Clemastine Fumarate and Progressive MS: A Closer Look at Unexpected Risks and Mechanisms

Clemastine (CLM) fumarate, an over-the-counter antihistamine, has generated considerable excitement as a potential remyelinating therapy for multiple sclerosis (MS). Early data from the phase II ReBUILD trial suggested that CLM could modestly enhance myelin repair, as demonstrated by improvements in visual evoked potentials and MRI biomarkers in patients with relapsing-remitting MS.

However, new evidence from an ongoing platform clinical trial, TRAP-MS, now paints a far more complex picture. In this study, CLM was evaluated in patients whose disability was advancing independently of new lesion formation, also called progression independent of relapse activity (PIRA). This population represents an unmet need, as current disease-modifying therapies (DMTs) largely target inflammatory lesion activity and offer little benefit once lesion formation slows.

TRAP-MS enrolled 16 patients in the CLM arm, with nine completing at least one six-month follow-up visit. Participants were required to have documented disability progression over at least 18 months prior to enrollment. Clinical progression was tracked using CombiWISE, a continuous, machine-learning-derived scale that integrates multiple neurological assessments and correlates with Expanded Disability status Scale (EDSS) scores.

TRAP-MS included strict safety rules. If three participants in a treatment arm experienced a five-fold increase in their disability progression rate compared with baseline, that arm would be stopped for toxicity. Three of nine CLM-treated patients (33.3 percent) reached this stopping point, prompting early closure of the CLM arm (P = 0.00015). By contrast, among 63 participants receiving six other study drugs, none reached this level of worsening over a much longer follow-up period (84.3 patient-years).

Unexpected Clinical and Biological Findings

Most CLM-treated participants experienced faster progression, with six out of nine patients showing an increased disability slope. In addition to neurological worsening, CLM was associated with systemic changes resembling metabolic syndrome:

• Weight gain occurred in 89 percent of patients
• LDL and total cholesterol rose in 88 percent
• C-reactive protein (CRP), a marker of inflammation, increased in 78 percent

These changes were not seen in participants receiving other investigational therapies. This pattern pointed toward metabolic syndrome and innate immunity activation.

Mechanistic Insights: The Role of Pyroptosis

By analyzing approximately 7,000 cerebrospinal fluid (CSF) proteins, researchers identified a striking increase in pathways related to purinergic signaling. Further experiments revealed that CLM acts as an allosteric modulator of the P2RX7 receptor, a channel highly expressed on microglia and oligodendrocytes. In the presence of even modest extracellular ATP, CLM amplified P2RX7 activity. This led to activation of the inflammasome, triggering pyroptosis, a highly inflammatory form of programmed cell death.

Reanalysis of publicly available RNA sequencing data from MS brain tissue revealed elevated P2RX7 expression and pyroptosis-related genes, particularly in chronic active lesions. These findings suggest that in the pro-inflammatory environment of progressive MS, CLM may inadvertently accelerate tissue damage rather than repair it.

Clinical Relevance and Broader Implications

The CSF pyroptosis signature was significantly higher in progressive MS compared with relapsing-remitting disease (P = 1.9 × 10⁻⁵) and correlated with both brain atrophy rates (P = 0.002) and overall MS severity (P < 0.001). Importantly, participants who worsened most on CLM already had elevated baseline pyroptosis scores, indicating a potential biomarker for susceptibility.

The initial hope that clemastine fumarate might repair myelin in progressive MS has been replaced with a more nuanced understanding. In this carefully monitored trial, CLM was linked to accelerated disability progression and systemic inflammation through a previously unrecognized mechanism involving P2RX7 and pyroptosis.

Reference:

Kocot J, Kosa P, Ashida S, et al. Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis. J Clin Invest. 2025;135(10):e183941. Published 2025 May 15. doi:10.1172/JCI183941