Monopar Begins Rolling NDA Submission for ALXN1840 in Wilson Disease

Monopar Therapeutics has initiated a rolling New Drug Application (NDA) submission to the FDA for ALXN1840 (tiomolibdate choline, also known as bis-choline tetrathiomolybdate), a first-in-class albumin tripartite complex activator for Wilson disease. If accepted and subsequently approved, ALXN1840 would be the first therapy with a novel mechanism of action approved for Wilson disease in the US in decades.¹

"Wilson disease is a serious, lifelong condition, and patients and their families have waited a long time for a new treatment option," Chandler Robinson, MD, chief executive officer of Monopar, said in a statement.¹ "Initiating the rolling NDA submission marks an important milestone in our efforts to bring this novel copper-sequestering therapy to patients." ALXN1840 previously received Fast Track and Orphan Drug designations, and was granted Rare Pediatric Disease designation in June 2026, which carries potential eligibility for a priority review voucher at approval.

Phase 3 FoCus trial design and primary results

The pivotal FoCus trial (NCT03403205) was a randomized, controlled, rater-blinded study that enrolled 214 patients with Wilson disease aged 12 years and older with preserved liver function. Participants were divided into two cohorts based on prior treatment, roughly 3:1 treatment-experienced to treatment-naive, and randomized 2:1 within each cohort to ALXN1840 or standard of care (penicillamine, trientine, zinc, or combination therapy). Of 214 enrolled, 207 were treated: 137 with ALXN1840 and 70 with standard of care.²

The trial met its primary endpoint, mean daily area under the effect-time curve for directly measured non-ceruloplasmin-bound copper over 48 weeks, with ALXN1840 producing copper mobilization roughly 3.2 times greater than standard of care overall (least squares mean difference, 2.18 µmol/L [SE, 0.244]; P < .0001). The effect held even in previously treated patients with a mean prior standard-of-care duration exceeding 10 years, and copper mobilization was rapid, with response detectable by week 4 and sustained through week 48.^2,3

Neurologic and global clinical benefit

New analyses presented at the 2026 European Academy of Neurology (EAN) Congress focused on the subset of FoCus patients with neurologic symptoms at baseline. On the rater-blinded Unified Wilson Disease Rating Scale (UWDRS) Part III, neurologic improvement was statistically significant and continued over time with ALXN1840 (P = .006) but not with standard of care (P = .435), with a greater proportion of ALXN1840-treated patients achieving improvement across multiple response thresholds. Global clinical improvement on the Clinical Global Impression-Improvement (CGI-I) scale at week 48 significantly favored ALXN1840 over standard of care (P < .001), and ALXN1840 produced similar or greater improvement on psychiatric and hepatic measures as well.³

"For Wilson disease patients with neurologic symptoms, meaningful improvement can be difficult to achieve with existing therapies, and some patients experience severe paradoxical worsening," said Aurélia Poujois, MD, PhD, of the Department of Neurology at Adolphe de Rothschild Foundation Hospital in Paris, who presented the EAN analyses.³ "These new analyses from the Phase 3 FoCus trial are encouraging because they show that ALXN1840 treatment was associated with continued neurologic improvement over time and greater global clinical benefit compared with standard of care."

Safety profile

Across phase 2 and phase 3 studies, ALXN1840 has been evaluated in 266 patients representing 645 patient-years of follow-up, with median treatment duration of 2.58 years and maximum exposure exceeding 8 years. Drug-related serious adverse events occurred in 4.9% of patients, including neurologic serious adverse events in fewer than 1%, with no treatment-related deaths reported.³

In the 48-week FoCus data specifically, adverse event rates were 100.1 per 100 patient-years with ALXN1840 versus 86.5 with standard of care, though the large majority in both arms were non-serious (94.1% and 92.7%, respectively); the most frequent adverse event with ALXN1840 was a reversible increase in alanine transaminase, occurring in 14.6% of patients, and no neurologic worsening was observed upon treatment initiation.²

Next steps

Monopar has not disclosed an expected completion date for the rolling submission or an anticipated PDUFA date, which will depend on when the final NDA sections are filed and accepted for review. ALXN1840's mechanism differs from existing chelators: rather than promoting urinary copper excretion, it forms tight complexes with albumin that suppress copper's redox reactivity, limit oxidative damage, block transport across the blood-brain barrier, and increase fecal copper excretion.⁴

REFERENCES
1. Monopar Initiates Rolling NDA Submission for ALXN1840 in Wilson Disease. News release. Monopar Therapeutics Inc. July 22, 2026. Accessed July 23, 2026. https://www.globenewswire.com/news-release/2026/07/22/3331283/0/en/Monopar-Initiates-Rolling-NDA-Submission-for-ALXN1840-in-Wilson-Disease.html
2. Bega D, Weiss K, Schilsky M, Czlonkowska A, et al. Efficacy and safety of ALXN1840 versus standard of care in Wilson disease: primary results from an ongoing phase 3, randomized, controlled, rater-blinded trial. Presented at: 2023 AAN Annual Meeting; April 22-27, 2023; Boston, MA. Abstract 002356. ClinicalTrials.gov identifier: NCT03403205. https://clinicaltrials.gov/study/NCT03403205
3. Monopar Presents New Analyses of Phase 3 FoCus Data at EAN 2026 Showing Greater Neurologic and Global Clinical Benefit with ALXN1840 Versus Standard of Care in Wilson Disease. News release. Monopar Therapeutics Inc. June 26, 2026. Accessed July 23, 2026. https://ir.monopartx.com/press-releases/detail/133/monopar-presents-new-analyses-of-phase-3-focus-data-at-ean
4. ALXN1840. Monopar Therapeutics Inc. Accessed July 23, 2026. https://www.monopartx.com/pipeline/alxn1840