A Phase 1b, open-label study to evaluate the safety and tolerability of the putative remyelinating agent, liothyronine, in individuals with multiple sclerosis
ECTRIMS Online Library. Newsome S. 09/11/19; 279395; 60
Scott D Newsome
Scott D Newsome

Abstract: 60

Type: Scientific Session

Abstract Category: Therapy - Neuroprotection and Repair

S.D. Newsome1, F. Tian1, K.C. Fitzgerald1, P. Bhargava1, T. Shoemaker2, S. Snoops1, D. Cooper3, J. Mammen3, E.M. Mowry1, P.C. Calabresi1

1Neurology, John Hopkins University School of Medicine, Baltimore, MD, 2Neurology, Rush University Medical Center, Chicago, IL, 3Endocrinology, John Hopkins University School of Medicine, Baltimore, MD, United States

Introduction: Thyroid hormones may play a direct role in remyelination and repair in the adult central nervous system by promoting differentiation of oligodendrocyte precursor cells into mature oligodendrocytes. Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone actions, liothyronine (synthetic T3) has the potential to induce reparative mechanisms and limit neurodegeneration in multiple sclerosis (MS).
Objective/Aim: To determine the safety and tolerability of ascending doses of liothyronine in individuals with MS.
Methods: We enrolled 20 patients with MS in this single center trial of oral liothyronine for 24 weeks. Participants received liothyronine according to a standardized dose-titration schedule. Eligibility criteria included euthyroid patients, 18-58 years old, 2010 McDonald MS and Expanded Disability Status Scale (EDSS) score 3.0-7.5. Main exclusion was known thyroid dysfunction. The primary outcome was safety and tolerability of liothyronine. Pre-specified secondary outcomes of interest included changes in timed 25-foot walk (T25FW), processing speed, depression, and health-related quality of life. We assessed change in a given pre-specified outcome associated with liothyronine treatment using mixed effects regression models adjusted for age, sex, disease subtype/duration and body mass index. Preliminary analyses stratifying by disease subtype were also performed. Biospecimens were collected for exploratory biomarkers of treatment response.
Results: Eighteen patients completed the study; 9 women, 11 relapsing MS, mean age 45.4, and baseline median/IQR for EDSS 3.75 (3.50-6.00). Liothyronine was tolerated well without treatment-related severe/serious adverse events or evidence of disease activation/clinical deterioration. Most common adverse events included gastrointestinal distress and abnormal thyroid function tests, although no clinical thyrotoxicosis occurred. In preliminary analyses, T25FW improved by 0.33 seconds in progressive patients (n=8; 95% CI: -0.45, -0.31; P= 0.007) and there was a trend for improved thinking/fatigue in relapsing patients (P=0.059).
Conclusions: Liothyronine appeared safe and was well-tolerated in patients with MS. A larger clinical trial will help assess whether liothyronine can promote oligodendrogenesis and enhance remyelination in vivo, limit axonal degeneration, and improve function.
Scott Newsome has received consultant fees for scientific advisory boards from Biogen, Genentech, Celgene, EMD Serono, is an advisor for Gerson Lehrman Group, a clinical adjudication committee member for a medDay Pharmaceuticals clinical trial and has received research funding from Biogen, Novartis, Genentech, Department of Defense, National MS Society, Patient Centered Outcomes Research Institute
(paid directly to institution).
Pavan Bhargava has received speaking honoraria from Sanofi Genzyme and received research funding from EMD Serono, Genentech, and Amylyx pharmaceuticals.
Thomas Shoemaker has received consultant fees from Genentech.
Ellen Mowry has grants from Biogen and Genzyme, is site PI for studies sponsored by Biogen and Sun Pharma, has received free medication for a clinical trial from Teva and receives royalties for editorial duties from UpToDate.
Peter Calabresi has received consulting fees from Disarm Therapeutics and Biogen and is PI on grants to JHU from Biogen and Annexon.
Fan Tian has nothing to disclose.
Kathryn C. Fitzgerald has nothing to disclose.
Sarah Snoops hasnothing to disclose.
David Cooper has nothing to disclose.
Jennifer Mammen has nothing to disclose.

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