Small remyelinating effect of metformin plus clemastine

In the Cambridge Centre for Myelin Repair (CCMR)-Two trial, a small but significant remyelinating effect was observed in patients with relapsing-remitting multiple sclerosis (RRMS) and chronic stable optic neuropathy. The combination of metformin and clemastine was well tolerated, with no safety concerns. However, 6 months of treatment did not improve impaired visual function.

 

Promoting myelin regeneration is a leading strategy to prevent disability progression in MS, said Dr Nick Cunniffe (University of Cambridge, UK). Metformin can promote remyelination by reversing age-associated deficits in the responsiveness of oligodendrocyte progenitor cells (OPCs) to pro-differentiation signals. Clemastine promotes OPC differentiation and demonstrated improvements in visual evoked potential (VEP) latency in a previous phase 2 trial [1]. The CCMR-Two trial (NCT05131828) evaluated the efficacy of metformin plus clemastine in promoting remyelination in patients with MS [2]. In this single-centre, randomised, placebo-controlled, double-blind phase 2 trial, participants had chronic stable optic neuropathy in one or both eyes. Of 70 eligible patients, 34 were randomised to metformin 1 g plus clemastine 5.36 mg twice daily, and 36 to placebo for 6 months. The primary endpoint was the mean change in P100 latency of the full-field VEP from baseline to week 26.

Metformin plus clemastine was associated with a small but statistically significant reduction in VEP latency. The adjusted difference was -1.2 ms (95% CI -2.4 to -0.1; P=0.042). No effects on the Expanded Disability Status Scale (EDSS) or visual function measures were observed. Active treatment was associated with a trend towards higher multifocal (MF)-VEP amplitude, but the impact on latency was minimal. Changes in the lesional magnetisation transfer ratio (MTR) suggested that treatment effects were most likely in less damaged lesions. The combination was well tolerated, with no adverse safety signals.

Dr Cunniffe concluded that the treatment effects were smaller than expected but may increase with longer follow-up. “There is growing justification for conducting longer-term trials and for extended follow-up of participants from previous remyelination studies.”

1. Green AJ, et al. Lancet. 2017;390(10111):2481-2489.
2. Cunniffe NG, et al. Evaluating the remyelinating efficacy and safety of the combination of metformin and clemastine in people with relapsing remitting multiple sclerosis (CCMR-Two): a randomised, placebo-controlled, double-blind, phase 2 clinical trial. O133, ECTRIMS 2025 Congress, 24-26 September  2025, Barcelona, Spain.

 

Medical writing support was provided by Michiel Tent.

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Posted on 29 September 2025