Statistically significant neurological improvement on the Unified Wilson Disease Rating Scale Parts II and III was sustained for up to six years in pooled analyses of ALXN1840 (tiomolybdate choline), based on three independent trials totaling 255 patients. Psychiatric outcomes improved as measured by the Brief Psychiatric Rating Scale over multiple years. In patients who crossed over from standard of care to ALXN1840, additional neurological gains were observed, including reversal in a majority who had previously worsened on standard therapy. Across more than 645 patient‑years of exposure, fewer than 1% of patients experienced drug‑related serious neurological adverse events. Median treatment duration was approximately 2.6 years for both efficacy and safety cohorts, with safety drawing from a fourth independent trial (n=266).
Monopar will present the long‑term neurological efficacy and safety dataset at the American Neurological Association Annual Meeting, following the company’s recent disclosure of long‑term hepatic and systemic results at EASL. The sequencing underscores a push to position ALXN1840 across the two clinical poles that define Wilson disease burden: neurologic dysfunction and hepatic injury. The company highlights consistency of neurological benefit across independent studies, a crossover effect favoring ALXN1840 after standard therapy, and a tolerability profile that avoids the neurological destabilization that has historically complicated copper‑modulating treatments.
Strategically, this is a repositioning of an advanced asset around patient‑centric, functionally meaningful endpoints and durability, rather than surrogate copper metrics. The pooled, long‑horizon signal appears designed to reset the narrative for regulators and clinicians by emphasizing sustained neurologic benefit, psychiatric stabilization, and safety over years of therapy. The crossover findings are particularly pointed: they frame ALXN1840 as a rescue option for patients who deteriorate on chelators, while also offering a pragmatic trial construct that can support both ethical equipoise and retention in a rare disease. The choice of UWDRS and BPRS foregrounds scales that matter to daily function and caregiver burden, but they will invite scrutiny on rater consistency and clinically meaningfulness thresholds.
For sites, the operational requirement is clear: neurologic and psychiatric rater training, centralized calibration, and long-term follow-up infrastructure will be pivotal. Centers of excellence may be advantaged given the need for stable rater pools and multi‑year retention, while community sites could need vendor support for ePRO capture of UWDRS Part II and psychiatric assessments. CROs will need robust scale management, blinded adjudication, and data quality plans tuned to functional endpoints rather than lab‑heavy readouts. Regulators will weigh the strength of pooled, multi‑study analyses against the expectation for prospective, randomized evidence in a heterogeneous, fluctuating disease; the consistency across studies helps, but endpoint selection and early‑worsening mitigation will be central to any registrational dialogue.
What comes next hinges on Monopar’s pivotal strategy: whether it pursues a randomized design with a delayed‑start or crossover component, anchors the primary endpoint on UWDRS change with predefined minimal clinically important differences, and integrates hepatic measures as key secondary endpoints. Acceptance of psychiatric outcomes as supportive evidence could become a differentiator, but only if rater variability is tightly controlled. Watch for regulatory feedback on endpoint hierarchy, plans to manage early neurological destabilization at initiation, and the company’s ability to assemble a global network of Wilson disease sites capable of multi‑year retention. Competition from entrenched chelators and payer expectations for head‑to‑head or switch data will shape adoption. The durability signal is encouraging; the open question is whether it can be converted into a prospectively powered, regulator‑aligned package in a small, dispersed patient population.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
