Background: Ocrelizumab (OCR) is a humanized monoclonal antibody that selectively targets CD20+B cells. In a randomized, double-blind, placebo-controlled Phase III study (ORATORIO), OCR significantly reduced disease activity in patients with primary progressive multiple sclerosis (PPMS).
Objectives: To evaluate the efficacy of OCR in the ORATORIO patient subgroups with and without T1 gadolinium-enhancing (Gd+) lesions at baseline.
Methods: A total of 732 patients were randomized (2:1) to receive OCR 600 mg or placebo (PBO) as two 300 mg intravenous infusions 14 days apart every 24 weeks for at least 120 weeks and until a prespecified number of 12-week confirmed disability progression (CDP) events occurred. Key eligibility criteria included age 18-55 years, diagnosis of PPMS (2005 revised McDonald criteria), Expanded Disability Status Scale (EDSS) score of 3.0-6.5, and documented history of elevated immunoglobulin index and/or presence of oligoclonal bands in the cerebrospinal fluid. Although not powered for comparisons, prespecified subgroups included age (≤ 45 vs > 45 years), sex, body mass index (< 25 vs ≥ 25), weight (< 75 vs ≥75 kg), region (US vs rest of world), treatment history, MS symptom duration, and disease activity (EDSS score ≤ 5.5 vs > 5 and presence/absence of T1 Gd+ lesions) at baseline. Efficacy of OCR on ≥ 12- and ≥ 24-week CDP, change in total T2 lesion volume at 120 weeks, and other secondary efficacy outcomes was evaluated in the subgroups with presence and absence of T1 Gd+lesions at baseline.
Results: Compared with PBO, OCR significantly reduced the relative risk of 12-week CDP by 24% (hazard ratio [HR], 0.76; p= 0.0321) and 24-week CDP by 25% (HR, 0.75; p=0.0365). T1 Gd+ lesions were present at baseline in 27.5% of OCR-treated patients vs 24.7% of PBO-treated patients. In patients with and without T1 Gd+lesions at baseline, respectively, OCR reduced: the risk of 12-week CDP by 35% (HR, 0.65; 95% CI, 0.40-1.06; p=0.0826) and 16% (HR, 0.84; 95% CI, 0.62-1.13; p=0.2441); the risk of 24-week CDP by 33% (HR, 0.67; 95% CI, 0.40-1.14; p=0.1417) and 19% (HR, 0.81; 95% CI, 0.59-1.10; p=0.1783); and total T2 lesion volume by −3.8% (95% CI, −7.0 to −0.5) vs +12.0% with PBO (95% CI, 7.2-17.1; p<0.001) and by −3.1% (95% CI, −5.0 to −1.1) vs +6.1% with PBO (95% CI, 3.3-9.0; p<0.001).
Conclusion: In this subgroup analysis of patients with or without T1 Gd+ lesions at baseline, OCR reduced clinical and MRI disease activity compared with PBO.
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