Retinoid-X receptor agonism promotes remyelination in relapsing-remitting multiple sclerosis: a phase 2 clinical trial

Abstract

BackgroundIn rodents, retinoid acid X receptor [RXR]-gamma agonists promote CNS remyelination.MethodsIn this double-blind phase 2a trial, participants with relapsing remitting multiple sclerosis (RRMS), stable on dimethyl fumarate, were randomised to bexarotene 300mg/m2 (a non-specific RXR agonist) or placebo for 6 months. The primary efficacy outcome was change in mean lesional magnetisation transfer ratio (MTR) for lesions below the within-patient median MTR. The secondary efficacy outcome was change in visual evoked potential (VEP) latency in eyes with electrophysiological evidence of optic neuropathy.Results52 patients were randomised to bexarotene or placebo. All bexarotene patients experienced adverse effects, notably central hypothyroidism (26 [100%]), hypertriglyceridaemia (24 [92%]), rash (13 [50%]) and neutropenia (10 [38%]). Two discontinued placebo and five discontinued bexarotene through adverse events.The primary efficacy outcome was negative (mean submedian lesion MTR change 0.25pu (bexarotene) vs 0.09pu (placebo), p=0.54), but significant effects were seen in grey matter lesions (p=0.008). Bexarotene reduced VEP latency in those with optic neuropathy (group difference 4·66 ms/eye, p=0·014).ConclusionsDespite a negative primary outcome, we found imaging and electrophysiological evidence of remyelination following RXR agonism in people with RRMS. Bexarotene’s safety profile precludes it’s use, but these data support selective RXR-gamma agonist development.william.brown@doctors.org.uk