FDA Approves Ravulizumab-cwvz for Rare Autoimmune Disease

On Monday, the FDA approved a label expansion for AstraZeneca’s complement inhibitor ravulizumab-cwvz (Ultomiris) for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients with anti–aquaporin-4 (AQP4) antibodies, according to a news release.¹

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The approval makes ravulizumab the first and only long-acting C5 complement inhibitor for this indication and is supported by data from the phase 3 CHAMPION-NMOSD trial (NCT04201262), published in the Annals of Neurology.²

NMOSD is a rare and severely disabling autoimmune neuroinflammatory disease of the central nervous system, affecting around 6000 individuals in the US.¹ The condition is characterized by recurrent, unpredictable relapses that may result in irreversible neurologic disability, as it most often affects the spine and optic nerves. Additionally, NMOSD can manifest as weakness in the limbs, painful spasms, uncontrollable vomiting, bowel dysfunction, and sleeping problems.

In the study, the researchers aimed to evaluate the safety and efficacy of ravulizumab, which binds the same complement component 5 epitope as the approved therapeutic eculizumab, but has a longer half-life.² This allowed for an extended dosing interval of 8 weeks instead of 2 weeks.

Patients received weight-based intravenous ravulizumab on day 1 of the study, maintenance doses on day 15, and then once every 8 weeks. Additionally, the researchers measured for safety, including adverse events, clinical laboratory parameters, vital-sign measurements, electrocardiogram parameters, and evaluation for the presence of suicidal ideation or behavior.

In total, 58 patients from 36 sites across 11 countries were enrolled in the study and received ravulizumab between December 1, 2019, and March 15, 2022. The placebo group included 47 patients who were enrolled between April 2014 and October 2017.

The study met its primary efficacy end point, preventing relapse in all patients over a median follow-up period of 73.5 weeks, compared with patients in the placebo arm who experienced 20 relapses. In relative arms of the study, ravulizumab reduced the risk of relapse by 98.6% (HR, 0.014; 95% CI, 0.000-0.103) compared with placebo.

Additionally, an exploratory analysis of physician-determined relapses found the HR of the primary end point for ravulizumab compared with placebo was 0.039 (95% CI, 0.009-0.164), which represented a 96.1% (95% CI, 83.6-99.1) reduction in risk of relapse (P < .0001).

Furthermore, the proportion of patients who were free from physician-determined relapses at week 48 was 0.965 in the ravulizumab arm and 0.506 in the placebo arm.

Ravulizumab was well tolerated in terms of safety, and most treatment-emergent events were mild or moderate in severity. However, 2 patients developed meningococcal infections, both of whom recovered with no sequelae. No deaths were reported due to treatment toxicities.

However, the researchers acknowledged some limitations to the study, including potential bias due to the unblinded nature of the study as well as potentially missed relapses.

Despite these limitations, the researchers believe the study found that ravulizumab significantly reduced the risk of relapse compared with placebo.

“Current risk mitigation strategies, including vaccination, education, and ongoing vigilance, are effective in managing the increased risk of meningococcal infection conferred by C5 inhibition,” wrote the researchers. “Building on existing experience with eculizumab in this setting, ravulizumab represents a potential new therapy for adults with AQP4+ NMOSD that combines strong efficacy, a well-established safety profile, and an 8-week dosing interval.”

"With today’s FDA approval, patients now have the option of a long-acting C5 inhibitor treatment that showed zero relapses in the pivotal CHAMPION-NMOSD trial, supporting the primary goal of relapse prevention in treating NMOSD,” Sean J. Pittock, MD, director of Mayo Clinic's Center for Multiple Sclerosis and Autoimmune Neurology and lead primary investigator in the CHAMPION-NMOSD trial, said in the news release announcing ravulizumab's approval.¹

References

1. Ultomiris approved in the US for the treatment of adults with neuromyelitis optica spectrum disorder (NMOSD). News release. AstraZeneca. March 25, 2024. Accessed March 28, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/ultomiris-approved-in-the-us-for-nmosd.html

2. Pittock SJ, Barnett M, Bennett JL, et al. Ravulizumab in aquaporin‐4–positive neuromyelitis optica spectrum disorder. Ann Neurol. 2023;93(6):1053-1068. doi:10.1002/ana.26626