Obinutuzumab β (MIL62) Shows 93.1% Relapse Risk Reduction in Phase 3 Trial for AQP4-IgG+ NMOSD
核心洞察
Obinutuzumab β (搜索) reduced adjudicated relapse risk by 93.1% versus placebo in the phase 3 BeInmost trial, with relapses in 4.4% vs 45.7% of patients (HR=0.069, P<0.0001).
The estimated 52-week relapse-free rate was 94.80% in the obinutuzumab β (搜索) group compared to 28.40% in the placebo group, with consistent benefit across all prespecified subgroups.
Open-label follow-up through May 2026 showed sustained efficacy with a 97.9% relapse risk reduction and no protocol-defined new relapses during extended observation (median 65.57 weeks).
Obinutuzumab β (搜索) (MIL62), a glycoengineered type II anti-CD20 (搜索) monoclonal antibody, reduced the risk of adjudicated relapse by 93.1% compared to placebo in patients with aquaporin-4 (搜索) immunoglobulin G-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (搜索) (NMOSD), according to results from the pivotal phase 3 BeInmost trial published in Nature Medicine.
The randomized, double-blind, placebo-controlled study, conducted at 32 centers across China, enrolled 91 participants between August 2023 and January 2025. At the prespecified event-driven primary endpoint analysis (data cutoff February 21, 2025), adjudicated relapse occurred in two of 45 participants (4.4%) receiving obinutuzumab β (搜索) versus 21 of 46 participants (45.7%) receiving placebo (hazard ratio = 0.069, 95% CI: 0.016–0.296, log-rank P < 0.0001).
"The main finding showed that the therapy met the prespecified primary endpoint," the authors stated, noting that the estimated 52-week relapse-free rate was 94.80% (95% CI: 80.61–98.69) in the obinutuzumab β (搜索) group compared to 28.40% (95% CI: 10.00–50.25) in the placebo group.
Secondary and exploratory outcomes
All prespecified secondary endpoints consistently favored obinutuzumab β (搜索). The adjudicated annualized relapse rate was significantly lower in the treatment group (0.092; 95% CI: 0.022–0.382) versus placebo (1.180; 95% CI: 0.677–2.058), yielding a rate ratio of 0.078 (95% CI: 0.018–0.333, P = 0.0006). Hospitalization due to NMOSD relapse occurred in 4.4% of obinutuzumab β recipients compared to 45.7% of placebo recipients (P < 0.0001).
At the last visit, the Expanded Disability Status Scale (EDSS) score decreased from baseline in the obinutuzumab β (搜索) group (least squares mean change, −0.37; 95% CI: −0.68 to −0.05), while the placebo group showed worsening (LSM change, 0.35; 95% CI: 0.03–0.66), resulting in a between-group LSM difference of −0.72 (95% CI: −1.16 to −0.27, P = 0.0021).
The cumulative number of active MRI lesions was significantly lower with obinutuzumab β (搜索) (0.02 ± 0.149 versus 0.54 ± 0.959, P = 0.0003), and the annualized active lesion rate was 0.048 versus 1.451 (rate ratio = 0.033, 95% CI: 0.004–0.254, P = 0.0010).
Exploratory endpoints further supported clinical benefit. The modified Rankin Scale score showed a between-group LSM difference of −0.37 (95% CI: −0.60 to −0.14, P = 0.0021), and the EuroQol five-dimension visual analog scale score remained stable with obinutuzumab β (搜索) while declining in the placebo group (between-group difference: 9.37; 95% CI: 3.03–15.72, P = 0.0042).
Pharmacodynamics and AQP4-IgG levels
Peripheral CD19+ B cells were rapidly depleted, with 86.0% (37/43) of participants achieving B cell depletion within 24 hours after the first dose. Sustained depletion was observed in more than 87.5% of participants at all subsequent timepoints.
Among the 23 patients who experienced adjudicated relapse during the randomized controlled period (RCP), AQP4-IgG levels were significantly increased from baseline at the time of relapse, with a mean increase of 43.9 U ml⁻¹ (P = 0.0060). In subgroup analyses, the two relapsing patients in the obinutuzumab β (搜索) group showed a mean change of −3.5 ± 4.95 U ml⁻¹, whereas the 21 relapsing placebo patients demonstrated a significant mean increase of 48.6 ± 68.84 U ml⁻¹ (P = 0.0052).
Safety profile
Treatment-emergent adverse events (TEAEs) were reported in 95.6% of obinutuzumab β (搜索) recipients and 95.7% of placebo recipients. Treatment-related adverse events (TRAEs) occurred in 66.7% and 45.7%, respectively. The most frequent TRAEs in the obinutuzumab β group were infusion-related reactions (22.2%), alanine aminotransferase increased (13.3%), lymphocyte count decreased (11.1%), and blood lactate dehydrogenase increased (11.1%).
Grade 3 or higher TRAEs occurred in 6.7% of obinutuzumab β (搜索) recipients and 6.5% of placebo recipients. One death occurred in the obinutuzumab β group: a 50-year-old woman with a 20-year history of severe NMOSD (baseline EDSS 6.5) who developed multiple organ dysfunction syndrome following a relapse treated with high-dose corticosteroids. The event was assessed by the investigator as unrelated to the study drug and attributed to advanced disease, high-dose corticosteroid exposure, and noncompliance.
Open-label extension data
As of May 14, 2026, 90 participants had received at least one dose of obinutuzumab β (搜索) across the RCP and open-label period (OLP), with a median follow-up of 65.57 weeks (95% CI: 57.57–67.14) from first administration. Among all obinutuzumab β-exposed participants, investigator-assessed first clinical relapse events occurred in two cases (2.2%), both during the RCP, with no protocol-defined new relapses during the OLP. Compared to the RCP placebo group, the hazard ratio was 0.021 (95% CI: 0.005–0.093), corresponding to a 97.9% reduction in relapse risk.
Longitudinal assessment of serum AQP4-IgG demonstrated sustained reduction after obinutuzumab β (搜索) treatment, with titers declining from a mean of 54.3 U ml⁻¹ at week 1 to 13.9 U ml⁻¹ by week 79 (P = 0.0156).
Infection-related TEAE rates declined after 52 weeks of treatment (50.5 per 100 person-years from week 53 onward versus 84.7 per 100 person-years overall) and were significantly lower than placebo RCP rates (149.5 versus 84.7 per 100 person-years, P = 0.0228). No new unexpected safety signals were identified.
Study design and limitations
The BeInmost trial employed an intensified first-year dosing schedule with four fixed administrations of 1,000 mg intravenous obinutuzumab β (搜索) on day 1, day 15, week 25, and week 27. All participants received protocol-mandated glucocorticoid bridging therapy consisting of prednisone 20 mg per day for 4 weeks followed by tapering for up to 4 additional weeks.
The authors acknowledged several limitations: the trial was conducted exclusively in China, enrolled only AQP4-IgG-seropositive patients, and the placebo-controlled design precludes direct comparison with other approved therapies. "More mature data from the ongoing OLP, including annualized relapse rates, will be critical to further define the long-term benefit of obinutuzumab β (搜索)," they noted.
Obinutuzumab β (搜索) was granted priority review by China's National Medical Products Administration (搜索) (NMPA) in May 2025 and received approval in February 2026.