Ocrelizumab Treatment Effect on Upper Limb Function in PPMS Patients with Disability: Subgroup Results of the ORATORIO Study to Inform the ORATORIO-HAND Study Design (P3.2-091)

Objective: To assess ocrelizumab efficacy on upper limb function in more disabled/older patients with primary progressive multiple sclerosis (PPMS) from the Phase III ORATORIO study (NCT01194570) to inform the design of the Phase IIIb ORATORIO-HAND study. Background: Ocrelizumab demonstrated efficacy versus placebo in reducing upper limb dysfunction (9-Hole Peg Test [9HPT]) in ORATORIO (Expanded Disability Status Scale [EDSS] ≤6.5). Ocrelizumab benefit in more disabled PPMS patients ineligible for inclusion in ORATORIO would fulfill an unmet need. Design/Methods: ORATORIO PPMS patients (N=732; EDSS 3.0–6.5; age 18–55 years) were randomized (2:1) to ocrelizumab or placebo for ≥120 weeks and until a pre-specified number of EDSS progression events occurred. Efficacy of ocrelizumab in preventing progression of upper limb function as measured by 12-week confirmed 20% worsening in 9HPT (average of both hands) was investigated in baseline subgroups: EDSS ≥6.0 (N=220), age >45 years (N=384), and 9HPT time >25 seconds (N=434). Results: Ocrelizumab reduced upper limb disability progression in more disabled/older PPMS patients. Risk reductions versus placebo in 9HPT progression were similar in patients with baseline EDSS score 25s (49% versus 44%, p=0.82). Progression events mainly occurred in patients with 9HPT >25s versus ≤25s (placebo: 34.3% vs 17.8%; ocrelizumab: 21.5% vs 9.9%); a weak trend for greater efficacy in patients ≤45 years versus >45 years was observed (p=0.29). Conclusions: ORATORIO-HAND is designed to further investigate the efficacy of ocrelizumab on upper limb function. Based on the 9HPT progression rates observed in ORATORIO, 1000 eligible patients (EDSS 3.0─8.0, age 18–65 years, 9HPT >25s), randomized (1:1) to ocrelizumab or placebo for ≥120 weeks (until a pre-specified number of progression events occur) will enable the assessment of ocrelizumab efficacy on confirmed 9HPT progression (primary endpoint). Screening will begin Q1 2019. Disclosure: Dr. Giovannoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie, Biogen, Novartis, Teva Neuroscience and Roche Diagnostics Corporation. He has also received consultancy fees for advisory board meetings for Merck-Serono, Genzyme-Sanofi, Synthon BV, and Physicians’ Summit and several medical education meetings. Dr. Giovannoni has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Disorders (Elsevier). Dr. Giovannoni has received research support from Takeda Pharmaceutical Company. Dr. Airas has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche, Merck . Dr. Airas has received research support from Sanofi-Genzyme. Dr. Bove has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche Genentech and Genzyme Sanofi. Dr. Bove has received research support from Akili Interactive. Dr. Boyko has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Schering, Merck, TEVA, Novartis, Sanofi-Genzyme, Actelion, Biocad, Generium. Dr. Cutter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO Pharmaceuticals, Biolinerx, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Merck, Merck/Pfizer, Opko Biologics, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva pharmaceuticals, NHLBI, NICHD, Atara Biotherapeutics, Axon, Biogen, Argenix, Brainstorm Cell Therapeutics, Charleston Labs Inc, Click Therapeutics, Genzyme, Genentech, GW Pharma, Klein-Buendel Incorporated, Medimmune, Medday, Novartis, Roche, Scifluor, Somahlution, Teva pharmaceuticals, TG Therapeutics, UT Houston. Dr. Cutter has received personal compensation in an editorial capacity for Statistical editor for the Journal of the American Society of Nephrology. Dr. Cutter has received research support from Via MGFA. Dr. Hobart has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda, Asubio, Bayer Schering, Biogen Idec, F. Hoffmann-La Roche Ltd, Genzyme, Merck Serono, Novartis, Oxford PharmaGenesis, Oxford Health Policy Forum and Teva. Dr. Kuhle’s institution has received compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis Pharmaceuticals, Protagen AG, Roche, Teva, Sanofi Genzyme, Swiss MS Society, and Merck Serono,. Dr. Kuhle has received research support from ECTRIMS Research Fellowship Programme, Bayer AG, Biogen, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Roche, Swiss MS Society, Swiss National Research Foundation, and University of Basel. Dr. Oh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with EMD-Serono, Novartis, Biogen-Idec, Sanofi-Genzyme, Roche, Celgene. Dr. Oh has received research support from Biogen-Idec, Sanofi-Genzyme. Dr. Tur has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Bayer, F. Hoffmann-La Roche Ltd, Ismar Healthcare, Merck Serono, Novartis, Sanofi and Teva. Dr. Tur has received research support from Postdoctoral research ECTRIMS Fellowships. Dr. Garas has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Model has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Manfrini has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd as an employee. Dr. Wolinsky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alkermes, Actelion, Acorda Therapeutics, Celgene, EMD Serono, GeNeuro, GW Pharma, MedDay Pharmaceuticals, Novartis, Otsuka, PTC Therapeutics, Roche/Genentech, Sanofi Genzyme, PlatformQ Health Education, PRIME, and Strategic Consultants Intl. Dr. Wolinsky has received royalty, license fees, or contractual rights payments from UTHealth to Millipore (Chemicon International) Corporation.