Alexion Reports Positive Late-Stage Results for Experimental Wilson Disease Therapeutic

AstraZeneca rare disease subsidiary Alexion reported positive high-level results from the FoCus phase 3 trial in Wilson disease that showed ALXN1840 met the primary endpoint with a statistically significant improvement in daily mean copper mobilization from tissues and demonstrated superiority compared with standard-of-care treatments.

Photo: Marc Dunoyer, CEO, Alexion

Wilson disease is a rare and progressive genetic condition in which the body’s pathway for removing excess copper is compromised. It affects one in 30,000 live births in the United States. Over time this results in the build-up of toxic copper levels in the liver, brain, and other organs, leading to damage that greatly impacts a patient’s life. Patients can develop a wide range of symptoms, including liver disease and/or psychiatric or neurological symptoms, such as personality changes, tremors, and difficulty walking, swallowing, or talking. In some cases, the damage and loss of function may be irreversible.

ALXN1840 is a potential new once-daily, oral medicine, that Alexion acquired in 2018 when it paid $855 million to buy Swedish biotech Wilson Therapeutics. It is designed to be the first targeted de-coppering therapy that selectively and tightly binds to, and removes, copper from the body’s tissues and blood. ALXN1840 has been granted Orphan Drug designation in the United States and European Union for Wilson disease.

The primary endpoint of the trial gauged the daily mean Area Under the Effect Curve (AUEC) for directly measured non-ceruloplasmin-bound copper (dNCC) over 48 weeks. This novel measure assesses the daily mean copper mobilized from tissues, reflecting the underlying burden of the copper accumulation.

In the trial ALXN1840 demonstrated approximately three times greater copper mobilization compared to standard of care. The trial enrolled 214 patients, including treatment-naïve participants and those who have been on standard of care therapy for an average of ten or more years. Additional analyses, including individual patient-reported outcomes and clinician-reported functional assessments, are ongoing and will be presented at an upcoming medical meeting.

“Where existing treatments remove copper from the blood, these 48-week phase 3 results demonstrate ALXN1840’s significant impact in mobilizing copper from tissues,” said Marc Dunoyer, CEO, Alexion. “As we advance this first innovation in Wilson disease treatment in more than 30 years, we will continue to follow these patients long term to further assess clinical impact on disease symptoms. We look forward to learning more about how we can evolve the treatment of this progressive and devastating disease.”

FoCus is a pivotal, phase 3, randomized, rater-blinded, multi-center clinical trial designed to evaluate the efficacy and safety of ALXN1840 versus standard of care in patients with Wilson disease aged 12 years and older. The primary endpoint assessed copper mobilization, defined as daily mean AUEC for directly measured dNCC over 48 weeks. 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. Patients who completed the primary 48-week treatment period of the trial were offered the opportunity to participate in an up to 60-month extension period to evaluate the long-term safety and efficacy of ALXN1840.

ALXN1840 was generally well-tolerated with most reported adverse events considered mild to moderate, and no neurological worsening upon initiation of treatment was observed. In the ALXN1840 treatment group, the most frequently reported adverse event was a reversible increase in transaminase levels.

“It is encouraging to see the effect of ALXN1840 on both treatment-naïve patients and those who have been on SoC for an average of ten or more years,” said Michael Schilsky, medical director of Adult Liver Transplant at Yale-New Haven Transplantation Center, Yale University, and principal investigator of the FoCus trial. “The phase 3 results provide evidence that tissue-bound copper remains built-up in the organs even in patients who have been on SoC therapy for many years, and the potential for ALXN1840 to provide a new approach to mobilize and safely sequester copper from tissues.”

Alexion is working closely with health authorities worldwide and intends to submit these data for review in the coming months.