Recently Diagnosed Early-Stage RRMS: Neda, ARR, Disability Progression, Serum Neurofilament and Safety: 1-Year Interim Data from the Ocrelizumab Phase IIIb ENSEMBLE Study

Background: Early treatment of multiple sclerosis (MS) and rapid onset of therapeutic effect provide long-term benefits on disease outcomes. Individual and composite measures of MRI and clinical disease activity and progression were assessed in ENSEMBLE, a treatment-naive early-stage relapsing-remitting MS (RRMS) population with active disease. Objectives: To report 1-year interim efficacy and safety data in ENSEMBLE (NCT03085810), a Phase IIIb study evaluating ocrelizumab in patients with early-stage RRMS. Methods: Patients (treatment-naive, diagnosis of early-stage RRMS [age 18–55 years inclusive; Expanded Disability Status Scale (EDSS) score ?3.5], disease duration ?3 years and active disease [?1 clinically reported relapse or ?1 sign of MRI activity within 12 months of enrollment]) received ocrelizumab 600 mg every 24 weeks. Biomarker and clinical assessments included: NEDA (with MRI rebaselining at Week 8; defined as absence of protocol-defined relapses, 24-week confirmed disability progression, T1-weighted contrast-enhancing and new/enlarging T2-weighted lesions [T1w-CEL and N/E T2w-L]), annualized relapse rate (ARR), EDSS score and serum neurofilament-light (NfL) levels. Results: Baseline demographics and disease characteristics of 678 patients (64.6% female) were consistent with early-stage disease (mean [SD]: age, 32.4 [9.1] years; baseline EDSS, 1.71 [0.95]; time since RRMS diagnosis, 0.36 [0.40] years; time since MS symptom onset, 1.10 [0.84] years) of which 74.6% had both MS relapse and MRI activity. At Weeks 24 and 48 most patients (91.2% [n/N=618/678] and 84.8% [n/N=545/643]) had NEDA. At Week 48 most patients had no T1w-CELs (94.2%; n/N=606/643) and no N/E T2w-L (95.2%; n/N=612/643). Adjusted ARR at Week 48 was 0.005 (95%CI, 0.003-0.009). Additionally, mean (SD) EDSS score improved significantly from 1.71 (0.95) at baseline to 1.55 (1.07) at Week 48 (p=0.002). Age-adjusted serum NfL levels (geometric mean, pg/mL [coefficient of variance]) at baseline and Week 48 were 10.5 (107.8%) and 4.55 (59.5%), versus 4.12 (36.2%) in age-matched healthy controls. Safety results were consistent with prior studies. Conclusions: Treatment-naive patients with early-stage RRMS in ENSEMBLE responded consistently well to ocrelizumab treatment based on clinical, MRI and biomarker measures; no new safety signals were observed.

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