Researchers from the National Institute of Allergy and Infectious Diseases (NIAID) have halted the clemastine fumarate arm of their ongoing TRAP-MS trial after three participants experienced a dramatic fivefold increase in disease progression, triggering protocol-defined safety stopping criteria. The unexpected findings, presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, represent a significant setback for the over-the-counter antihistamine that had shown promise in earlier studies.
The clemastine arm was terminated when three of nine participants demonstrated increased disability five times faster than their 18-month baseline progression slopes. "When we compare the results in clemastine arm with all other patients treated with the remaining drugs, the probability that our patients progressed by chance is lower than 0.01%," said senior investigator Bibi Bielekova, MD, with NIAID.
TRAP-MS Trial Design and Safety Concerns
The TRAP-MS phase 1/2 trial, sponsored by NIAID and begun in 2017, was designed to investigate the effects of four repurposed drugs on MS biomarkers either alone or in combination. The study enrolled an estimated 250 adults with MS and is scheduled for primary completion in 2025. Besides clemastine fumarate, the trial includes pioglitazone (Actos), dantrolene (Ryanodex, Revonto, and Dantrium), and pirfenidone (Pirespa).
In the clemastine arm, nine patients received 8 mg daily divided into three doses of 2, 2, and 4 mg. Cerebrospinal fluid samples were collected at baseline and six months after treatment initiation. The three patients whose worsening symptoms triggered the stopping criteria had increased levels of C-reactive protein and erythrocyte sedimentation rate and gained weight, which study authors described as "suggestive of systemic pro-inflammatory state."
Notably, none of the remaining 55 patients treated with other TRAP-MS therapies for 106.9 patient-years triggered safety criteria, providing what study authors called "evidence for clemastine toxicity."
Mechanistic Insights into Toxicity
Lead author Joanna Kocot, PhD, a NIAID fellow, revealed that clemastine treatment caused significant changes in purinergic metabolism and confirmed the toxic effect was due to pyroptosis, a form of inflammatory cell death. "We found that clemastine treatment causes significant changes in purinergic metabolism," Kocot said during the ACTRIMS presentation. "We also confirmed that this toxic effect of clemastine was because of pyroptosis."
Mechanistic studies using various cell lines, including THP-1 cells, primary human monocyte-derived macrophages, and iPSC-derived oligodendrocytes, demonstrated that clemastine activates inflammasome in human macrophages and prompts pyroptosis in both macrophages and oligodendrocytes. These adverse effects were blocked by P2RX7 antagonist, suggesting the drug's toxicity operates through P2RX7 signaling pathways.
The patients on clemastine with worsening symptoms were older, more disabled, and more obese than the other six patients in the clemastine arm, according to Dr. Bielekova's conference presentation.
Expert Perspectives and Clinical Implications
The findings have generated debate among MS researchers. Paul J. Tesar, PhD, professor of innovative therapeutics at Case Western Reserve University School of Medicine, called the results unexpected but likely indicative of clemastine toxicity. "From the limited data disclosed thus far, it does seem likely that clemastine is causing toxicity, possibly through increased inflammation, and accelerating disease progression," said Dr. Tesar, who was not involved in the study.
Dr. Tesar noted that "the promiscuous nature of clemastine — it binds to many protein targets — and its known side effects make it undesirable as a mainstay treatment for people with multiple sclerosis."
However, Ari Green, MD, medical director of the University of California at San Francisco Multiple Sclerosis Center and lead author of the initial 2017 clinical trial showing clemastine's potential for myelin repair, expressed skepticism about the new findings. "We can't conclude much about an effect based on three patients, and the risk that this is a chance effect is extraordinarily high," Dr. Green said. "It's premature to make any attribution of what they saw to clemastine itself."
Previous Promise and Current Concerns
Clemastine fumarate, available for decades under brand names Tavist and Dayhist, had shown promise in earlier research. A 2017 randomized controlled trial (ReBUILD) published in The Lancet demonstrated that clemastine met its primary endpoint of efficacy in treating chronic demyelinating injury in MS, reducing latency delay by 1.7 ms/eye (95% CI, 0.5-2.9; P = 0.0048) in visual-evoked potentials.
The drug's potential remyelinating properties, combined with animal studies suggesting immune activity reduction, led to off-label use among MS patients. Dr. Green estimated that "hundreds or perhaps thousands of patients with MS may already take the drug because of the early positive findings."
Dr. Bielekova defended the study's conclusions, noting that the pyroptosis score derived from CSF biomarkers was elevated in MS and higher in progressive MS than in relapsing-remitting MS. "From all drugs we tested, only clemastine increased this CSF pyroptosis score," she said.
Despite the controversy, experts agree on the need for caution. "Nobody should take clemastine without the supervision of a doctor," Dr. Green urged. "It's actually best done in the context of clinical trials."
The study was funded by NIAID, with authors reporting no disclosures. Dr. Tesar disclosed being cofounder of Convelo Therapeutics, a biotechnology company developing remyelinating therapeutics for MS.
