Ravulizumab Generates Positive Phase 3 Data in Myasthenia Gravis With FDA Review Pending

James F. Howard, MD

Findings from the phase 3 CHAMPION MG trial (NCT03920293) showed that ravulizumab (Ultomiris; Alexion), a terminal compliment C5 inhibitor, provided rapid and sustained improvement of symptoms in patients with generalized myasthenia gravis (gMG) for up to 26 weeks.¹ The FDA is currently reviewing a supplemental new drug application (sNDA) for the therapeutic in gMG and is expected to make a decision during the second quarter of 2022.²

These data, presented at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, March 13-16, build upon findings previously announced in July 2021. A total of 175 patients enrolled in 85 centers worldwide were randomly assigned 1:1 to receive either ravulizumab infusion or placebo for 26 weeks. Following that period, investigators observed that treatment with ravulizumab was associated with a statistically significant improvement in Myasthenia Gravis Activities of Daily Living (MG-ADL) total score compared with placebo (–3.1 vs –1.4 for placebo; P <.001).

At the time of the original data readout, primary investigator James F. Howard, MD, Distinguished Professor of Neuromuscular Disease, University of North Carolina School of Medicine, said in a statement, “The treatment landscape for people living with gMG has advanced and expanded rapidly in recent years, empowering both patients and caregivers. However, as a clinician and scientist, I know the work is not done. These phase 3 Ultomiris results reinforce the critical role complement inhibition plays in treating gMG."³

In this phase 3, double-blind study, patients on the study drug received body weight-based doses of 2400 to 3000 mg induction on day 1, then 3000 to 3600 mg every 8 weeks on day 15. Patients had anti-acetylcholine receptor antibody-positive (AChR Ab+) gMG and were allowed to be on stable-dose AChR and immunosuppressant therapy throughout the study.

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Quantitative Myasthenia Gravis (QMG) total score, a secondary end point, showed statistically significant improvements following ravulizumab treatment compared with placebo (P <.001). Additionally, the proportion of patients who achieved an improvement of at least 5 points in QMG was also statistically significant relative to placebo (P = .005). Both improvements in MG-ADL and QMG scores were observed within 1 week, with maintenance of benefit through week 26.¹

Additional secondary end points assessing quality of life measures, such as Revised 15-Component Myasthenia Gravis Quality of Life score (P = .064) and Neuro-QOL Fatigue score (P = .373), did not meet statisticalsignificance at week 26. Furthermore, the proportion of patients who achieved an improvement of at least 3 points in MG-ADL score (ravulizumab: 56.7%; placebo: 34.1%; nominal P = .0005) was not considered statistically significant based on hierarchical testing.³

During the randomized controlled period, both groups showed minimal differences in adverse events (AEs), the most frequent being headache (ravulizumab: 18.6%; placebo: 25.8%), diarrhea (ravulizumab: 15.1%; placebo: 12.4%), and nausea (ravulizumab: 10.5%; placebo: 10.1%). Among serious AEs, the most frequent included MG crisis (ravulizumab: 1.2%) and MG worsening (placebo: 3.4%).

Ravulizumab is currently approved in the US for the treatment of adults and children 1 month and older with paroxysmal nocturnal hemoglobinuria. It is also approved in the US and Japan for atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy in adult and pediatric patients, as well as in the European Union for the treatment of adults and children with a body weight of at least 10 kg with aHUS.

Individuals who completed the randomized controlled period were eligible to move on to an open-label extension where they received ravulizumab for an additional 26 weeks. After 52 weeks of treatment, the treatment effects of the therapeutic were sustained. Additionally, patients who received placebo in the randomized controlled period and switched to ravulizumab at the beginning of the open-label extension showed immediate and sustained improvement in MG-ADL and QMG scores in a similar magnitude and time course to that observed in the ravulizumab group during the randomized controlled period.³

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REFERENCES
1. Vu T, Meisel A, Mantegazza R, et al. Efficacy and safety of ravulizumab in anti-acetylcholine receptor antibody-positive generalized myasthenia gravis: phase 3 CHAMPION MG study. Presented at MDA Clinical and Scientific Conference; March 13-16, 2022. Poster 68

2. Ultomiris regulatory submission accepted under FDA priority review in the US for adults with generalized myasthenia gravis. News release. AstraZeneca. December 21, 2021. https://www.astrazeneca.com/media-centre/press-releases/2021/ultomiris-accepted-for-fda-priority-review-for-gmg.html

3. Alexion announces positive topline results from phase 3 study of Ultomiris (ravulizumab-cwvz) in adults with generalized myasthenia gravis. News release. Alexion. July 15, 2021. https://ir.alexion.com/news-releases/news-release-details/alexion-announces-positive-topline-results-phase-3-study