Monopar Therapeutics (Nasdaq: MNPR) has announced the publication of Phase II data showing that ALXN1840 (tiomolibdate choline) produced a statistically significant improvement in copper balance in Wilson disease patients. The effects were driven by increased fecal copper excretion — a mechanistic distinction from existing chelation therapies that rely primarily on urinary copper removal.
The data, published in Hepatology Communications, come from the ALXN1840-WD-204 study (NCT04573309), an open-label, single-arm Phase II trial conducted across two centers in the United Kingdom and New Zealand. Nine patients with Wilson disease were admitted to a clinical research unit, placed on a copper-controlled diet, and initiated on daily ALXN1840 dosing. Copper intake and output were collected during a pre-treatment baseline period and throughout multiple weeks of treatment.
The patient population is notable in context: participants had been on standard of care therapy for a mean of 16 years prior to enrollment, suggesting that the residual copper burden being addressed was not a product of treatment naivety but of long-term, inadequately resolved copper accumulation.
Key results
The primary signal was a statistically significant reduction in daily copper balance from baseline. Over 21 days, the cumulative mean decrease in copper balance was −6.08 mg (95% CI: −10.18 mg to −1.98 mg). During the 15 mg/day treatment period specifically, the mean daily copper balance change from baseline was −0.37 mg (p=0.005); across the overall study period, the figure was −0.29 mg (p=0.023).
A secondary finding reinforced the mechanistic picture: daily fecal copper output relative to intake increased by approximately 50% compared to baseline (p=0.041). The trial also recorded immediate increases in plasma total copper and directly measured non-ceruloplasmin-bound copper (dNCC), consistent with copper mobilization and the formation of albumin tripartite complexes (ATCs) — stable structures comprising copper, tiomolibdate choline, and albumin.
ALXN1840 was generally well tolerated across the nine-patient cohort, with no serious adverse events reported.
Mechanism of action
ALXN1840 operates through a distinct mechanism relative to the approved oral copper chelators that currently define Wilson disease treatment. Rather than binding copper for urinary excretion — the approach taken by Orphalan's Cuvrior (trientine tetrahydrochloride) and Bausch Health's Cuprimine (penicillamine) — tiomolibdate choline acts as an ATC activator. It mobilizes excess copper into stable complexes with albumin, suppressing copper's redox reactivity, limiting oxidative damage, and blocking transport across the blood-brain barrier. The fecal excretion route observed in this Phase II data is consistent with that mechanism.
The existing approved landscape for Wilson disease includes penicillamine, trientine dihydrochloride (marketed as Syprine), zinc acetate (Galzin), and trientine tetrahydrochloride (Cuvrior, approved by the US FDA in May 2022). Each of these agents carries meaningful limitations: penicillamine has a well-documented adverse effect profile including nephrotoxicity and autoimmune reactions, and can paradoxically worsen neurological symptoms on initiation; Cuvrior's label is restricted to stable, de-coppered adults previously tolerant to penicillamine; and zinc acetate functions through intestinal copper blockade rather than active removal, limiting its utility in patients with existing copper overload.