Effect of Ocrelizumab on Clinical Disability in Two Identical Phase III, Double-Blind, Double-Dummy, Interferon ß-1a–Controlled Studies
Accrual of neurological disability is a manifestation of disease progression in multiple sclerosis (MS). Selective B-cell targeting may be a potential therapeutic approach for MS, particularly early in the disease course when inflammatory mechanisms drive subclinical and clinical disease activity. Ocrelizumab (OCR) is a humanized monoclonal antibody that selectively targets CD20+ B cells.
To evaluate the effect of OCR on clinical disability in relapsing MS (RMS) compared with interferon β-1a (IFNβ-1a) in two Phase III, randomized, double-blind, double-dummy trials (OPERA I and OPERA II).
In OPERA I and OPERA II, patients were randomized (1:1) to receive OCR 600 mg via intravenous infusion every 24 weeks or subcutaneous IFNβ-1a 44 μg three times weekly over a total study period of 96 weeks. Pooled analyses of OPERA I and OPERA II efficacy were considered to be valid if treatment differences between the OCR and IFNβ-1a groups for annualized relapse rate (ARR) through week 96 and 12-week confirmed disability progression were broadly consistent between the two studies. We performed a pooled analysis of OPERA I and OPERA II to assess the proportion of patients with improved, stable, or worsened Expanded Disability Status Scale (EDSS) scores at week 96 compared with baseline. Stable disability status was defined as no greater than ± 0.5 change in EDSS scores.
Consistency of baseline characteristics and treatment effects across both studies met predetermined criteria for pooled efficacy analysis. Compared with IFNβ-1a, OCR reduced risk of 12-week confirmed disability progression (CDP) by 40% (p=0.0006) and 24-week CDP by 40% (p=0.0025) in a prespecified pooled analysis. Compared with IFNβ-1a, higher proportions of OCR-treated patients had improved EDSS scores (20.2% [n=146] vs 15.0% [n=98]; adjusted odds ratio [aOR] 1.288; p=0.0866]). Significantly fewer patients in the OCR group had worsened EDSS scores compared with IFNβ-1a (10.1% [n=73] vs 16.6% [n=109]; aOR 0.575, p=0.0009).
Pooled analysis of the OPERA I and OPERA II studies showed that a higher proportion of OCR-treated patients had improved disability status and significantly less disability worsening over 96 weeks compared with IFNβ-1a–treated patients. These results support that CD20+B-cell targeting with OCR has a robust effect on the accrual of clinical disability in RMS.
Supported by F. Hoffmann-La Roche Ltd.