Ocrelizumab treatment in multiple sclerosis shows disability improvement in relapsing forms

Importance: In multiple sclerosis (MS), high-efficacy disease-modifying therapies (HEDMTs) effectively control relapse-associated worsening (RAW), but progression independent of relapse activity (PIRA) remains inadequately addressed. As HEDMTs become the standard of care, developing new therapies that target this residual progression is a critical unmet need. Objective: This study quantifies disability progression in MS patients treated with ocrelizumab to evaluate how confirmed EDSS disability progression (EDSS-CDP) would perform as an endpoint in future trials using HEDMT as comparators. Design: Retrospective longitudinal cohort study. Setting: Pooled dataset from four multicenter phase III and IV clinical trials. Participants: 1,859 people with (pw) relapsing MS (RMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS) who were treated with ocrelizumab within the OPERA I/II, ORATORIO, and CONSONANCE trials. Intervention: Ocrelizumab. Main Outcomes and Measures: We developed a hierarchical Bayesian model to analyze longitudinal EDSS trajectories using two components: an offset effect, used to capture changes occurring rapidly after treatment onset, followed by a steady, long term linear progression over time. We used this model to simulate future clinical trial scenarios, assuming different drug effects on the offset and the long term linear progression. Results: Our model accurately describes longitudinal EDSS changes and the risk of EDSS-CDP in ocrelizumab-treated subjects. Disability improvement (offset effect) was most prominent in pwRMS, while pwPPMS exhibited the highest long-term progression rates. Baseline T1 gadolinium-enhancing lesions were associated with a greater initial benefit. Simulations of typical phase III trials suggest that the hazard ratio on the EDSS-CDP endpoint is mostly influenced by the magnitude of the offset effect rather than the impact on long-term linear progression. Conclusions and Relevance: We attribute the disability improvement observed shortly after treatment onset to resolving focal inflammation, and the long-term steady progression rate to disease mechanisms not fully addressed by ocrelizumab. Our simulation results show that within the current trial paradigm, which uses EDSS-CDP as a measure of disability progression, the ability of a treatment to induce an initial improvement is the primary determinant of success. These results emphasize the urgent need for both innovative clinical trial designs and more sensitive endpoints to adequately assess the next generation of MS therapies targeting gradual disability progression.