Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension

Abstract

Objective: To assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA: I/II studies in relapsing multiple sclerosis.

Methods: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.

Results: Of patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-β-1a (16.1% vs 21.3% at year 5; p = 0.014). Patients continuing OCR maintained and those switching from IFN-β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3-5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-β-1a (-1.87% vs -2.15% at year 5; p < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.

Conclusion: Compared with patients switching from IFN-β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.

Classification of evidence: This study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.

Clinical trial identifiers: NCT01247324/NCT01412333.

Figure 1. Patient disposition in the pooled OPERA I and OPERA II intent-to-treat (ITT) population

Percentages in parentheses are of the ITT population. ^aClinical cutoff date: February 5, 2018; patients entering the open-label extension (OLE) phase who completed the double-blind period (DBP): interferon (IFN)-β-1a 623/660 (94.4%) and ocrelizumab (OCR) 702/726 (96.7%). ^b88.4%, and ^c88.7%, of patients who entered the OLE completed year 3. SFU = safety follow-up.

Figure 2. Annualized relapse rate (ARR) in double-blind controlled treatment phase (DBP) study years 1 and 2 and open-label extension (OLE) years 1–3

Estimates are from analysis based on generalized estimating equation Poisson regression model with repeated measurements using unstructured covariance matrix, adjusted by randomized treatment, study, baseline Expanded Disability Status Scale (<4.0 vs ≥4.0), geographic region (United States vs rest of the world), year, and treatment-by-year interaction. Log-transformed exposure time is included as an offset variable. ^aThe total number of relapses for all patients in the treatment group divided by the total patient-years of exposure to that treatment. ^bDBP year 1 and DBP year 2 data include the intention-to-treat population (number of patients available); year 3 (OLE year 1), year 4 (OLE year 2), and year 5 (OLE year 3) data include the OLE ITT population (number of patients available). Clinical cutoff date: February 5, 2018. IFN = interferon; OCR = ocrelizumab.

Figure 3. Time to onset of confirmed disability progression (CDP) and confirmed disability improvement (CDI) for at least 24 weeks during double-blind controlled treatment phase (DBP) and open-label extension (OLE) periods

Time to onset of (A) CDP and (B) CDI. Curves show Kaplan-Meier estimates of the proportion of patients with disability progression/improvement events relative to the original double-blind treatment period baseline throughout double-blind and OLE periods. Without imputation. Intention-to-treat (ITT) population. Pooled OPERA I and OPERA II population; DBP clinical cutoff dates: April 2, 2015, and May 12, 2015, respectively; OLE clinical cutoff date: February 5, 2018. Data shown up to week 240, the last visit all ongoing patients completed. HR = hazard ratio; IFN = interferon; OCR = ocrelizumab.

Figure 4. Total number of T1 gadolinium (Gd)-enhancing lesions and new or enlarging T2 lesions in the double-blind controlled treatment phase (DBP) and open-label extension (OLE)

(A) T1 Gd-enhancing lesions and (B) new or enlarging T2 lesions in the DBP and OLE. ^aDBP week 24, DBP year 1, and DBP year 2 data include the intention-to-treat (ITT) population; year 3 (OLE year 1), year 4 (OLE year 2), and year 5 (OLE year 3) data include the OLE ITT population; clinical cutoff date: February 5, 2018. ^bUnadjusted rate. IFN = interferon; OCR = ocrelizumab.

Figure 5. Percentage change from baseline and annualized, in whole brain volume (WBV), cortical gray matter volume (CGMV), and white matter volume (WMV) in the double-blind controlled treatment phase (DBP) and open-label extension (OLE)

Percentage change (A.a, B.a, C.a) from baseline and (A.b, B.b, C.b) annualized, in (A) WBV, (B) CGMV, and (C) WMV in the DBP and OLE mixed-effect model of repeated measures (MMRM) plot, intention-to-treat (ITT) population. Pooled OPERA [Rebif] I and OPERA II (clinical cutoff date: February 5, 2018); p values shown for difference in adjusted means. Graph includes patients with assessment at baseline and at least 1 postbaseline value. Estimates are from analysis based on MMRM using unstructured covariance matrix: percentage change = baseline brain volume + geographic region (United States vs rest of the world) + baseline Expanded Disability Status Scale (<4.0 vs ≥4.0) + study + week + treatment + treatment × week (repeated values over week) + baseline brain volume × week. ^aThe bars represent the annualized change in WBV, CGMV, or WMV occurring during the time period delineated by the axis label and the preceding 24 or 48 weeks. BL = baseline; CI = confidence interval; IFN = interferon; OCR = ocrelizumab.