Compliment C5 Inhibitors in NMOSD Safe Following Rituximab Use


A recent analysis of the PREVENT and CHAMPION-NMOSD found no significant differences in safety outcomes for patients with AQP4+ NMOSD who were treated with rituximab prior to starting C5 complement inhibitors in specific timeframes.

Michael Levy, MD, PhD, associate professor of neurology at Harvard Medical School

Michael Levy, MD, PhD

A new post hoc analysis of the phase 3 PREVENT (NCT01892345) and CHAMPION-NMOSD (NCT04201262) studies showed no differences in safety outcomes among patients with anti-aquaporin-4 positive neuromyelitis optical spectrum disorder (AQP4+ NMOSD) who were treated with rituximab months prior to starting treatment with a compliment C5 inhibitor (C5IT) such as ravulizumab (Ultomiris; AstraZeneca) or eculizumab (Soliris; Alexion).1

The analysis included 38 patients with AQP4+ NMOSD who received rituximab 3-12 months prior to their first dose of a C5IT from either the PREVENT or CHAMPION-NMOSD trials and 116 patients from the same trials who did not. A mean time of 6.53 months from last rituximab dose to first C5IT dose was recorded (standard deviation, 1.96).

"The main findings from this study are that rituximab does not increase the risk of infections or any complications when switching to complement therapy (eculizumab or ravulizumab) for NMOSD," lead author Michael Levy, MD, PhD, associate professor of neurology at Harvard Medical School, told NeurologyLive®. "There are no differences in adverse effects when comparing people who used complement therapy if they had been on rituximab in the previous 6 months or the previous 12 months compared with those who did not use rituximab recently."

The findings were presented at MSMilan 2023, the joint ECTRIMS-ACTRIMS meeting, held October 11-13, in Milan, Italy, by Levy, research director of the Division of Neuroimmunology & Neuroinfectious Disease at Massachusetts General Hospital, and colleagues. Levy et al noted these results offer important evidence to guide clinical decision-making when considering switching from rituximab to C5IT in this patient population who received rituximab in the preceding 3–12 months.

Clinical Takeaways

  • The new post hoc analysis suggests that the timing of switching from rituximab to C5 complement inhibitors (C5IT) does not significantly impact safety outcomes for patients with AQP4+ NMOSD.
  • Patients with AQP4+ NMOSD who received rituximab in 1 year prior to the enrollment of the study showed a consistent safety profile during the transition to C5IT.
  • Evaluating safety outcomes during transitions from rituximab to C5IT is crucial as patients often switch to more effective therapies to prevent future relapses.

The analysis included patients from both PREVENT and CHAMPION-NMOSD, phase 3 studies that evaluated safety and efficacy of eculizumab and ravulizumab, respectively, in adult patients with AQP4+ NMOSD. Patients who received rituximab less than 3 months within screening were not permitted to enroll in either trial. Investigators assessed safety outcomes including treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and deaths or withdrawals because of TEAEs.

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The incidence of reported TEAEs (PREVENT, 94.7%; CHAMPION-NMOSD, 90.5%) and TESAEs (PREVENT, 21.2%; CHAMPION-NMOSD, 24.1%) among patients with AQP4+ NMOSD was similar in both study groups. The majority of adverse events were mild or moderate in severity and were analyzed by investigators as unrelated to C5IT. The most common type of TEAE in both groups was infections and infestations (PREVENT, 71.1%; CHAMPION-NMOSD, 71.6%).

In the 1 year prior to enrollment treated with rituximab group, no deaths were reported, and no patients experienced a TEAE or TESAE leading to withdrawal of C5IT. When researchers analyzed the time since the last rituximab use, no differences in TEAE or TESAE incidence rates were observed in patients who had rituximab between 3 and 6 months of receiving C5IT compared with those who received rituximab in between 9 and 12 months.

"The implications for this research is to reassure neurologists and simplify the process for patients with NMOSD who are switching to complement therapy from B cell therapy (like rituximab). There are no additional studies planned in this group. There is no concern, so there is nothing to fix," Levy told.

Rituximab is often prescribed as an off label in early lines of therapy for patients with AQP4+ NMOSD. For more context, the serum half life and duration of action with ravulizumab is prolonged compared with eculizumab as a result of 4 amino acid substitutions into the frame of eculizumab that augments endosomal pH-dependent C5 binding and enhances recycling. Despite this effective treatment, authors noted that patients frequently need to be transitioned to more efficacious therapies such as C5ITs to prevent future relapses. Therefore, researchers recommended the important consideration of safety outcomes in patients who transition from rituximab to C5IT as conducted in this new analysis.

Click here for more coverage of MSMilan 2023.

1. Levy M, Parks B, Allen K, et al. Safety Findings in Patients With AQP4+ NMOSD Who Received Eculizumab or Ravulizumab in the PREVENT and CHAMPION-NMOSD Studies and Had Received Rituximab Within 1 Year Prior to Enrolment. Presented at: 2023 MSMilan; October 11-12; Milan, Italy. Abstract P378.

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