FDA Rejects AstraZeneca’s Ultomiris Label Expansion in NMOSD

AstraZeneca plant_iStock, Roland Magnusson

Pictured: AstraZeneca's production plant in Sweden/iStock, Roland Magnusson

The FDA has denied AstraZeneca’s supplemental application for its C5 complement inhibitor Ultomiris (ravulizumab-cwvz), seeking approval for the treatment of adults with neuromyelitis optica spectrum disorder, the company announced Wednesday.

In its complete response letter, the regulator asked AstraZeneca to improve Ultomiris’ Risk Evaluation and Mitigation Strategy (REMS) and include a background check for patients’ meningococcal vaccination status or require prophylactic antibiotic use before treatment.

There were no issues with AstraZeneca’s efficacy and safety data for Ultomiris, and the FDA did not request additional analyses of its Phase III findings.

AstraZeneca, through its rare disease unit Alexion, will work closely with the FDA to determine how to best adjust the REMS program, according to Wednesday’s announcement by the company.

Ultomiris is a long-acting monoclonal antibody that works by inhibiting the C5 complement protein, which in turn leads to the sustained and complete suppression of the complement cascade. When left unchecked, the hyperactivation of the complement pathway results in an uncontrollable immune response that also ends up attacking healthy cells.

The mechanism of action won Ultomiris its first FDA approval in December 2018 for paroxysmal nocturnal hemoglobinuria. The intravenous treatment has since picked up several other approvals, including atypical hemolytic uremic syndrome in October 2019 and generalized myasthenia gravis in April 2022.

For its latest application, AstraZeneca used data from the Phase III CHAMPION-NMOSD trial, a global open-label study with nearly 60 patients enrolled. To be eligible, neuromyelitis optica spectrum disorder (NMOSD) patients need to have tested positive for anti-APQ4 antibodies and have had at least one attack or relapse within the last 12 months.

In October 2022, AstraZeneca announced that Ultomiris had met the primary endpoint in CHAMPION-NMOSD, leading to a significant and clinically meaningful 98.6% reduction in the risk of relapse, as compared with an external placebo group. At 48 weeks, there were no cases of relapse in the Ultomiris arm, while only 63% of external placebo comparators were relapse-free at this time point.

NMOSD is a rare and debilitating autoimmune disease characterized by the pathologic and excessive activation of the immune system that damages otherwise healthy tissues and cells in the central nervous system. The disorder manifests as vision problems, intense pain, abnormal skin sensations and impaired coordination and movement. At its most severe, NMOSD can lead to loss of vision, paralysis and premature death.

If approved in this indication, Ultomiris will be indicated for the exact same four diseases targeted by its own Soliris (eculizumab). Both are C5 complement inhibitors, working through similar mechanisms of action and each carrying a boxed warning for serious meningococcal infections.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

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