Long-Term Treatment With Ocrelizumab in Patients With Early-Stage Relapsing MS: Nine-Year Data From the OPERA Studies Open-Label Extension

Abstract

Background and objectives: Patients with multiple sclerosis (MS) may demonstrate better disease control when treatment is initiated on high-efficacy disease-modifying therapies (DMTs) from onset. This subgroup analysis assessed the long-term efficacy and safety profile of the high-efficacy DMT ocrelizumab (OCR) as first-line therapy for early-stage relapsing MS (RMS).

Methods: Post hoc exploratory analyses of efficacy and safety were performed in a subgroup of treatment-naive patients with RMS who received ≥1 dose of OCR in the multicenter OPERA I/II (NCT01247324/NCT01412333) studies. Patients were randomized to OCR or interferon β-1a for 96 weeks (double-blind controlled treatment period [DBP]), before switching to OCR in the open-label extension (OLE). Efficacy assessments included no evidence of disease activity (NEDA-3), 24-week confirmed disability progression (CDP), MRI lesion activity, change in whole-brain volume; with safety outcomes assessed over a 9-year treatment period.

Results: Overall, 757 patients were included (interferon-treated n = 382, mean age 36.3 years, 65.7% female; OCR-treated n = 375, mean age 35.5 years, 64.0% female); 505 of 757 (66.7%) completed 9 years of follow-up. The difference in NEDA status between OCR-treated and interferon-treated patients achieved during the DBP (72.5% and 43.8%, respectively, odds ratio 3.48, 95% CI 2.52-4.81) was maintained throughout the 7-year OLE (48.2% vs 25.7%; odds ratio 2.72, 95% CI 1.94-3.82). No 24-week CDP was observed in 78.7% of OCR-treated patients over 9 years. Brain volume loss over the entire study period remained numerically higher among patients starting OCR later (p = 0.09 at OLE at week 336). During the DBP, safety profiles in both groups were similar; no new safety signals were observed during the OLE. Over >9 years of continuous OCR treatment, the rate of infections remained low and stable over time.

Discussion: A higher proportion of OCR-treated patients achieved NEDA status compared with interferon-treated patients during the DBP, which was maintained throughout the OLE. After switching to OCR, disability accrual and brain volume loss among interferon-treated patients became similar to the OCR-OCR group, but disability and brain volume loss accrued during interferon treatment were not recovered. Possible study limitations include assessment bias due to unmaintained blinding during the OLE. These data support OCR as first-line therapy for these patients.

Classification of evidence: This study provides Class II evidence that OCR delays disease progression in treatment-naïve patients with early-stage RMS.

Figure 1. Summary of Treatment Disposition at OLE Week 336 (Year 9)^a of Follow-up

The total ITT population referred to here includes those patients completing the double-blind treatment phase and meeting the criteria for analysis as part of the early RMS, treatment-naive subgroup. Of the 382 and 375 patients included in the IFN–OCR and OCR–OCR cohorts, respectively, the number of participants who discontinued due to study withdrawal, being lost to follow-up, lack of efficacy, died, or had AEs was calculated; percentages in parentheses. ^a 96 weeks (2 years) in the double-blind period plus 267 weeks (7 years) in the OLE. AE = adverse event; IFN = interferon; ITT = intention-to-treat; OCR = ocrelizumab; OLE = open-label extension.

Figure 2. (A) Time to Onset of cCDP for at Least 24 Weeks During the DBP and (B) Time to Onset of CDP for at Least 24 Weeks During the DBP and OLE

Curves show Kaplan–Meier estimates of the proportion of patients with (A) cCDP and (B) CDP events throughout the DBP and OLE treatment period (OLE week 336; 9 years). cCDP = composite CDP; CDP = confirmed disability progression; DBP = double-blind controlled treatment period; HR = hazard ratio; IFN = interferon; OCR = ocrelizumab; OLE = open-label extension; W = week.

Figure 3. Percentage Change in Total Brain Volume From Baseline in the DBP and OLE

Adjusted mean and 95% CI estimates of percentage change from baseline in total normalized brain volume were from a mixed-effects model of repeated measures using unstructured covariance matrix with the following explanatory variables: treatment (IFN vs OCR), baseline normalized brain volume, geographic region (the United States vs ROW), baseline EDSS category (<2, ≥2), treatment duration, as well as the interactions of study week with treatment (IFN vs OCR) and with baseline normalized brain volume. DBP = double-blind controlled treatment period; EDSS = Expanded Disability Status Scale; IFN = interferon; OCR = ocrelizumab; OLE = open-label extension; PBVC = percentage brain volume change; ROW = rest of world.