ALXN1840 generates rapid, sustained copper mobilization in Wilson disease

In individuals with Wilson disease (WD), a rare disease of copper metabolism, ALXN1840 led to significantly greater copper mobilization compared with standard of care (SoC), findings from a rater-blinded phase III study have shown.

“ALXN1840 is the first novel targeted de-coppering therapy that selectively and avidly binds copper in a tripartite complex to remove copper from the body’s tissues and blood … [In our study,] ALXN1840 rapidly mobilized copper and the effect was maintained throughout the 48-week study period,” said Dr Frederick Askari from the University of Michigan Health System, Ann Arbor, Michigan, US, at AASLD’s The Liver Meeting 2022.

The primary endpoint of mean daily dNCC AUEC* was markedly increased with ALXN1840 vs SoC in the total population (3.12 vs 0.79; p<0.0001). “An increase in dNCC reflects the extent of copper mobilized from stores … ALXN1840 mobilizes additional copper stores even after years of prior SoC treatment,” Askari noted.

Two cohorts were formed after screening participants for the trial. Cohort 1 comprised previously treated (treatment-experienced) patients who received SoC** for >28 days. Cohort 2 included the newly diagnosed group who were either treatment-naïve or pretreated with SoC for ≤28 days. Following which, patients were randomized to either ALXN1840 (n=137) or SoC (n=70). [The Liver Meeting 2022, abstract 156]

 

Secondary efficacy endpoints

“Baseline UWDRS*** Parts II and III scores were low, suggesting mild neurologic disease,” said Askari. Part II scores were patient/caregiver reported, while Part III was reported by a neurologist based on blinded neurologic examinations.

For Part II scores, comparisons between ALXN1840 and SoC were not significantly different in both symptomatic (mean, 8.9 vs 7.2) and overall cohorts (mean, 3.9 vs 3.5). At week 48, there were trends toward modest improvements in scores for symptomatic patients at baseline as opposed to the overall study cohort, noted Askari.

Part III scores were also not significantly different between the ALXN1840 and SoC groups, both in the overall cohort (mean, 15.8 vs 11.5) and the subgroup of symptomatic patients (mean, 20.0 vs 14.2).

CGI-I^# scores improved at week 48 with ALXN840 than SoC. “Low baseline CGI-I scores indicate that patients were mildly ill … Greater CGI-I score reduction from baseline indicates greater symptom improvement,” Askari said.

“No significant differences were observed in CGI scores when adjusting for multiplicity. When not adjusting for multiplicity however, CGI scores were significantly improved with ALXN1840 vs SoC at 48 weeks,” he continued.

 

Safety

Despite having more adverse events (AEs) in the ALXN1840 vs the SoC arm (87 percent vs 77 percent), most were not serious or quickly resolved, and were deemed unrelated to the intervention.

ALT^## increase was the most common AE tied to ALXN1840 (15 percent), but this aligned with phase II evidence. “ALT events typically occurred in the first 4–12 weeks of therapy … Events were generally mild to moderate, asymptomatic, reversible, and manageable through dose reduction and/or temporary dose interruption,” Askari explained.

Over 48 weeks, ALXN1840 demonstrated an acceptable safety profile and was well tolerated.

 

Tightly binds copper

High treatment discontinuation and low treatment adherence rates have been reported with currently available drugs for the treatment of WD, owing to tolerability and efficacy issues. “One of the big advantages of ALXN1840 is that it not only forms a stable tripartite complex, but it also binds copper more tightly and at a higher affinity than currently available drugs,” said Askari.

The extension phase is underway to evaluate the longer-term effects of ALXN1840 on patients with WD. “In the first 48 weeks, you might not expect to see such a substantial change … so we are excited to be monitoring these patients in the 5-year follow-on extension phase, where further neurologic recovery [may] occur,” said Askari.