Researchers Hope Goal of Myelin Repair Is Closer Even With Poor Trial Results

September 26, 2020

Researchers hope that a more targeted retinoid acid X receptor compound could repair myelin without the adverse effects seen in every patient in this trial, which tested an already approved cancer drug.

Even though a clinical trial showed a small-molecule cancer drug could not be safely repurposed for myelin repair in multiple sclerosis (MS), investigators are hopeful that the findings will move the field closer to a possible treatment since results indicate that such repair is possible.

At a presentation Saturday morning during the final day of MSVirtual2020: 8th Joint ACTRIMS-ECTRIMS Meeting, results of a phase 2a trial investigating bexarotene showed that as a remyelinating therapy in patients with relapsing-remitting multiple sclerosis (RRMS), it created serious adverse effects (AEs) in every patient. Bexarotene is sold under the name Targretin and is approved for cutaneous T-cell lymphoma.

Prior work has shown that retinoid acid X receptor (RXR) gamma agonists promote oligodendrocyte progenitor cell differentiation and remyelination. Oligodendrocytes are cells that can reach out to nearby axons and wrap them in the protective myelin sheath, which MS destroys, resulting in a wide range of effects, including numbness, weakness, vision problems, and mobility problems.

Bexarotene is a nonspecific RXR agonist, but researchers hope that a more targeted RXR compound could repair myelin without the AEs seen in the current trial, which was conducted by the UK’s Cambridge Centre for Myelin Repair.

In the double-blind, placebo-controlled trial, 52 participants aged 18 to 50 years with RRMS and stable on dimethyl fumarate for at least 6 months were randomized 1:1 to bexarotene 300 mg/m2 or placebo for 6 months. The patients had at least 5 lesions on a typical MRI brain scan. Two patients in the placebo group withdrew before drug administration began and 1 patient in the bexarotene group withdrew.

The primary efficacy outcome was the change in mean lesional magnetization transfer ratio (MTR) for lesions whose baseline MTR was below the median lesional MTR for that patient. MTR is a novel imaging technique that attempts to assess myelin content and nerve fiber density.

The secondary efficacy outcome was change in full-field visual evoked potential latency in eyes with electrophysiological evidence of optic neuropathy (baseline latency > 118ms).

The modified intention-to-treat analysis showed that all 26 bexarotene patients experienced AEs, notably central hypothyroidism (100%), hypertriglyceridemia (92%), rash (50%), and neutropenia (38%).

Two discontinued placebo because of AEs; 5 discontinued bexarotene because of rash, neutropenia, triglyceridemia, and mood disturbance.

Although the primary efficacy outcome was negative, the treatment difference in submedian lesions was statistically significantly greater than in supermedian lesions (P = .007).

“This suggests that bexarotene has a biological effect on MTR and that this effect is dependent on baseline lesional MTR,” the researchers wrote.

In addition, bexarotene treatment had a statistically significant result in ophthalmology outcomes.