In the Phase 2 ALXN1840-WD-204 copper balance study in Wilson disease, tiomolybdate choline (ALXN1840) produced a rapid and sustained reduction in daily copper balance versus pre-treatment baseline in eight patients, driven primarily by increased fecal copper excretion. The improvement was observed during the initial 15 mg once-daily period through day 28 and persisted over the total treatment window to day 39, which included either 15 mg every other day or 30 mg once daily.
The core development is a data refresh at AASLD that re-centers ALXN1840 on a hard pharmacodynamic readout tied directly to its mechanism of action. Monopar highlighted new nonclinical and clinical supporting analyses alongside the Phase 2 signal, positioning the asset—originally advanced under the ALXN code—for late-stage discussions. While numerical effect sizes and safety rates were not provided, the dataset underscores the drug’s intended mode of copper control via gastrointestinal binding and excretion rather than systemic chelation.
Strategically, the move reads as a targeted repositioning. By emphasizing copper balance and fecal excretion, Monopar is leaning into a mechanistic narrative that distinguishes tiomolybdate choline from penicillamine and trientine, and that could sidestep concerns about rapid copper mobilization in the early treatment period. It also suggests a path to a pragmatic registrational design grounded in reproducible PD endpoints, potentially stitched to clinical outcomes. The tension is clear: regulators have grown less tolerant of surrogate-heavy packages without concurrent functional benefit, yet biomarker-led strategies remain attractive in rare metabolic diseases to streamline trial size and duration. With gene therapy programs encroaching on the Wilson disease landscape, a small-molecule option that can demonstrate tight copper control with manageable monitoring could compete on operational simplicity—if clinical benefit and safety hold.
For sites, the implications are concrete. Copper balance work requires standardized stool and urine collection, rigorous handling, and centralized quantification—logistics that favor experienced metabolic centers and vendors with validated assays and chain-of-custody processes. Short-interval sampling and dose adjustments across 15 mg daily, every-other-day, and 30 mg regimens add coordination complexity. Still, they may reduce patient burden if a less-than-daily schedule proves viable. CROs with rare disease footprints and central labs with capacity for high-variability matrices will be central to execution. For sponsors and payers, the key question is translatability: does improved copper balance at one month predict neurologic and hepatic outcomes that matter clinically, and can those be demonstrated within a timeframe suitable for review and reimbursement? In the absence of detailed safety reporting, sites and regulators will closely examine for copper deficiency, hematologic shifts, and hepatic lab trends that have historically shaped tetrathiomolybdate risk management.
Next steps will hinge on regulatory dialogue around endpoint hierarchy. A viable registration plan will likely require a composite of PD and clinical measures—neurologic scales, hepatic function tests, and possibly patient-reported outcomes—alongside 24-hour urinary copper. Comparator selection and patient mix (treatment-naïve versus stable on chelation) will determine both feasibility and interpretability. Funding and partnering are nontrivial, given the specialized site network and assay infrastructure required. Watch for clarity on dose selection, a safety cut with longer follow-up, and whether Monopar seeks parallel scientific advice to align FDA and EMA on surrogate acceptability. With gene therapy programs advancing and generics entrenched, the bar is moving; ALXN1840’s route to approval will depend less on PD elegance and more on whether that copper balance translates into durable, measurable clinical benefit without creating new monitoring burdens for sites.
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.
