Bexarotene Demonstrates Long-Term Remyelinating Effects in Relapsing Multiple Sclerosis

Chris McMurran, PhD

A recently published substudy of the Cambridge Centre for Myelin Repair One (CCMR-One) trial showed that treatment with bexarotene, a nonselective retinoid X receptor agonist, resulted in durable improvements in visual evoked potential (VEP) latency in patients with relapsing multiple sclerosis. Overall, these data suggest that bexarotene has a remyelinating effect in humans, sustained years after the treatment period has concluded.

CCMR-One was a double-blind, placebo-controlled, phase 2a trial that recruited patients with relapsing-remitting MS, aged 18-50 years old, who had been receiving dimethyl fumarate for at least 6 months. The recently published follow-up analysis investigated the long-term effects of bexarotene in 20 participants (bexarotene, n = 12; placebo, n = 8) followed on average 27 months after their trial involvement.

Led by Chris McMurran, PhD, a junior doctor at the Cambridge University Hospitals NHS Foundation Trust, full-field VEP (FF-VEP) latency was performed on a Nicolet Synergy system (Optima Medical Ltd, UK). At both the CCMR One baseline and follow-up visit, 38 of 40 FF-VEP recordings were of sufficient quality to be analyzed. With all eyes included (24 bexarotene and 14 placebo), there was a statistically significant difference between the follow-up and baseline P100 latencies of the 2 trial arms, with an adjusted treatment difference of –7.79 (95% CI, –14.76 to –0.82; P = .044).

"This substudy of CCMR One is, to our knowledge, the second conducted at a time years remote from participation in a remyelination trial and the first to return a statistically significant result over this time scale,” the study authors wrote. "We conclude that this supports the increasingly clear position that pharmacological promotion of remyelination in people living with multiple sclerosis is possible and indicates a sustainability to repair following treatment with a remyelinating drug."

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Since their participation in the original study, no patients have had an episode of acute optic neuritis in the follow-up substudy. When only eyes with a baseline P100 latency greater than 118 ms were included (20 bexarotene and 7 placebo), the trend to improvement in P100 VEP latency remained but was not statistically significant. Overall, in this group, the adjusted treatment difference was –5.39 (95% CI, –16.11 to 5.32; P = .343).

All participants had a repeated Expanded Disability Status Scale (EDSS) assessment that was analyzed on a multiple regression model. All told, after adjusting for age and gender, the between-group difference in EDSS was –0.31 (95% CI, –1.37 to 0.74; P = .569), signifying no treatment difference. In a sensitivity analysis that excluded participants that had clinical relapses or radiological activity after trial participation, the EDSS difference was –0.25 (95% CI, –1.32 to 0.81; P = .644).

There were a few noted limitations to the analysis, including the fact that there was a small number of patients who agreed to participate. In addition, when observing eyes with a baseline P100 latency greater than 118 ms, the treatment effect size was larger than that observed in the CCMR One trial, which may reflect the small numbers in the placebo group (7 eyes). Lastly, a potential confounding factor is that the follow-up clinic used a VS+ device, in comparison to a synergy (Optica medical) set-up during the trial.

This was not the first time VEP latency changes were observed after exposure to a putative remyelination drug. Before CCMR One, the ReBUILD study of clemastine and the RENEW trial of opicinumab demonstrated similar effects. In ReBUILD, sustained VEP improvements were observed 2 months after clemastine discontinuation in one of the trial groups.² In RENEW, the VEP was repeated 8 weeks after IMP discontinuation, at which point the treatment difference in the per-protocol sample had increased to -9.1 ms, from −7.6 ms at the end of the 24-week treatment period.³

REFERENCES
1. McMurran CE, Mukherjee T, Brown JW, Coles AJ, Cunniffe NG. Bexarotene leads to durable improvements in visual evoked potential latency: a follow-up study of the Cambridge Center for Myelin Repair One trial. Mult Scler Journ. 2024;0(0). doi:10.1177/13524585241233177
2. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): A randomised, controlled, double-blind, crossover trial. Lancet 2017;390:2481–2489.
3. Cadavid D, Balcer L, Galetta S, et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): A randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2017;16(3):189–199.