysfunction is reversible.

The benefits were observed in both treatment-naive and treatment-experienced patients, although the effect appeared even more pronounced in treatment-naive patients. Importantly, there was minimal evidence of paradoxical neurologic worsening in the TMC group.

What do these findings suggest about the potential of TMC to improve outcomes while reducing the risk of deterioration?

This is really the key question. We already know that standard-of-care therapies work and have transformed outcomes in Wilson disease. However, these findings suggest that TMC could provide a better option, particularly for neurologically affected patients.

The study suggests that TMC may offer superior neurologic outcomes with a much lower risk of paradoxical worsening. Given that neurologic deterioration can occur in up to one-quarter of patients receiving standard chelation therapy, reducing this risk would represent a major clinical advance.

These data support the possibility that TMC could become a preferred first-line treatment option, especially in patients presenting with neurologic disease.

If approved, could TMC redefine first-line treatment in neurologic Wilson disease, and how do you see it fitting into future clinical practice?

That would certainly be my hope. Based on these data, I believe TMC could become a preferred first-line treatment, particularly for neurologically affected patients because of the lower risk of worsening.

There are also practical advantages. Standard chelating therapies are often taken multiple times daily and usually require separation from food by several hours, which can make adherence difficult. TMC is a once-daily medication taken with food, which could simplify treatment and potentially improve long-term adherence.

Overall, the combination of favorable neurologic outcomes, lower deterioration risk and simplified dosing makes TMC a potentially very attractive future treatment option in Wilson disease.

What do you think were the most important therapeutic and treatment updates presented at AAN 2026?

There were many important updates this year. In movement disorders and neurodegeneration, one particularly interesting development was tavapadon for Parkinson’s disease. This selective D1 agonist appears to offer robust motor benefit with potentially improved tolerability compared with traditional dopamine agonists, including lower risks of impulse control disorders and hallucinations.

There was also major interest in cell-based therapies for advanced Parkinson disease. Large ongoing clinical trials are evaluating whether transplanted cells can provide both symptomatic benefit and potential neuroprotective effects, which could significantly change the treatment paradigm.

Outside movement disorders, there were also important developments in neuroimmunology, particularly Fc receptor-targeted therapies for conditions such as Myasthenia gravis and Chronic inflammatory demyelinating polyneuropathy.

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