Oreja‐Guevara, Celia

Objective CHAMPION‐NMOSD (NCT04201262) is a phase 3, open‐label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with anti–aquaporin‐4 antibody–positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half‐life, enabling an extended dosing interval (8 vs 2 weeks). Methods The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION‐NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight‐based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on‐trial relapse. Results The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient‐years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient‐years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%–100.0%, p < 0.0001). Median (range) study period follow‐up time was 73.5 (11.0–117.7) weeks for ravulizumab. Most treatment‐emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment. Interpretation Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications. ANN NEUROL 2023;93:1053–1068

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

During PREVENT (a phase 3, randomized, double-blind, placebo-controlled, time-to-event study) and its open-label extension (interim analysis), 33 adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD) received eculizumab monotherapy for a median of 2.8 years (range, 14 weeks–5.2 years). At 192 weeks (~4 years), 96% of these patients were free from adjudicated relapses (Kaplan–Meier analysis; 95% confidence interval, 75.7–99.4). During PREVENT, 95% (20/21) of patients receiving eculizumab monotherapy had no disability worsening. Eculizumab monotherapy provides effective long-term relapse prevention, relieving the chronic immunosuppression burden in patients with AQP4-IgG + NMOSD. ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144.

ObjectiveDuring PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin‐4 immunoglobulin G‐positive neuromyelitis optica spectrum disorder (AQP4‐IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open‐label extension (OLE; NCT02003144) evaluating eculizumab's long‐term safety and efficacy.MethodsPatients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.ResultsAcross PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient‐years (PY). Treatment‐related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab‐treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse‐free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab‐treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.InterpretationThis analysis demonstrates that eculizumab's long‐term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long‐term eculizumab treatment to reduce relapse risk in patients with AQP4‐IgG+ NMOSD. ANN NEUROL 2021;89:1088–1098