Phase 3 Topline Results Show Rituximab Noninferior to Cladribine in Reducing New or Enlarging Brain Lesions in Relapsing-Remitting MS

New late breaking data presented at the 2025 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 24-26, in Barcelona, Spain, from the phase 3 NOR-MS trial (NCT04121403) showed that rituximab was noninferior to cladribine for limiting new or enlarging brain lesions, and potentially superior in efficacy among patients with active relapsing-remitting multiple sclerosis (RRMS) over 96 weeks.¹

Among 265 patients with RRMS in the primary analysis, only 3% of patients who received rituximab developed at least 1 new or enlarging T2 MRI lesion at 96 weeks (n = 4), compared with 17% of those treated with cladribine (n = 17). Patients in the rituximab arm had a mean number of new or enlarging T2 MRI lesions of 0.05 lesions (SD, 0.30) compared with 0.46 lesions (SD, 1.77) in the cladribine arm. The adjusted mean difference in lesion counts favored rituximab (–0.356; 95% CI, –0.577 to –0.135), meeting the prespecified noninferiority margin of 0.3 and falling in a range consistent with superiority.

NOR-MS was a prospective, randomized, open-label, blinded-end point multicenter trial conducted in Norway. The study enrolled 269 patients with active RRMS between October 2019 and August 2022 to directly compare rituximab and cladribine. Participants were aged 18 to 65 years, had an Expanded Disability Status Scale (EDSS) score of 5.5 or lower, and demonstrated active RRMS. Among those included in the primary analysis, the majority were treatment naïve (65%), had a mean age of 38.4 years (range, 18-65), 62% were women, had a median disease duration of 1.8 years (IQR, 0.4-6.9), and median EDSS of 1.5 (IQR, 1.0-2.5).

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Presented by lead author Mathias Herstad Øverås, MD, a PhD student in the Department of Neurology at Oslo University Hospital in Norway, the primary end point was the number of new or enlarging T2 MRI lesions between 12 and 96 weeks. Additionally, the primary efficacy measure was the difference between the predicted marginal mean for the 2 treatments with a 95% confidence interval and a noninferiority margin of 0.3. Secondary efficacy end points included annualized relapse rate, change in EDSS score, achievement of no evidence of disease activity, and 6-month confirmed disability progression.

All told, the trial was notable as the first head-to-head phase 3 evaluation of a B-cell–depleting monoclonal antibody against an immune-reconstitution therapy in RRMS. These results potentially align with prior findings from a target trial emulation, which demonstrated that rituximab had superior efficacy compared with cladribine over a median follow-up of 4.5 years.² Authors noted that both agents are widely used for the treatment of MS but act through distinct mechanisms as rituximab targets CD20-positive B cells whereas cladribine induces selective lymphocyte depletion followed by immune reconstitution.

Safety was assessed through blood sample analysis and monitoring of adverse events. In the trial, serious infections occurred in 3.8% of rituximab recipients (n = 5) compared with 2.2% of patients who received cladribine (n = 3). Authors noted that lymphopenia was reported more frequently in the cladribine group, affecting 89% of patients, versus 21% in the rituximab group.

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REFERENCES
1. Øverås MH, Skattebøl L, Brustad HK, et al. Efficacy and safety of rituximab versus cladribine in relapsing-remitting multiple sclerosis: Primary results from the NOR-MS randomized controlled phase 3 non-inferiority trial. Presented at ECTRIMS Congress; September 24-26, 2025; Barcelona, Spain. Late-Breaking Abstract P415.
2. Rød BE, Høgestøl EA, Torkildsen Ø, et al. Comparative effectiveness of rituximab and cladribine in relapsing-remitting multiple sclerosis: A target trial emulation. Mult Scler. 2025;31(8):975-984. doi:10.1177/13524585251342727