Regional variation of remyelination with bexarotene 1 of 4
Experimental work before the trial Huang et al 2 of 4
Primary endpoint failed but MTR of demyelinated lesions is improved by bexarotene 3 of 4
Bexarotene restores conduction in demyelinated optic nerves 4 of 4
Background
Scientific rationale
The rationale for this trial rests on the work of Professor Robin Franklin and colleagues at the University of Cambridge. Read the key paper here: : Huang Franklin Nat Neurosci bexarotene.
Huang and colleagues discovered that the retinoid acid receptor RXR-gamma was expressed during remyelination in the rat; and that human oligodendrocyte lineage cells expressed RXR-gamma in active and remyelinated multiple sclerosis lesions. Antagonism of RXR-gamma severely inhibited oligodendrocyte differentiation in culture, and in RXR-gamma knock-outs differentiation of oligodendrocyte precursor cells after demyelination was delayed. The key finding, that informs this trial, was that administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures, and to aged rats after demyelination, caused increased remyelination of axons. The scientific motivation behind this trial was to assess whether RXR-agonists promote remyelination in people with multiple sclerosis. An important observation from the Franklin group is that remyelination is normally effective and rapid in young animals but declines in efficiency with age.
Bexarotene is an agonist of the retinoid X receptor (RXR) (acting on the alpha, beta and gamma subtypes), which is licensed for human use. Whilst there is recognition that more selective agonists might have fewer adverse effects, none of the newly synthesised compounds are licensed. We therefore proposed bexarotene as the most suitable agent to test the role of RXR agonists in human remyelination.
Funded by the MS Society, with additional support from the Horne Family Trust and the Grand Charity of the Freemasons.
Conclusions:
We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies.
Trial results
Presented at ECTRIMS on Septemebr 26th 2020
Published in the Lancet Neurology 2021; 20: 709–20
Background Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis.
Methods This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18–50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m² of body surface area per day of oral bexarotene or oral placebo for
6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than
the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed.
Findings Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs
none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group
(0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene–placebo difference 0·16 pu, 95% CI –0·39 to 0·71; p=0·55).
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