@article{fe1ac4f4aa694a47ac30b854230a1182,
title = "Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability",
abstract = "Introduction: Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa, randomized, controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS. Methods: Randomization was 2:1 (fingolimod:placebo). Treatment duration was 4 weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole-blood gene expression. Results: Thirty participants were randomized; 28 were administered a drug (fingolimod 18, placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo, with no statistical difference). Forced expiratory volume in 1 second (FEV1) and FEV1/slow vital capacity changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (P < 0.001). Nine immune-related genes were significantly downregulated in the fingolimod arm, including forkhead box P3 (P < 0.001) and CD40 ligand (P = 0.003). Discussion: Fingolimod is safe and well-tolerated and can reduce circulating lymphocytes in ALS patients. Muscle Nerve 56: 1077–1084, 2017.",
keywords = "FOXP3, RNA profiling, circulating lymphocytes, clinical trial, neuroinflammation, target engagement",
author = "Berry, {James D.} and Sabrina Paganoni and Nazem Atassi and Macklin, {Eric A.} and Namita Goyal and Michael Rivner and Ericka Simpson and Stanley Appel and Grasso, {Daniela L.} and Mejia, {Nicte I.} and Farrah Mateen and Alan Gill and Fernando Vieira and Valerie Tassinari and Steven Perrin",
note = "Funding Information: Additional supporting information can be found in the online version of this article. Abbreviations: AE, adverse event; ALS, amyotrophic lateral sclerosis; ALSFRS-R, ALS Functional Rating Scale—Revised; ALSTDI, ALS Therapy Development Institute; AV, atrioventricular; BMI, body mass index; CNS, central nervous system; CSF, cerebrospinal fluid; ECG, electrocardiogram; FDA, U.S. Food and Drug Administration; FEV1, forced expiratory volume in 1 second; FOXP3, forkhead box P3; HR, heart rate; MGH, Massachusetts General Hospital; MS, multiple sclerosis; PFT, pulmonary function test; PET, positron emission tomography; SAE, serious adverse event; S1P, sphingosine 1-phosphate; SOD1, superoxide dismutase 1; SVC, slow vital capacity Key words: circulating lymphocytes; clinical trial; FOXP3; neuroinflamma-tion; RNA profiling; target engagement Funding: This work was supported by the ALS Therapy Development Institute (to T.D.I.). Study drug and placebo were provided by Novartis Pharmaceuticals. Disclosures: J.D.B. has consulted with Biogen-IDEC, Denali Therapeutics, and Neuraltus Pharmaceuticals, and has received research support from Voyager Therapeutics, GSK, Cytokinetics, Brainstorm Cell Therapeutics, Novartis, ALS Therapy Development Institute, ALS Association, Muscular Dystrophy Association, and National Institutes of Health (NIH). S.P. has received funding from the NIH (Career Development Award 2K12HD001097-16), Target ALS, the Salah Foundation, and the Spastic Paraplegia Foundation, and has provided consulting for Roche and Pison Techology. N.A. is funded by an NIH Career Development Award and has research grants from the Harvard Neuro-Discovery Center, ALS Association, ALS Finding a Cure, Spastic Paraplegia Foundation, and Voyager Pharmaceuticals. He provides consulting for Biogen IDEC, Mitsubishi Tanabe, and Denali Therapeutics. E.M. has served on Data and Safety Monitoring Boards for Acorda Therapeutics and Shire Human Genetic Therapies and has received research funding from the Adolph Coors Foundation, ALS Association, ALS Therapy Alliance, ALS Therapy Development Institute, Autism Speaks, Biotie Therapies, California Institute of Regenerative Medicine, Michael J. Fox Foundation, Muscular Dystrophy Association, Food and Drug Administration, Health Resources and Services Adminstration, Patient-Centered Outcomes Research Institute, and NIH. N.G. has received research funding as a principal investigator or subinvestigator from Alexion, Alnylam, Amicus, Baxter, Bio-Blast, Biogen Idec, Biomarin, CSL Behring, Cyto-kinetics, Genzyme, Grifols, GSK, Idera, Ionis Pharmaceuticals, Myositis Association, Novartis, and Ultragenyx. She has received travel subsidies and honoraria as an advisory board member for Mallinckrodt and Novartis. M.R. is on the speakers bureau for Allegan Pharmaceuticals. He is currently funded by the NIH as a co-investigator (1R01NS090083: “Characterization of Agrin/LRP4 Antibody-positive Myasthenia Gravis”). S.A. is a member of the ALSTDI board, Avanir Speaker{\textquoteright}s Bureau, Neuraltus Scientific Advisory Board, and is a scientific consultant for Mitsubishi Tanabe Pharma America. N.I.M. currently receives funding from the NIH (NIH-NINDS 5U01NS077179-S), and previously received funding from NIH (T32 NS048005-08, 2T32 MH019733-19), the National Parkinson Foundation, Rappaport Foundation, and American Academy of Neurology. A.G., F.V., V.T. and S.P. are employees of ALSTDI. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Correspondence to: J.D. Berry; e-mail: jdberry@partners.org VC 2017 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc. Published online 29 June 2017 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.25733",
year = "2017",
month = dec,
doi = "10.1002/mus.25733",
language = "English (US)",
volume = "56",
pages = "1077--1084",
journal = "Muscle and Nerve",
issn = "0148-639X",
publisher = "John Wiley and Sons Inc.",
number = "6",
}