Low Disease Activity Over 4 Years of Ocrelizumab Therapy in Treatment-Naive Patients With Early-Stage Relapsing-Remitting Multiple Sclerosis; the Phase IIIb ENSEMBLE Study (S46.004)

Objective: To report 4-year efficacy and safety data from the ENSEMBLE trial (NCT03085810) of ocrelizumab (OCR) in patients with early-stage relapsing-remitting multiple sclerosis (RRMS). Background: Early and sustained treatment of MS with high-efficacy therapy reduces the risk of long-term disease progression. ENSEMBLE is a multicenter, open-label, single-arm Phase IIIb study, evaluating the efficacy and safety of OCR in patients with early-stage RRMS. Design/Methods: At the time of enrollment, eligible patients were treatment naive, aged 18–55 years, had an active early-stage RRMS with a disease duration ≤3 years, Expanded Disability Status Scale (EDSS) ≤3.5 and ≥1 clinically reported relapse(s) or ≥1 signs of magnetic resonance imaging (MRI) activity (T1-weighted contrast-enhancing lesions or new/enlarging T2-weighted lesions, with MRI measurements rebaselined at W8) in the prior 12 months. Patients received OCR 600 mg every 24 weeks for 192 weeks. Key endpoints were no evidence of disease activity (NEDA)-3 (defined as no relapses, no 24-week [W] confirmed disability progression [CDP] and no MRI activity), annualized relapse rate (ARR), mean change in EDSS score from baseline (BL) and safety. Results: BL characteristics (N=678) were consistent with early-stage RRMS (patients ≤40 years with a median age of 31.0 years; duration since MS symptom onset, 0.78 years; duration since RRMS diagnosis, 0.24 years; mean BL EDSS score [SD], 1.71 [0.95]). At W192, the majority of patients had NEDA (n=394/593, 66.4%), 85.0% had no MRI activity, 90.9% had no relapses and 81.8% had no 24W-CDP. Adjusted ARR at W192 was low, 0.020 (95% CI, 0.015–0.027). No new or unexpected safety signals were observed. Conclusions: Disease activity based on clinical and MRI measures was minimal in most patients treated with ocrelizumab over 4 years in the ENSEMBLE study. Safety was consistent with the known profile of ocrelizumab, with no new signals. Disclosure: Dr. Bermel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Bermel has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi/Genzyme. Dr. Bermel has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech/Roche. Dr. Bermel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Viela Bio. Dr. Bermel has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Bermel has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck Serono. Dr. Bermel has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Astra Zeneca. Dr. Bermel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for LabCorp. Dr. Bermel has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TG Therapeutics. The institution of Dr. Bermel has received research support from Biogen. The institution of Dr. Bermel has received research support from Roche. The institution of Dr. Bermel has received research support from Novartis. Dr. Bermel has received intellectual property interests from a discovery or technology relating to health care. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS Celgene. Dr. Hartung has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Geneuro. Dr. Hartung has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Hartung has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers Neurology. Prof. Brochet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Prof. Brochet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for celgene. Prof. Brochet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for jansen. Prof. Brochet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for biogen. Prof. Brochet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for novartis. Prof. Brochet has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for merck. Prof. Brochet has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for biogen. Prof. Brochet has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for celgene. Dr. Benedict has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Benedict has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Roche. Dr. Benedict has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Benedict has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Benedict has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bristol Meyers Squibb. Dr. Benedict has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Benedict has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Benedict has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Brystal Mier Squibb. Dr. Benedict has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for EMD Serono. The institution of Dr. Benedict has received research support from Genzyme. The institution of Dr. Benedict has received research support from Biogen. The institution of Dr. Benedict has received research support from Bristol Myer Squib. Dr. Benedict has received intellectual property interests from a discovery or technology relating to health care. Prof. Berger has received personal compensation in the range of $10,000-$49,999 for serving as a speaker at scientific meetings and participant of local and international advisory boards with various companies producing and markerting treatments for multiple sclerosis (Almirall, Biogen, Biologix, Bionorica, Celgene-BMS, Merck, Novartis, Roche, Sanofi-Genzyme, TG Therapeutics, UCB). William M. Carroll, MBBS, MD, FRACP has nothing to disclose. The institution of Dr. Vollmer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen IDEC. The institution of Dr. Vollmer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech/Roche. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Siranax. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Meyers Squib. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Viela Bios. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. The institution of Dr. Vollmer has received research support from Rocky Mountain MS Center. The institution of Dr. Vollmer has received research support from Biogen. The institution of Dr. Vollmer has received research support from Actelion. The institution of Dr. Vollmer has received research support from Genentech/Roche. The institution of Dr. Vollmer has received research support from Anokion. The institution of Dr. Vollmer has received research support from TG Therapeutics. Dr. Holmoy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Norwegian MS Society. Dr. Holmoy has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Holmoy has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Holmoy has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Dr. Holmoy has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Holmoy has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Karabudak has nothing to disclose. Joep Killestein has nothing to disclose. Dr. Nos has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for F. Hoffmann-La Roche Ltd.. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Almirall, Bayer, Biogen, Bristol Meyers and Squibb Merck, Roche, Sanofi, TEVA. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for University of Catania and AISM/FISM, Fondazione Italiana Sclerosi Multipla. Ms. Perrin Ross has received personal compensation in the range of $0-$499 for serving as a Consultant for Horizon. Ms. Perrin Ross has received personal compensation in the range of $0-$499 for serving as a Consultant for EMD Serono. Ms. Perrin Ross has received personal compensation in the range of $0-$499 for serving as a Consultant for Alexion. Ms. Perrin Ross has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Ms. Perrin Ross has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Vanopdenbosch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for celgene. Dr. Vanopdenbosch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen . Dr. Vanopdenbosch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for F Hoffmann La Roche. Dr. Vanopdenbosch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Vanopdenbosch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Dr. Vanopdenbosch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Wuerfel has received personal compensation for serving as an employee of MIAC AG. The institution of Dr. Wuerfel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Actelion. The institution of Dr. Wuerfel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. The institution of Dr. Wuerfel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Thomas Kunzel has received personal compensation for serving as an employee of Roche. Karen Kadner has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd. Inessa Kulyk has received personal compensation for serving as an employee of Roche. Inessa Kulyk has stock in Roche. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion(Janssen/J&J). Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BiogenIdec. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS/Celgene. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Inc. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion (Janssen/J&J). Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Atara Biotherapeutics. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer Healthcare. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for BiogenIdec. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Clene Nanomedicine. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GRI Bio. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Magenta Therapeutics. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. The institution of Dr. Freedman has received research support from Sanofi Genzyme.

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