PMID- 35261318 OWN - NLM STAT- MEDLINE DCOM- 20220726 LR - 20220811 IS - 1477-0970 (Electronic) IS - 1352-4585 (Print) IS - 1352-4585 (Linking) VI - 28 IP - 10 DP - 2022 Sep TI - Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial. PG - 1526-1540 LID - 10.1177/13524585221076717 [doi] AB - BACKGROUND: Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS). OBJECTIVE: To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM). METHODS: Patients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions. RESULTS: Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity. CONCLUSION: Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144. FAU - Arnold, Douglas L AU - Arnold DL AUID- ORCID: 0000-0003-4266-0106 AD - NeuroRx, Montreal, QC, Canada/Montreal Neurological Institute, McGill University, Montreal, QC, Canada. FAU - Piani-Meier, Daniela AU - Piani-Meier D AD - Novartis Pharma AG, Basel, Switzerland. FAU - Bar-Or, Amit AU - Bar-Or A AD - Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. FAU - Benedict, Ralph Hb AU - Benedict RH AD - Department of Neurology, University at Buffalo, Buffalo, NY, USA. FAU - Cree, Bruce Ac AU - Cree BA AUID- ORCID: 0000-0001-7689-2533 AD - UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA. FAU - Giovannoni, Gavin AU - Giovannoni G AD - Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. FAU - Gold, Ralf AU - Gold R AD - Department of Neurology, St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany. FAU - Vermersch, Patrick AU - Vermersch P AD - Univ. Lille, Inserm U1172 LilNCog, CHU Lille, FHU Precise, Lille, France. FAU - Arnould, Sophie AU - Arnould S AD - Novartis Pharma AG, Basel, Switzerland; *at the time of writing. FAU - Dahlke, Frank AU - Dahlke F AD - Novartis Pharma AG, Basel, Switzerland; *at the time of writing. FAU - Hach, Thomas AU - Hach T AD - Novartis Pharma AG, Basel, Switzerland; *at the time of writing. FAU - Ritter, Shannon AU - Ritter S AD - Novartis Pharma AG, Basel, Switzerland; *at the time of writing. FAU - Karlsson, Goril AU - Karlsson G AD - Novartis Pharma AG, Basel, Switzerland; *at the time of writing. FAU - Kappos, Ludwig AU - Kappos L AUID- ORCID: 0000-0003-4175-5509 AD - Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) and MS Center, Departments of Head, Spine and Neuromedicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital, University of Basel, Basel, Switzerland. FAU - Fox, Robert J AU - Fox RJ AUID- ORCID: 0000-0002-4263-3717 AD - Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. CN - EXPAND Clinical Investigators LA - eng SI - ClinicalTrials.gov/NCT01665144 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20220309 PL - England TA - Mult Scler JT - Multiple sclerosis (Houndmills, Basingstoke, England) JID - 9509185 RN - 0 (Azetidines) RN - 0 (Benzyl Compounds) RN - RR6P8L282I (siponimod) SB - IM MH - Atrophy/pathology MH - Azetidines MH - Benzyl Compounds MH - Brain/diagnostic imaging/pathology MH - Gray Matter/diagnostic imaging/pathology MH - Humans MH - Magnetic Resonance Imaging/methods MH - *Multiple Sclerosis/pathology MH - *Multiple Sclerosis, Chronic Progressive/diagnostic imaging/drug therapy/pathology PMC - PMC9315182 OTO - NOTNLM OT - MRI OT - Secondary progressive multiple sclerosis OT - brain integrity OT - gray matter OT - magnetization transfer ratio OT - myelination OT - siponimod COIS- Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.L.A. has received personal fees from Acorda, Albert Charitable Trust, Biogen, Celgene, Frequency Therapeutics, GeNeuro, MedDay, Merck Serono, Novartis, Roche, Sanofi Aventis, and Wave Life Sciences; grants from Biogen, Immunotec, and Novartis; and has equity interest in NeuroRx, outside the submitted work. A. B.-O. has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, MedImmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi Genzyme. R.H.B.B. has received honoraria, speaking, or consulting fees from Biogen, Celgene, EMD Serono, Genentech, MedDay, Novartis, and Roche; research support from Biogen, Genentech, and Novartis; and royalties from Psychological Assessment Resources. B.A.C.C. has received personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, EMD Serono, Novartis, Sanofi, TG Therapeutics, and Therini; and research support from Genentech. G.G. has received compensation for serving as a consultant or speaker for or has received research support from AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/Actelion, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Novartis, Sanofi Genzyme, Roche/Genentech, and Teva. R.G. has received compensation for serving as a consultant or speaker from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience; and he or the institution he works for has received research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience; he has also received fees for service as a journal editor from SAGE and Thieme Verlag. P.V. has received fees for service and consulting fees from AB Science, Biogen, Celgene, Imcyse, Merck, Novartis, Roche, Sanofi Genzyme, and Teva, and research support from Novartis, Roche and Sanofi Genzyme. L.K.'s institution (University Hospital Basel) has received steering committee, advisory board and consultancy fees used exclusively for research support in the department, as well as support of educational activities, from Actelion, Allergan, Almirall, Baxalta, Bayer, Biogen, Celgene/Receptos, CSL-Behring, Desitin, Eisai, Excemed, F. Hoffmann-La Roche Ltd., Genzyme, Japan Tobacco, Merck, Minoryx, Novartis, Pfizer, Sanofi Aventis, Santhera, and Teva; and license fees for Neurostatus-UHB products. Research at the MS Center in Basel has been supported by grants from Bayer, Biogen, the European Union, Innosuisse, Novartis, Roche, the Swiss MS Society, and the Swiss National Research Foundation. R.J.F. has received personal fees from Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis, and Teva; grants from Novartis; and other support from Biogen and Novartis (clinical trial contracts). D.P.-M., S.A., T.H., S.R., and G.K. are the employees of Novartis Pharma AG. F.D. was an employee of Novartis Pharma AG, at the time of writing. EDAT- 2022/03/10 06:00 MHDA- 2022/07/27 06:00 PMCR- 2022/07/26 CRDT- 2022/03/09 08:42 PHST- 2022/03/10 06:00 [pubmed] PHST- 2022/07/27 06:00 [medline] PHST- 2022/03/09 08:42 [entrez] PHST- 2022/07/26 00:00 [pmc-release] AID - 10.1177_13524585221076717 [pii] AID - 10.1177/13524585221076717 [doi] PST - ppublish SO - Mult Scler. 2022 Sep;28(10):1526-1540. doi: 10.1177/13524585221076717. Epub 2022 Mar 9.