A Novel Functional Composite Endpoint To Characterize Disease Progression In Patients With Secondary Progressive Multiple Sclerosis

Objective: To evaluate a novel functional composite endpoint (CEP) based on disability progression and cognitive processing speed (CPS) to characterize disease progression in patients with secondary progressive multiple sclerosis (SPMS) more effectively. Background: Physical disability, as measured by the Expanded Disability Status Scale (EDSS) score, and CPS as measured by the Symbol Digit Modalities Test (SDMT), are functional domains of high clinical relevance for patients with SPMS. EDSS and SDMT cover different aspects of progression. A clinically meaningful CEP, using information from both EDSS- and SDMT-based events, will utilize clinical trial data more effectively thus yielding useful information while minimizing patients’ exposure to trial risks. Design/Methods: We analyzed time to clinically meaningful changes in EDSS and SDMT, i.e., 6-month confirmed disability progression on EDSS (1.0-point worsening from ≤5.0 baseline score or 0.5-point worsening from >5.0 baseline score; 6mCDPEDSS), SDMT (4.0-point confirmed worsening from baseline; 6mCWSDMT), and on the proposed CEP in patients from placebo-controlled trial of siponimod in SPMS (EXPAND). We present hazard ratios (HR) and 95% confidence intervals (CI) using a Cox proportional hazards model and the corresponding Kaplan-Meier estimates. Results: Of 1645 patients: 358 had EDSS-progression, of which 279 (78%) had no progression on SDMT; 287 had SDMT-progression, of which 208 (72%) had no progression on EDSS; 79 patients progressed on both EDSS and SDMT. Compared to placebo, siponimod reduced the risk of progression (HR [95% CI]: 6mCDPEDSS 0.74 [0.60; 0.92], p=0.0058, 6mCWSDMT 0.75 [0.59; 0.95], p=0.0163 and CEP 0.75 [0.63; 0.88], p=0.0008). At the end of the core study, 62% of siponimod-treated patients versus 52% on placebo remained CEP free. Conclusions: Combining SDMT and EDSS resulted in higher sensitivity for change and therapeutic effects in a large SPMS clinical trial. If confirmed in further patient samples, introduction of this compound measure would allow for lower sample sizes in future clinical trials. Disclosure: Dr. Kappos’ institution has received compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, Sanofi-Aventis, Santhera, Teva and Vianex, and license fees for Neurostatus-UHB products. Dr. Kappos’ institution has received research support from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations. Dr. Vermesch has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Roche, Novartis, Teva, Sanofi, Celgene, Actelion and Merck. Dr. Vermesch has received research support from Roche, Sanofi, Novartis and Biogen. Dr. Cree has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Abbvie, Akili, Biogen, EMD Serono, GeNeuro and Novartis. Dr. Benedict has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie, Biogen Idec, EMD Serano, Novartis, Genzyme/Sanofi Aventis, Teva, Genentech, and Roche. Dr. Benedict has received research support from Biogen Idec and Genzyme. 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. Bar-Or has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Atara Biotherapeutics, Biogen, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme. Dr. Bar-Or has received research support from Atara Biotherapeutics, Biogen, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme. Dr. Gold has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Baxter, Bayer Schering, Biogen, CLB Behring, Celgene, Genzyme, Merck Serono, Novartis, Roche, Stendhal, Talecris, and Teva Pharmaceuticals. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Diseases, Experimental Neurology and the Journal of Neuroimmunology. Dr. Gold has received research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer, Schering Pharma, Genzyme, Merck Serono, and Novartis. Dr. Arnould has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis Pharma Basel, AG. Dr. Rouyrre has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis Pharma AG. Dr. Karlsson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis Pharma AG. Dr. Piani Meier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis Pharma AG. Dr. Dahlke has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis Pharma AG. Dr. Wolf has nothing to disclose. Dr. Tomic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG. Dr. Fox has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Allozyne, Avanir, Biogen Idec, MedDay, Novartis, Questcor, Teva Pharmaceutical Industries, and Xenoport. Dr. Fox has received research support from Biogen (clinical trial contracts) and Novartis (research study support).