Retinoid-X receptor agonist promotes remyelination

In a double-blind, placebo-controlled phase 2a trial, the non-specific retinoid-X receptor agonist bexarotene promoted remyelination in MS patients [1]. Bexarotene was very poorly tolerated and its use in MS is not recommended by the authors. However, they believe that their data support the development of selective retinoid-X receptor gamma agonists.

The trial assessed the safety and efficacy of bexarotene, which is licensed for the treatment of cutaneous T cell lymphoma, as a remyelinating therapy in people with relapsing-remitting MS. The 52 randomised participants were aged 18-50 years, had an EDSS score of 6 or less and at least 5 MRI brain lesions, and were stable on dimethyl fumarate for at least 6 months. They were randomised 1:1 to bexarotene 300 mg/m² or placebo for 6 months. The primary efficacy endpoint was change in magnetisation transfer ratio (MTR) of those lesions with the lowest tissue integrity at baseline, that is those with MTR values below the “within-patient” median (the submedian). Analysis was by intention to treat.

The primary efficacy outcome was not met. There was no significant difference in mean submedian lesion MTR change. This difference, adjusted for baseline MTR, EDSS, age, gender, and site, was 0.16 pu (0.25 pu in the bexarotene group vs 0.09 pu in the placebo group; P=0.54). In an exploratory analysis at lesion level, the treatment difference in submedian lesions was significantly greater than in supermedian lesions (P=0.001-0.007). This suggests a biological effect of bexarotene on MTR which depends on baseline lesional MTR. When lesions were divided by location, there were statistically significant treatment differences in cortical grey matter lesions, deep grey matter lesions, and brainstem lesions. Furthermore, bexarotene reduced full field visual evoked potential (VEP) latency versus placebo in all eyes and in the 52 eyes with delayed VEPs at baseline.

All 26 patients in the bexarotene group experienced adverse effects: 6.12 on average. Patients in the placebo group experienced on average 1.63 adverse events. In the experimental group, 100% experienced hypothyroidism, and 92% hypertriglyceridaemia, while 50% had rash and 38% neutropenia. In the bexarotene and placebo group, there were 0 and 1 serious adverse events, respectively.

1. Brown J, et al. Phase 2 clinical trial evidence that a retinoid-X receptor agonist promotes remyelination in people with relapsing-remitting multiple sclerosis. MSVirtual 2020, LB01.02

 



Posted on 25 November 20205 September 2024