FDA Approves Alexion's Ravulizumab-cwvz for Neuromyelitis Optica Spectrum Disorder
The approval is supported by phase 3 data which showed ravulizumab-cwvz met its primary end point of time to first on-trial relapse, with no relapses observed in 58 patients with NMOSD over a median treatment duration of 73 weeks.
Michael Levy, MD, PhD
Credit: Harvard Medical School
The FDA has approved ravulizumab-cwvz (Ultomiris; Alexion), a terminal compliment C5 inhibitor, for the treatment of patients with anti-aquaporin (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD). With the decision, ravulizumab-cwvz becomes the fourth approved therapy for this patient population, following behind eculizumab (Soliris; Alexion), inebilizumab (Uplizna; Horizon Therapeutics), and satralizumab (Enspryng; Genentech).1
In September 2023, the FDA issued a complete response letter to the company for the supplemental biologics license application (sBLA) of ravulizumab-cwvz for NMOSD. In its response, the agency requested modifications to enhance the Risk Evaluation and Mitigation Strategy program and did not need any additional analysis or reanalysis of the phase 3 CHAMPION-NMOSD study (NCT04201262), the supporting trial for ravulizumab-cwvz’s sBLA.
"Complement inhibition is a very powerful treatment for prevention of NMOSD relapses. Now that ravulizumab-cwvz is approved, it makes it easier for patients to take a once every 2 months infusion rather than once every 2 weeks. The safety issues regarding infections with encapsulated organisms are essentially the same as eculizumab and other complement inhibitors. I am hopeful an improved [Risk Evaluation and Mitigation Strategy] program will help to address those concerns," Michael Levy, MD, PhD, associate professor of neurology at Harvard Medical School and also serves as the chairman for the medical advisor board at The Sumaira Foundation, told NeurologyLive®.
In May 2022, ravulizumab-cwvz met its primary end point of time to first on-trial relapse, with no relapses observed in 58 patients with NMOSD over a median treatment duration of 73 weeks.2 Less than 2 weeks after receiving FDA approval to treat generalized myasthenia gravis (gMG), these data on ravulizumab-cwvz showed benefit in adults with anti-AQP4 antibody-positive NMOSD. The therapeutic demonstrated statistically significant and clinically meaningful reductions in the risk of relapse compared with those on placebo from the external PREVENT trial (NCT01892345), a phase 3 study that evaluated eculizumab.
CHAMPION-NMOSD was an open-label, multicenter trial that evaluated the efficacy and safety of ravulizumab-cwvz in 58 patients with anti-AQP4 NMOSD who had at least 1 attack or relapse in the 12 months prior to the screening visit. These patients also had Expanded Disability Status Scale scores of 7 or less, had body weight of at least 40 kg at trial entry, and were allowed to stay on stable supportive immunosuppressive therapy for the duration of the trial.
On day 1, patients received a single weight-based loading dose of ravulizumab-cwvz, followed by regular weight-based maintenance dosing beginning on day 15, every 8 weeks. The primary end point, time to first on-trial relapse, could have occurred either when all patients completed or discontinued prior to the week 26 visit and 2 or more adjudicated relapses were observed, or when all patients completed or discontinued prior to the week 50 visit if fewer than 2 adjudicated relapses were observed.
Sean J. Pittock, MD
Credit: Mayo Clinic
“C5 inhibition has been proven to offer efficacy in reducing the risk of NMOSD relapses by blocking the complement system, a part of the immune system, from attacking healthy cells in the spinal cord, optic nerve and brain. 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 of Mayo's Neuroimmunology Laboratory, said in a statement.1
Presented at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 26-28, in Amsterdam, Netherlands, data from the phase 3 CHAMPION-NMOSD trial showed ravulizumab-cwvz significantly lowered the risk of relapse and Hauser Ambulation Index (HAI) worsening.2 Ravulizumab-cwvz was originally FDA-approved in 2018 to treat adults with paroxysmal nocturnal hemoglobinuria and was later expanded to include children and adolescents in 2021.
Led by Pittock, the analysis included 58 patients on a weight-based intravenous loading dose of ravulizumab-cwvz (2400-3000 mg) on day 1, followed by weight-based maintenance doses (3000-3600 mg) on day 15 and once every 8 weeks thereafter. Ravulizumab-cwvz binds to the same complement component 5 epitope as eculizumab (Soliris; Alexion), a previously approved therapy for NMOSD, and thus, for ethical reasons, investigators used individuals from the placebo arm (n = 47) of the PREVENT study.
The primary end point of time to first adjudicated on-trial relapse was met in the ravulizumab-cwvz arm, as zero relapses were observed over 84.01 patient-years (PY) of treatment. In comparison, there were 20 adjudicated relapses in the placebo arms over 46.93 PY of treatment, representing a 98.6% relapse risk reduction (RRR) with ravulizumab-cwvz. At 48 weeks, 100% of the patients on ravulizumab-cwvz were relapse free compared with 63% of those on placebo.
In CHAMPION-NMOSD, the median follow-up time was 73.5 weeks for ravulizumab-cwvz and 36.0 weeks for placebo. At the conclusion of the trial, the ARR of 0.00 with ravulizumab-cwvz was superior to both the predefined comparator ARR of 0.25 and the placebo ARR of 0.42 (95% CI, 0.27-0.66; P <.0001). Additionally, only 3.4% of patients on ravulizumab-cwvz experienced clinically important worsening in HAI score compared with 23.4% of those on placebo (odds ratio [OR], 0.16; 95% CI, 0.03-0.77; P = .023).
Similar to what was reported in the initial findings, the safety profile of ravulizumab-cwvz was consistent with previous studies. In the ravulizumab-cwvz and placebo groups, 93.1% and 95.7% of patients, respectively, experienced at least 1 treatment-emergent adverse event (TEAE). Serious AEs were less frequent in the active drug group, with only 13.8% reported compared with 55.3% in the placebo arm. There were no deaths in the study, and 2 vaccinated patients in the ravulizumab-cwvz group reported meningococcal infections; however, both recovered with no sequelae and 1 continued in the trial.
“Alexion has been at the forefront of innovation in NMOSD, striving to offer patients a future without fear of life-altering or even fatal relapses. Building on the established efficacy of C5 inhibition for people living with AQP4 Ab+ NMOSD, we are proud to deliver a transformative, long-acting treatment option that has the potential to eliminate relapses with a convenient dosing schedule every eight weeks. We are grateful to the NMOSD community for their ongoing collaboration and input, which enables us to advance science for rare diseases," Marc Dunoyer, chief executive officer at Alexion, said in a statement.1
