News

Article

Biological Effects Seen in Small Scale Study of Remyelinating Agent for MS

Author(s):

The findings provided safety and tolerability data for using liothyronine in future, larger studies of multiple sclerosis, with the potential to be observed in combination with other therapies.

Scott Newsome, DO, professor of neurology at Johns Hopkins School of Medicine

Scott Newsome, DO

Liothyronine, a thyroid hormone replacement therapy used to treat hypothyroidism, demonstrated safety and tolerability as a potential remyelinating agent in a recently published phase 1b study (NCT92596751) of individuals with multiple sclerosis (MS). All told, proteomic changes in cerebrospinal fluid among treated patients suggested a biological effect of triiodothyronine (T3) treatment within the central nervous system (CNS).

Published in Neurotherapeutics, the single-center study featured 20 individuals with either relapsing or progressive MS who were followed for a 24-week treatment period. Led by Scott Newsome, DO, professor of neurology at Johns Hopkins School of Medicine, the study’s goal was to assess safety and tolerability of ascending doses of liothyronine.

Previous research has shown that thyroid hormones may play a direct role in remyelination and repair in the adult CNS by promoting maturation of oligodendrocytes. Furthermore, thyroid hormones have been shown to reduce oxidative stress and thus may have the capacity to prevent mitochondrial dysfunction as well. While several immune modulating therapies exist, there is an urgent need for novel therapies that have neuroreparative and neuroprotective properties.

Of the cohort, the median Expanded Disability Status Scale (EDSS) scores were 3.5 (IQR, 3.5-6.0), with most patients having relapsing MS (12 o 20). In terms of safety, the most common relevant adverse events (AEs) reported were gastrointestinal distress, fatigue, headaches, insomnia, and palpitations. Two of the study participants did not complete the trial, one of which self-discontinued treatment after their week 18 visit due to a treatment-emergent AE that was deemed possibly related to the study drug. The patient, who had a prior history of diverticulitis and a long-standing history of irritable bowel syndrome, developed bowl incontinence and abdominal pain which resolved after stopping treatment.

Key Takeaways

1. Liothyronine showed safe and well-tolerated potential as a remyelinating agent in patients with multiple sclerosis (MS), suggesting a role in CNS repair.

2. Thyroid hormones may offer neuroreparative and neuroprotective properties, reducing oxidative stress and potentially preventing mitochondrial dysfunction in MS.

3. Adverse events like gastrointestinal distress, fatigue, headaches, and palpitations were managed through dose reduction, warranting careful monitoring and individualized treatment plans, particularly for patients with pre-existing gastrointestinal conditions. Larger trials are needed to confirm liothyronine's efficacy and explore combination therapies for enhancing remyelination and CNS repair in patients with MS.

Throughout the study, investigators observed stable electrocardiogram findings, with no required dose adjusting needed. Although patients were on stable disease-modifying therapy, there were no observed relapses or disability progression that occurred during the study. Lab monitoring data revealed that serum thyroid function tests did change over time but did not result in clinical thyrotoxicosis. Following a recommended dose escalation schedule change by an independent Data Safety Monitoring Board, 8 of the 20 participants required a dose reduction. This led to fewer systemic side effects, including the prevalence of gastrointestinal AEs decreasing from 70% to 33%, and headaches decreasing from 86% to 8%.

READ MORE: World Health Organization Adds Several MS Treatments to List of Essential Medicines

Throughout the trial, secondary outcome measures such as EDSS, Symbol Digit Modalities Test, Multiple Sclerosis Functional Composite, Functional Assessment of Multiple Sclerosis (FAMS), and Beck Depression Inventory-II, were sustained while on treatment. Patients with progressive MS demonstrated slight improvements in timed 25 foot walk test while those with relapsing MS showed trends of improvement on FAMS.

Using a proteomics platform, 46 measured proteins (19 increased, 27 decreased) changed over the course of the study (P <.05). These included proteins related to immune function such as TACI, NKp46, IgA, and IgD, and angiogenesis such as Cadherin-5, sTIE-1, and ANGPT2. Of note, angiogenesis-related proteins predominantly demonstrated an increase with liothyronine treatment and the majority of immune-related proteins decreased with treatment.

Investigators concluded that a larger clinical trial could determine whether liothyronine can promote oligodendrogenesis and enhance remyelination in vivo, limit axonal degeneration, and improvement function. "Future studies may also need to consider combination therapies that focus on different aspects of augmenting remyelination and repair in MS," they wrote.

REFERENCE
1. Newsome SD, Tian F, Shoemaker T, et al. A phase 1b, open-label study to evaluate the safety and tolerability of the putative remyelinating agent, liothyronine, in individuals with MS. Neurotherapeutics. Published online July 17, 2023. doi:10.1007/s13311-023-01402-3.
Related Videos
Mikael Cohen, MD
Robert J. Fox, MD; Andreas Muehler, MD, MBA
1 KOL is featured in this series.
1 KOL is featured in this series.
Wallace Brownlee, MBChB, PhD, FRACP
© 2024 MJH Life Sciences

All rights reserved.