Ravulizumab's Effective and Safe in AQP4+ NMOSD Regardless of Prior Rituximab Use

A new post hoc analysis of the CHAMPION-NMOSD trial (NCT04201262) revealed that ravulizumab-cwvz (Ultomiris; Alexion) treatment was associated with sustained disease control and a manageable safety profile in patients with aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD), regardless of prior exposure to rituximab. The findings, published in the Multiple Sclerosis Journal, showed no adjudicated relapses during treatment with ravulizumab-cwvz in either subgroup.¹

In this analysis of 58 patients, 36.2% were previously exposed to rituximab and 63.8% were rituximab-naïve. The mean age was 48.2 (SD, 13.4) years in the rituximab-exposed cohort and 47.0 (SD, 14.3) years in the rituximab-naïve cohort, with 66.7% and 51.4% of patients aged 45 years or older, respectively. Prior to ravulizumab-cwvz initiation, 57.1% rituximab-exposed patients experienced a relapse between their first rituximab dose and study entry.

Prior efficacy data from the trial showed that there were no patients that had adjudicated relapses with ravulizumab-cwvz versus 20 with placebo (relapse risk reduction [RRR], 98.6%; P <.0001). The annualized relapse rate (ARR) of those on the therapy was 0.00 (upper 95% CI, 0.04), which was superior to a predefined comparator ARR (0.25; P <.0001). There were fewer patients who experienced clinically important Hauser Ambulation Index score worsening with ravulizumab (2 out of 58 patients; 3.4%) compared with placebo (11/47; 23.4%; P = .023), demonstrated by odds ratio of 0.16 (95% CI, 0.03–0.77).³

“The results of this post hoc analysis support consideration of ravulizumab for patients previously treated with [rituximab] and may inform future research aimed at advancing personalized treatment strategies for patients with NMOSD,” lead author Jeffrey L. Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, and colleagues wrote.¹ “Future work should include observational studies and real-world data analyses to characterize long-term outcomes after treatment transitions, as well as biomarker-based investigations of immune reconstitution to refine sequencing strategies and timing between [rituximab] and complement inhibition.”

CHAMPION-NMOSD was a phase 3, multicenter, externally controlled, open-label interventional study evaluating the safety and efficacy of ravulizumab-cwvz in adults with AQP4-Ab+ NMOSD.³ All enrolled patients from CHAMPION-NMOSD were included in this analysis, with data analyzed through June 14, 2024. Patients were administered weight-based intravenous ravulizumab-cwvz, consisting of a loading dose followed by maintenance dosing every 8 weeks, and were stratified by prior rituximab exposure. Key assessed outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), relapse rates, and vaccination timing relative to the last rituximab dose.

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Most patients in both cohorts experienced at least 1 TEAE, the majority of which were mild or moderate and not considered related to ravulizumab-cwvz. TESAEs occurred in 28.6% of rituximab–exposed patients and 24.3% of rituximab -naïve patients, with most events similarly assessed as unrelated to treatment. In the rituximab -exposed group, infections and infestations accounted for the highest proportion of TESAEs (14.3%), with 3 events occurring in 3 separate patients, whereas in the rituximab-naïve group, infections and infestations were reported in 10.8% of patients, also with each event occurring in a different individual.

All told, the proportion of patients experiencing at least 1 TEAE was similar between rituximab-exposed and rituximab-naïve groups (95.2% vs 94.6%). Among TEAEs occurring in at least 10% of the overall cohort, COVID-19 was most frequently reported (48.3%), followed by headache (32.8%) and urinary tract infection (UTI; 17.2%). UTIs were reported more often in rituximab-exposed patients compared with rituximab-naïve patients (33.3% vs 8.1%), and all events were nonserious and grade 1–2 in severity. In contrast, COVID-19 (54.1% vs 38.1%) and back pain (18.9% vs 4.8%) were more commonly reported in rituximab-naïve patients.

Among 21 patients with prior rituximab exposure, vaccination timing was also evaluated, with 19 receiving their first meningococcal vaccination after rituximab. The mean time from last rituximab dose to first vaccination was 5.58 (SD, 3.78) months (range, 2.7–19.9). Most patients (68.4%) were vaccinated in 6 months of their last dose, including 15.8% in 3 months and 52.6% between 3 and 6 months, whereas 31.6% received vaccination more than 6 months after their last rituximab dose.

“This retrospective analysis introduces certain inherent limitations, including small sample size, heterogeneity in [rituximab] washout intervals, and potential confounding from prior and concomitant therapies. The study was not powered for between-group comparisons and results should be interpreted descriptively,” Bennett et al noted.¹ “Despite these constraints, this remains the largest controlled-trial cohort of [rituximab]-exposed patients initiating ravulizumab.”

REFERENCES
1. Bennett JL, Bhattacharyya S, Zabeti A, et al. Safety and efficacy of ravulizumab in patients with NMOSD previously treated with rituximab: A post hoc analysis of the CHAMPION-NMOSD trial. Mult Scler. 2026;32(4):396-408. doi:10.1177/13524585261425076
2. Pittock S, Barnett M, Bennett J, et al. Efficacy and safety of ravulizumab in adults with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: outcomes from the phase 3 CHAMPION-NMOSD trial. Presented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts. Abstract 002.
3. 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