Antihistamine clemastine may worsen MS disease progression
Treatment triggers type of cell death, trial data show
Clemastine fumarate, an antihistamine, boosted disease progression by more than five times in adults with progressive multiple sclerosis (MS), according to data from a Phase 1/2 trial.
“Likely nobody in the MS field, us included, knew about this potential [clemastine] toxicity until we collected the data presented here,” the researchers wrote.
Experiments suggested that clemastine accelerated disability by triggering pyroptosis, an inflammatory type of programmed cell death, which was shown to contribute to disease progression in the absence of lesion activity even without clemastine toxicity.
The study, “Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis,” was published in the Journal of Clinical Investigation.
MS is marked by immune-mediated damage to the myelin sheath, a fatty protective coating on nerve fibers. This results in inflammation, which further damages the myelin sheath, nerve cells, and cells that produce myelin called oligodendrocytes.
Disease progression in trial participants
Clemastine fumarate is a first-generation oral antihistamine used in adults and children to relieve allergy symptoms temporarily.
In a previous Phase 2 trial called ReBUILD (NCT02040298), clemastine significantly boosted the speed of nerve impulses and showed potential to repair myelin in people with relapsing forms of MS.
Building on these findings, a clemastine arm was added to the ongoing Phase 1/2 TRAP-MS (NCT03109288) clinical trial. The study is testing several experimental MS therapies simultaneously in patients who continued to experience worsening disability independent of lesion activity (PIRA).
Of the nine patients on daily clemastine who completed at least one follow-up visit after six months of treatment, three (33.3%) experienced a progression of disability that was more than five times faster than before the treatment. The probability that this result occurred by chance was 0.015%, the researchers noted. These patients received 8 mg of clemastine daily, either alone or in combination with their current disease-modifying therapies.
In comparison, the accelerated disability progression was not observed in the other six treatment arms of TRAP-MS, representing 42 patients, which were evaluating other medicines including the antidiabetic pioglitazone, the muscle-relaxant dantrolene, and the antifibrotic pirfenidone.
“We conclude that [clemastine] accelerated disability progression in these patients with advanced progressive MS,” the researchers wrote.
In addition to boosting disability progression, most of the clemastine-treated patients experienced an increase in body weight (89%), total cholesterol (88%), low-density lipoprotein (LDL) cholesterol, or the “bad” cholesterol (88%), and CRP, a marker for body-wide inflammation. These changes were not seen with the other drugs tested in TRAP-MS.
To investigate the underlying mechanisms of clemastine-driven adverse effects, the team measured the levels of proteins in the cerebrospinal fluid, which surrounds the brain and spinal cord, collected before and after clemastine treatment.
Data showed that clemastine altered the metabolism of certain DNA building blocks. It also activated pyroptosis, a highly inflammatory form of programmed cell death, in immune macrophages via a protein receptor called P2RX7. Moreover, clemastine helped to induce the cell death of myelin-producing oligodendrocytes, which express high levels of P2RX7, especially in the spinal cord.
The researchers then examined whether pyroptosis contributes to the progression of MS disability in those not treated with clemastine.
In MS brain tissue, P2RX7 expression and the pyroptosis signaling pathway signatures were higher in oligodendrocytes, as well as a type of immune cell in the brain called microglia. P2RX7 expression was highest in chronic active MS lesions, followed by periplaque white matter — areas surrounding lesions — and chronic inactive lesions, compared with active lesions.
“We hope our results will lead to a proof-of-principle clinical trial of the brain-penetrant P2RX7 inhibitor in MS,” the team wrote.
Using data from clinical trials, measures of how much pyroptosis was occurring were significantly higher in progressive MS than in healthy donors and in relapsing-remitting MS patients. These also correlated significantly with rates of brain tissue loss and MS disease severity.
Before clemastine treatment, the pyroptosis score was elevated in all three patients who experienced accelerated disability progression with clemastine in the TRAP-MS study and continued to increase after initiating treatment with this medication.
These results implicate “pyroptosis as an important [disease-driving] mechanism of PIRA-associated [brain and spinal cord] tissue destruction in MS,” the researchers wrote.
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