Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis

Abstract

Objective: To assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS).

Methods: Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg).

Results: In patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks.

Conclusion: Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively.

Classification of evidence: This study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

Figure 1. The number of new T1 gadolinium (Gd)-enhancing lesions in the phase II population

Intention-to-treat population. Interferon (IFN)–β-1a was administered as a 30 μg IM injection once a week. ^aNegative binomial model adjusted for baseline T1 Gd-enhancing lesions (present vs absent), baseline Expanded Disability Status Scale (EDSS) score (≤2.5 vs >2.5), and geographic region (US vs rest of world). ^b Error bars are 95% confidence intervals.

Figure 2. The number of new or enlarging T2 lesions in the phase II population

Intention-to-treat population. Interferon (IFN)–β-1a was administered as a 30 μg IM injection once a week. ^aEnlarging T2 lesions were newly enlarging. ^bNegative binomial model adjusted for baseline T2 lesion volume, baseline Expanded Disability Status Scale (EDSS) score (≤2.5 vs >2.5), and geographic region (US vs rest of world). ^cError bars are 95% confidence intervals.

Figure 3. The proportion of patients free of T1 gadolinium (Gd)-enhancing lesions in the phase II population

Intention-to-treat population. Interferon (IFN)–β-1a was administered as a 30 μg IM injection once a week. Proportion of patients free of T1 Gd-enhancing lesions at week 24: placebo 74.5%; IFN-β-1a 30 μg 61.4%; ocrelizumab 600 mg 100%. ^a For the calculation of total number of new Gd-enhancing T1 lesions on MRI scans of the brain at a specific week and before week 24, the missing value at a time point is not going to be imputed.

Figure 4. The adjusted annualized relapse rate (ARR) in the pooled OPERA intention-to-treat (ITT) population

Intention-to-treat population. Interferon (IFN)–β-1a was administered as an SC infusion 3 times per week at a dose of 44 μg. ^a Adjusted by study, baseline Expanded Disability Status Scale (EDSS) score (<4.0 vs ≥4.0), and geographic region (US vs rest of world) using Poisson model. ^b Compared with IFN-β-1a.

Figure 5. The probability of first protocol-defined relapse in the pooled OPERA intention-to-treat (ITT) population

Intention-to-treat population. Interferon (IFN)–β-1a was administered as an SC infusion 3 times per week at a dose of 44 μg. Probability of relapse estimates (95% confidence interval [CI]) at weeks 8, 16, 24, 48, 72, and 96 were calculated using Kaplan-Meier and Greenwood formula. p Values not adjusted for multiplicity of testing. HR = hazard ratio.