Comprehensive Insights into Ocrelizumab: From Early-stage RRMS to Long-term Treatment and Subcutaneous Administration

• Ocrelizumab proves superior to first-line therapies in early RRMS, promoting better outcomes.
• Long-term data spanning a decade validate Ocrelizumab’s sustained efficacy and safety across MS stages, enhancing patient management.

At the 2024 American Academy of Neurology conference, significant findings were presented regarding Ocrelizumab’s efficacy and safety in multiple sclerosis (MS) treatment. These included insights from the Phase IIIb ENSEMBLE Trial and the Matched Real-world NTD MS Registry Cohort, demonstrating low disease activity over four years of Ocrelizumab therapy in treatment-naive patients with high-activity, early-stage relapsing-remitting MS. Additionally, the ENSEMBLE Study showcased promising outcomes of 10 years of Ocrelizumab treatment, revealing its long-term efficacy and safety. Furthermore, results from the OCARINA II Phase III Study highlighted the effectiveness of subcutaneous Ocrelizumab administration in MS patients.

Early treatment with high-efficacy DMTs can benefit MS outcomes. In the ENSEMBLE study, ocrelizumab was compared to first-line therapies in early RRMS. At 120 weeks, 79.1% of ocrelizumab patients achieved NEDA-2 vs. 61.6% in the first-line therapy group. The odds ratio favored ocrelizumab (OR: 2.30, 95% CI: 1.50–3.52), mainly driven by reduced relapse rates. Treatment switches, including to high-efficacy DMTs, were observed across treatment pathways in the first-line therapy cohort, indicating potential adjustments based on disease activity or treatment response. This highlights the favorable effectiveness of ocrelizumab compared to first-line therapies in achieving NEDA-2 in early-stage RRMS, emphasizing the importance of early initiation of high-efficacy DMTs in MS management.

In ENSEMBLE study, focusing on patients with early, high-activity relapsing-remitting multiple sclerosis (HA RRMS), ocrelizumab demonstrated sustained efficacy and safety over a 4-year treatment period. The majority of patients in this subgroup achieved no evidence of disease activity (NEDA-3), defined as no relapses, no 24-week confirmed disability progression (CDP), and no MRI activity. Notably, no new or unexpected safety signals emerged during the study. In the overall ENSEMBLE population, older age at diagnosis was identified as a predictor of not achieving NEDA, emphasizing the importance of considering patient age in treatment planning. These findings underscore the effectiveness of ocrelizumab in managing early, high-activity RRMS and highlight the relevance of predictive factors in treatment outcomes.

OCR also demonstrates sustained efficacy and safety in patients with relapsing and primary progressive multiple sclerosis (pwRMS/pwPPMS) over 10 years of treatment. In the OCR-OCR group, after a decade, over three-quarters (76.6%) of pwRMS were free from 48-week confirmed disability progression (48W-CDP) on the Expanded Disability Status Scale (EDSS), and 91.9% did not require a walking aid. Similarly, in pwPPMS on OCR-OCR, 36.4% and 18.6% were free from 48W-CDP-EDSS and 48W-composite CDP (cCDP) events, respectively, with 80.4% not needing a wheelchair. Early initiation of OCR significantly lowered the risk of disability progression in both pwRMS and pwPPMS cohorts (HR, CI: 0.77, 0.61–0.96, p=0.0183; 0.58, 0.41–0.84, p=0.003; 0.74, 0.61–0.91, p=0.0041; 0.78, 0.65–0.93, p=0.0064; 0.70, 0.48–1.03, p=0.0708). Throughout the 10-year period, adverse event rates remained consistent with the controlled treatment period, with infrequent treatment withdrawal and malignancy rates within expected levels. Serious infection rates were low and stable in both pwRMS and pwPPMS, regardless of immunoglobulin G levels. These findings highlight OCR’s long-term therapeutic potential and its crucial role in managing multiple sclerosis.

A new formulation of OCR, administered subcutaneously (SC) along with recombinant human hyaluronidase (rHuPH20), is being developed for treating relapsing and primary progressive multiple sclerosis (RMS/PPMS). In a recent study, patients aged 18 to 65 with RMS/PPMS (Expanded Disability Status Scale score 0–6.5) were randomized to receive either OCR 600mg intravenously (IV) or 920mg OCR SC, chosen based on pharmacokinetic data. The study aimed to compare serum OCR levels, MRI lesion activity, relapse rates, immunogenicity, B-cell depletion, and safety between the two formulations. Both groups showed balanced demographics and disease characteristics. At Week 12, OCR SC demonstrated a 29% higher serum concentration compared to OCR IV. OCR SC effectively suppressed MRI and relapse activity up to Week 24, similar to OCR IV. Both formulations rapidly and consistently depleted B-cells, with a safety profile consistent with previous findings. No new safety concerns were observed, and no antibodies against OCR or rHuPH20 were detected. 

Conclusion 

The presentations at the AAN conference 2024 showcased the consistent efficacy and safety of ocrelizumab across various stages of MS. Insights from clinical trials and real-world data underscored its benefits in early-stage RRMS, where ocrelizumab demonstrated superior effectiveness in achieving NEDA-2 compared to first-line therapies, emphasizing the importance of early initiation of high-efficacy DMTs. Additionally, the ENSEMBLE study highlighted ocrelizumab’s sustained efficacy and safety over four years in high-activity RRMS patients, with the majority achieving NEDA-3. Moreover, long-term data revealed that ocrelizumab effectively mitigated disability progression in both relapsing and primary progressive MS cohorts over a decade, with consistent safety profiles. The unveiling of a new subcutaneous formulation of ocrelizumab further adds to its therapeutic potential, demonstrating comparable efficacy, B-cell depletion, and safety to the intravenous formulation. These findings collectively underscore ocrelizumab’s pivotal role in MS management and its promise in improving long-term outcomes for patients.