In 2011, Prof Franklin’s team showed that agonists of the retinoid X receptor led to remyelination of demyelinated lesions in rats (Huang 2011 Nat Neurosci).
This led us to undertake the “Cambridge Centre for Myelin Repair” One trial of bexarotene [a drug already licensed for some skin cancers] in people with relapsing-remitting MS.
The “primary endpoint” was not met, in that the people taking bexarotene did not have an overall improvement in the level of “MTR” in their MRI brain lesions, but there were improvements in lesional MTR in particular parts of the brain, for instance grey matter.
Bexarotene also improved the latency of visual evoked potentials in those eyes with delayed latency at baseline. These findings all suggest a modest effect of bexarotene to induce remyelination. Notably, efficacy was greater in younger people.
Bexarotene was poorly tolerated causing hypothyroisim in all participants, hyper-triglyceridaemia in most and 5/26 had to withdraw from treatment.
These data are published in detail in
1: Brown JWL, Cunniffe NG, Prados F, Kanber B, Jones JL, Needham E, Georgieva Z, Rog D, Pearson OR, Overell J, MacManus D, Samson RS, Stutters J, Ffrench-Constant C, Gandini Wheeler-Kingshott CAM, Moran C, Flynn PD, Michell AW, Franklin RJM, Chandran S, Altmann DR, Chard DT, Connick P, Coles AJ. Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study. Lancet Neurol. 2021 Sep;20(9):709-720. doi: 10.1016/S1474-4422(21)00179-4. PMID: 34418398.
2: McMurran CE, Mukherjee T, Brown JWL, Michell AW, Chard DT, Franklin RJM, Coles AJ, Cunniffe NG. Remyelination in humans due to a retinoid-X receptor agonist is age-dependent. Ann Clin Transl Neurol. 2022 Jul;9(7):1090-1094. doi: 10.1002/acn3.51595. Epub 2022 May 19. PMID: 35587315; PMCID: PMC9268872.
3: Brown JWL, Prados F, Altmann DR, Kanber B, Stutters J, Cunniffe NG, Jones JL, Georgieva ZG, Needham EJ, Daruwalla C, Wheeler-Kingshott CG, Connick P, Chandran S, Franklin R, MacManus D, Samson R, Coles A, Chard D. Remyelination varies between and within lesions in multiple sclerosis following bexarotene. Ann Clin Transl Neurol. 2022 Oct;9(10):1626-1642. doi: 10.1002/acn3.51662. Epub 2022 Sep PMID: 36116011; PMCID: PMC9539389.
Researchers wishing to investigate the CCMR1 dataset are encouraged to apply here.