ECTRIMS 2025: Drug combo shows promise for myelin repair in trial
Diabetes medication, antihistamine has effect in relapsing-remitting MS patients
Combining the diabetes medication metformin and the antihistamine clemastine significantly increased myelin repair in people with relapsing-remitting multiple sclerosis (RRMS), according to results from a Phase 2 clinical trial.
However, the effects were small, and participants showed no improvements in disability or visual function after six months of treatment.
Given this is the third trial showing a significant remyelination effect from this drug combo, and it may take years for a significant reduction in disability to emerge, the findings support the launch of further long-term trials to study this combination in MS, according to Nick G. Cunniffe, MD, PhD, a clinical lecturer in neurology at the University of Cambridge.
Cunniffe shared the data at this year’s European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting, held Sept. 24-26 both online and in Barcelona, Spain. His presentation was titled: “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.”
Repair of myelin could theoretically restore lost function
MS occurs when the immune system mistakenly attacks the myelin sheath, a protective layer around nerve fibers that helps them send electrical signals more efficiently.
While several disease-modifying therapies (DMT) are approved to treat relapsing forms of MS, these mainly work by reducing the inflammatory attacks to prevent further damage. Existing therapies cannot repair damage that has already occurred.
Repairing myelin, a process called remyelination, could theoretically restore lost function and reduce disability in MS patients. For that reason, a major goal of modern MS research is to identify treatments that can promote remyelination.
Metformin and clemastine are medications approved for other indications that may potentially help promote myelin repair. Preclinical data have indicated that metformin can restore the regenerative capacity of aged oligodendrocyte progenitor cells, allowing them to respond to drugs like clemastine, which boost their differentiation into mature oligodendrocytes.
Oligodendrocytes are the cells mainly responsible for making new myelin in the brain and spinal cord.
Trial measured changes in electrical signal
Building on these data, the CCMR-Two Phase 2 clinical trial (NCT05131828) was launched to test if a combination of metformin and clemastine could promote remyelination in RRMS patients taking a stable dose of their DMT for at least six months. A total of 70 patients were enrolled and randomly assigned to receive 1 g metformin and 5.36 mg clemastine, or a matching placebo, twice daily for six months.
The trial’s main goal was to assess changes in a measure called visual evoked potential (VEP), which assesses the time it takes for an electrical signal to travel from the eye to the brain. When myelin is damaged, electrical signals travel more slowly. Thus, a shorter VEP latency means the signals are traveling faster and is suggestive of remyelination.
To be eligible for the trial, patients needed to have an abnormally long VEP latency in at least one eye. Cunniffe noted that nearly half of the patients who expressed interest in the trial were not able to participate because their VEP measurements were within normal ranges.
A total of 67 participants completed the study. Results showed that the average VEP latency was 1.2 milliseconds shorter in patients given the active treatment compared with patients given the placebo.
This difference was statistically significant, but Cunniffe noted the effect was “smaller than we expected, and it’s certainly not of the magnitude that we would anticipate would be clinically detectable by our participants over six months.”
Measures of disability and visual function at the end of the trial showed no significant differences between patients given the combination or a placebo. MRI measures also generally didn’t show significant differences, though analyses did indicate that lesions with less myelin damage were more likely to show signs of remyelination after treatment with metformin and clemastine.
Our main reflection is that we believe this provides justification [for] longer-term remyelination trials, and also demonstrates the real need … to follow-up participants from previous remyelination trials so that we can capture the long-term benefits of these drugs.
Safety data showed the combo was generally well tolerated. Common side effects included gastrointestinal issues, as well as fatigue and sedation, which are known to be common side effects of metformin and clemastine, respectively.
“There was no effect on clinical function from six months of treatment, but that is not unexpected,” Cunniffe said, noting that it might take years of follow-up to detect a statistically meaningful effect on disability progression from a small amount of remyelination.
Cunniffe said the takeaway from this study is that it’s worth performing further long-term studies of the metformin plus clemastine combo as a potential remyelination therapy for MS.
“Our main reflection is that we believe this provides justification [for] longer-term remyelination trials, and also demonstrates the real need … to follow up participants from previous remyelination trials so that we can capture the long-term benefits of these drugs,” Cunniffe said, noting that efforts are already underway to gather more long-term data from this patient cohort.
Note: The Multiple Sclerosis News Today team is providing live coverage of the 41st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Sept. 24-26. Go here to see the latest stories from the conference.
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