Retinoid-X receptor agonism promotes remyelination in relapsing-remitting multiple sclerosis: a phase 2 clinical trial. Issue 6 (27th May 2022)

• Record Type: Journal Article
• Authors: L Brown, J William; Cunniffe, Nicholas G; Prados, Ferran; Kanber, Baris; Connick, Peter; lin, Robin Frank-; Chandran, Siddharthan; Altmann, Daniel; Chard, Declan T; Coles, Alasdair J
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 93:Issue 6(2022)
• Page Start: A92
• Page End: A92
• Publication Date: 2022-05-27
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2022-ABN.300
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: In rodents, retinoid acid X receptor [RXR]-gamma agonists promote CNS remyelination. Methods: In 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. Results: 52 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). Conclusions: Despite 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. [e-mail]