Magnetization Transfer Imaging in Secondary Progressive Multiple Sclerosis Patients Treated with Siponimod: Results from the Phase 3 EXPAND Study (4037)

Objective: To determine the effect of siponimod versus placebo on magnetization transfer ratio (MTR) changes as a marker of alterations in myelin density in different brain regions, and assess the degree of MTR recovery within MTR lesions. Background: MTR is widely used for estimating myelin content in the brain. In the EXPAND study, siponimod significantly reduced disability progression, cognitive decline, and total brain volume loss versus placebo in secondary progressive multiple sclerosis patients. In preclinical studies, siponimod showed pro-myelinating effects. Design/Methods: This prospective exploratory MTR sub-study included 633 patients (siponimod [n=409]; placebo [n=224]). MTR changes were analyzed in normal appearing brain tissue (NABT), cortical grey matter (cGM) and normal appearing white matter (NAWM) at baseline, Month (M) 12, and M24. MTR variability across different scanners was reduced by MTR normalization. Absolute change from baseline in median normalized MTR (nMTR) expressed in percent units was derived from mixed models for repeated measures. MTR recovery metrics were assessed in new MTR lesions comparing decrease in nMTR from pre- to post-lesion time points in placebo and siponimod-treated patients. Results: Absolute changes from baseline in median nMTR in brain tissues for siponimod versus placebo at M12 and M24 were: −0.016 versus −0.024 (−38%, P=0.32) and −0.022 versus −0.056 (−61%, P=0.019) for NABT; −0.019 versus −0.026 (−27%; P=0.42) and −0.025 versus −0.056 (−55%; P=0.047) for cGM; and 0.002 versus −0.019 (−105%; P=0.021) and −0.001 versus −0.045 (−98%; P=0.0018) for NAWM. Lesion MTR recovery favored siponimod (−1.321) versus placebo (−1.506; difference 0.185 [0.056; 0.314]; P=0.005). Conclusions: Siponimod demonstrated a consistent and significant effect versus placebo on the decrease of MTR over time in normal-appearing tissues. Siponimod also improved MTR recovery in newly formed lesions, an effect that could be consistent with promotion of remyelination observed in preclinical studies. Disclosure: Dr. Arnold has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant fees from Albert Charitable Trust, Biogen, Celgene, F. Hoffmann-La Roche, Frequency Therapeutics, MedDay, Merck Serono, Novartis, Sanofi-Aventis. Dr. Arnold holds stock and/or stock options in NeuroRx Research. Dr. Arnold has received research support from Research grants from Albert Charitable Trust, Biogen, Celgene, F. Hoffmann-La Roche, Frequency Therapeutics, MedDay, Merck Serono, Novartis, Sanofi-Aventis. Dr. Cree has received personal compensation from Akili, Alexion, Atara, Biogen, EMD Serono, Novartis, TG Therapeutics.Amit Bar-Or has participated as a speaker in meetings sponsored by, and received consulting fees from, Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, Janssen/Actelion, MAPI, MedImmune, Merck/EMD Serono, Novartis and Sanofi-Genzyme. Grant support from Janssen/Actelion, Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Roche/Genentech, MAPI, MedImmune, Merck/EMD Serono, Novartis and Sanofi-Genzyme.Dr. Giovannoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie, Actelion, Atara Biotherapeutics, Bayer, Biogen, Canbex Therapeutics, Five Prime Therapeutics, GSK, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Oxford PharmaGenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva, and UCB. Dr. Giovannoni has receive research support from AbbVie, Actelion, Atara Biotherapeutics, Bayer, Biogen, Canbex Therapeutics, Five Prime Therapeutics, GSK, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Oxford PharmaGenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva, and UCB.Dr. Gold has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis. 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. Vermersch has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Almirall, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi, Servier, and Teva. Dr. Vermersch has received research support from Almirall, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi, Servier, and Teva.Dr. Piani Meier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG, Basel, Switzerland. Dr. Arnould has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis. Dr. Ritter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharmaceuticals Corporation, NJ, USA. Dr. Karlsson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG, Basel, Switzerland. Dr. Kappos has received research support from Bayer, Biogen, Innosuisse, Novartis, the Swiss MS Society, the Swiss National Research Foundation, and the European Union.Dr. Fox has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Robert Fox has received compensation for serving as a consultant or speaker from Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis, and Teva. He, or the institution he works for, has received research support from Novartis.. Dr. Fox has received research support from He, or the institution he works for, has received research support from Novartis..