Alexion Reports Positive Results from Phase 3 Trial of ALXN1840 in Wilson Disease

Alexion, AstraZeneca Rare Disease said results from the positive FoCus phase 3 trial in Wilson disease showed that ALXN1840, an investigational once-daily, oral medicine, met its primary endpoint demonstrating three-times greater copper mobilization from tissues compared to the standard of care, including in patients who had been treated previously for an average of 10 years.

Photo: Marc Dunoyer, CEO of Alexion Rare Disease

In the trial, people taking ALXN1840 experienced rapid copper mobilization, with a response at four weeks and sustained through 48 weeks. Results from the trial were presented on June 23 at the 2022 International Liver Congress in London.

“These data from the largest global trial in Wilson disease to date show significant copper mobilization from the tissues with ALXN1840, even in patients who were on standard of care for over a decade on average,” said Karl Heinz Weiss, director of the Department of Internal Medicine at Salem Medical Center Heidelberg and investigator in the FoCus phase 3 trial. “These results have the potential to reframe the way doctors can think about the disease given that current therapies focus on removing copper from the blood. We are also encouraged by initial neurological improvement with ALXN1840 in those who were symptomatic and believe that assessing individual patient experiences may provide a better understanding of the impact on daily life.”

Wilson disease is a rare and progressive genetic condition in which the body’s pathway for removing excess copper is compromised. This may result in the accumulation of copper in a person’s liver, brain, or other vital organs. Although the disease is present at birth, the age of diagnosis occurs between five to 35 years. Damage from excess copper build-up in tissues and organs may lead to symptoms of liver, neurological and psychiatric diseases, which may be irreversible. Even after standard of care treatment is initiated, some patients experience worsening of disease, especially of neurologic symptoms.

ALXN1840 is a potential new once-daily, oral medicine in development for the treatment of Wilson disease that is designed to selectively and tightly bind to and remove copper from the body’s tissues and blood.

FoCus is a pivotal phase 3, randomized, controlled, rater-blinded trial designed to evaluate the efficacy and safety of ALXN1840 versus standard of care (SoC) in patients with Wilson disease aged 12 years and older. The primary endpoint assessed copper mobilization over 48 weeks, defined as daily mean Area Under the Effect Curve (AUEC) for directly measured non-ceruloplasmin-bound copper (dNCC). In the trial, 214 patients were enrolled in one of two cohorts on a 3:1 basis (treatment-experienced:treatment-naïve). Each cohort was then randomized 2:1 (ALXN1840:SoC). The first cohort enrolled 161 patients who received SoC (chelation therapy with penicillamine or trientine, zinc therapy or a combination of both chelation and zinc therapy) for more than 28 days and the second cohort enrolled 53 patients who were treatment-naïve or had received SoC for 28 days or less. Key secondary endpoints assessed over the 48-week period included change in neurological function as measured by the Unified Wilson Disease Rating Scale (UWDRS) Part II and III.

Change in neurological scale scores and clinician-reported functional assessments with ALXN1840 treatment were also evaluated in a post-hoc analysis as secondary endpoints in the Phase III trial.

In patients who were symptomatic at baseline, there were greater improvements in neurological scores for those treated with ALXN1840 compared to SoC (Unified Wilson Disease Rating Scale [UWDRS] part II symptomatic ALXN1840 -1.7, SoC -0.8; UWDRS Part III symptomatic ALXN1840 -2.91, SoC -1.31). However, there were no significant differences between treatment groups observed at 48 weeks.

Most patients in the trial had low symptom scores at baseline, so there was minimal room for total score improvement (UWDRS Part II ALXN1840 -0.6, SoC -0.3; UWDRS Part III ALXN1840 -2.20, SoC -1.02). As people with Wilson disease experience a highly varied degree of symptoms, this total score may not reflect the extent of disease severity.

ALXN1840 was well tolerated and the long-term safety and efficacy of ALXN1840 is being assessed in an up to 60-month extension period.

“Many people with Wilson disease continue to experience symptoms even after years of intervention with current therapies, illuminating an urgent need to re-evaluate the standard of care,” said Marc Dunoyer, CEO of Alexion, AstraZeneca Rare Disease. “Alexion has conducted rigorous scientific research to bring fresh thinking to Wilson disease around the importance of copper mobilization from the tissues. These data further our efforts to potentially introduce a novel treatment for patients who have gone decades without meaningful innovation.”

In addition to the phase 3 trial, two ongoing mechanistic trials in Wilson disease are also underway. Alexion is working closely with health authorities worldwide and intends to submit these data for review. ALXN1840 has been granted Orphan Drug designation in the United States and the European Union for Wilson disease.

Author: Rare Daily Staff