Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis: The Phase IIIb ENSEMBLE 4-Year, Single-Arm, Open-Label Trial

Abstract

Background and objectives: Early treatment of multiple sclerosis (MS) reduces disease activity and the risk of long-term disease progression. Effectiveness of ocrelizumab is established in relapsing MS (RMS); however, data in early RMS are lacking. We evaluated the 4-year effectiveness and safety of ocrelizumab as a first-line therapy in treatment-naive patients with recently diagnosed relapsing-remitting MS (RRMS).

Methods: ENSEMBLE was a prospective, 4-year, international, multicenter, single-arm, open-label, phase IIIb study. Patients were treatment naive, aged 18-55 years, had early-stage RRMS with a disease duration ≤3 years, Expanded Disability Status Scale (EDSS) score ≤3.5, and ≥1 clinically reported relapse(s) or ≥1 signs of brain inflammatory activity on MRI in the prior 12 months. Patients received IV ocrelizumab 600 mg every 24 weeks. Effectiveness endpoints over 192 weeks were proportion of patients with no evidence of disease activity (NEDA-3; defined as absence of relapses, 24-week confirmed disability progression [CDP], and MRI measures, with prespecified MRI rebaselining at week 8), 24-week/48-week CDP and 24-week confirmed disability improvement, annualized relapse rate (ARR), mean change in EDSS score from baseline, and safety. Cognitive status, patient-reported outcomes, and serum neurofilament light chain (NfL) were assessed. Descriptive analysis was performed on the intention-to-treat population.

Results: Baseline characteristics (N = 678) were consistent with early-stage RRMS (n = 539 patients, 64.6% female, age 40 years and younger; median age: 31.0 years; duration since: MS symptom onset 0.78 years, RRMS diagnosis 0.24 years; mean baseline EDSS score [SD] 1.71 [0.95]). At week 192, most of the patients had NEDA-3 (n = 394/593, 66.4%), 85.0% had no MRI activity, 90.9% had no relapses, and 81.8% had no 24-week CDP over the study duration. Adjusted ARR at week 192 was low (0.020, 95% CI 0.015-0.027). NfL levels were reduced to and remained within the healthy donor range, by week 48 and week 192, respectively. No new or unexpected safety signals were observed.

Discussion: Disease activity based on clinical and MRI measures was absent in most of the patients treated with ocrelizumab over 4 years in the ENSEMBLE study. Safety was consistent with the known profile of ocrelizumab. Although this single-arm study was limited by lack of a parallel group for comparison of outcome measures, the positive benefit-risk profile observed may provide confidence to adopt ocrelizumab as a first-line treatment in newly diagnosed patients with early RMS.

Classification of evidence: This study provides Class IV evidence that adult patients with early-stage MS who were treatment naive maintained low disease activity (NEDA-3) over 4 years with ocrelizumab treatment; no new safety signals were detected.

Trial registration information: ClinicalTrials.gov Identifier NCT03085810; first submitted March 16, 2017; first patient enrolled: March 27, 2017; available at clinicaltrials.gov/ct2/show/NCT03085810.

Figure 1. (A) Study Design and (B) Patient Disposition

EDSS = Expanded Disability Status Scale; ITT = intention-to-treat; MS = multiple sclerosis; OCR = ocrelizumab; RRMS = relapsing-remitting multiple sclerosis; T1 Gd+-L = T1 gadolinium-enhancing lesion.

Figure 2. Four-Year Kaplan-Meier Plot of Time to Onset of 24-Week (A) CDP and (B) Composite CDP in Patients With RRMS Treated With OCR

Time to onset of (A) CDP and (B) cCDP. Curves show Kaplan-Meier estimates of the proportion of patients with disability progression events relative to the baseline throughout the open-label treatment period. Patients who discontinued the study due to lack of efficacy or death without confirmed progression of disease were imputed as having an event at the time of discontinuation. ITT population. Clinical cutoff date: April 19, 2022; snapshot date: July 8, 2022; the snapshot contains data up to week 192 of the treatment period of each individual patient. cCDP = composite confirmed disability progression; CDP = confirmed disability progression; ITT = intention-to-treat; OCR = ocrelizumab; RRMS = relapsing-remitting multiple sclerosis.

Figure 3. Four-Year Percent Change in Whole-Brain Volume (Week 192, Rebaselined at Week 8) in Patients With RRMS Treated With OCR

The annualized rate of BVL reported in patients with MS ranges from −0.46% to −1.34% per year^e10 and that associated with healthy controls and normal aging is −0.05 to −0.50 per year.^e11,e12 Whole-brain volume loss over time in the ENSEMBLE RRMS ITT population (percent change [95% CI]). Whole-brain volume was recorded as an absolute normalized value at week 8; relative percentage change from week 8 was obtained for each subsequent visit using SIENA for whole brain. Clinical cutoff date: April 19, 2022; snapshot date: July 8, 2022; the snapshot contains data up to week 192 of the treatment period of each individual patient. BVL = brain volume loss; ITT = intention-to-treat; MS = multiple sclerosis; OCR = ocrelizumab; PBVC = percentage brain volume change; RRMS = relapsing-remitting multiple sclerosis; SIENA = Structural Image Evaluation, using Normalization, of Atrophy.

Figure 4. Age-Adjusted Serum NfL Levels in the ENSEMBLE Population Compared With Healthy Donors at (A) Baseline (Plus Cofactors Affecting Baseline NfL Levels) and (B) Distribution Over Time (Plus Geometric Mean Serum NfL Levels Over Time, to Week 192)

Geometric means derived by using ANCOVA in the ENSEMBLE early-MS cohort (median age 31 years) demonstrated strong and significant reduction from baseline at week 48 and later visits (p < 0.001). The on-treatment (ocrelizumab) values of this MS cohort are comparable with a healthy donor cohort with similar demographics. ANCOVA = analysis of covariance; EDSS = Expanded Disability Status Scale; HC = healthy control; MS = multiple sclerosis; NfL = neurofilament light; T1 Gd+-L = T1 gadolinium-enhancing lesion.