New findings from the TRAP-MS trial (NCT03109288) revealed that treatment with clemastine fumarate, an over-the-counter antihistamine, resulted in increased disability accumulation in patients with non-lesional multiple sclerosis (MS) activity through potentiating intrathecal P2RX7 signaling and pyroptosis. Presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 29 to March 2, in West Palm Beach, Florida, investigators thus halted the clemastine arm and concluded that pyroptosis is a mechanism of central nervous system (CNS) tissue injury that underlies MS non-lesional activity.1
In the trial, investigators halted the clemastine arm because of 3 participants who increased in disability 5-times faster than compared with 18-month “baseline” progression slopes, ultimately triggering the protocol-defined safety stopping criteria. Authors noted that none of the remaining 55 patients treated for 106.9 patient-years with other TRAP-MS therapies had triggered the safety criteria. Notably, the patients treated with clemastine had increased erythrocyte sedimentation rate/C-reactive protein and gained weight. Investigators noted that this was corroborated by cerebrospinal fluid (CSF) proteomic profiling that demonstrated activation of innate immunity, increased purinergic/ATP signaling, and enhancement of immunogenic cell death, including pyroptosis.
Top Clinical Takeaways
- Clemastine fumarate, initially included in the TRAP-MS trial for CSF remyelination insights, unexpectedly increased disability accumulation, leading to trial discontinuation.
- Patients treated with clemastine exhibited elevated erythrocyte sedimentation rate/C-reactive protein, weight gain, and CSF proteomic changes indicative of enhanced innate immunity and pyroptotic cell death.
- Mechanistic studies revealed clemastine's activation of inflammasome and pyroptosis in macrophages and oligodendrocytes, highlighting potential CNS injury pathways in MS progression.
Presented by lead author Joanna Kocot, PhD, Rocky Beth fellow at National Institutes of Health, clemastine was added to the ongoing platform TRAP-MS trial to identify CSF remyelination signature and to gather the safety data on the use of the antihistamine in patients still progressing on disease-modifying therapies by non-lesional activity. Among the participants, 9 patients with MS had at least 1 clinical follow-up visit on clemastine that was scheduled every 6 months. Researchers collected CSF before and after 6 months from when clemastine treatment was administered. There were approximately 7000 CSF proteins quantified by DNA aptamers (SOMAScan). Authors then performed mechanistic studies on THP-1 cells, THP1-Gasdermin-D (GSDMD) knock-out cells, primary human monocyte-derived macrophages, and iPSC-derived oligodendrocytes.
READ MORE: Epigenetic Age Acceleration Shows Association With Secondary Progressive Multiple Sclerosis
Through publications that described the potentiation of ATP signaling by clemastine led investigators to hypothesize that clemastine causes CNS injury by enhancement of pyroptotic cell death in macrophages/microglia and in oligodendrocytes. Authors further noted that these have the highest P2RX7 RNA levels out of all of the human cells. Further research with in-vitro mechanistic studies and bulk RNA sequencing confirmed that clemastine, in the presence of sub-lytic doses of extracellular ATP, activates inflammasome in human macrophages and prompts pyroptosis (GSDMD-dependent lytic cell death) in not only in macrophages but also in oligodendrocytes. Investigators noted that these adverse effects of clemastine were blocked by P2RX7 antagonist. In the reanalyzes of published snRNAseq studies, findings showed that P2RX7 expression and pyroptosis increased in microglia and oligodendrocytes in the MS brain tissue.
In a previous randomized controlled trial (ReBUILD, NCT02040298) published in The Lancet assessingclemastine fumarate as a treatment of chronic demyelinating injury in MS, the agent met its primary end point of efficacy, suggesting that myelin repair can be achieved even following prolonged damage.2 In this prior study, investigators randomly assigned patients 1:1 to receive either clemastine fumarate 5.36 mg orally twice daily for 90 days followed by placebo for 60 days (group 1, n = 25), or placebo for 90 days followed by clemastine fumarate 5.36 mg orally twice daily for 60 days (group 2, n = 25).
Conducted by lead author Ari J Green, chief of the division of neuroimmunology and glial biology in the Department of Neurology at University of California, San Francisco, and colleagues, the primary outcome of the study was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. Clemastine treatment reduced the latency delay by 1.7 ms/eye (95% CI, 0.5-2.9; P = 0.0048) when analyzing the trial as a crossover. Although clemastine treatment had an association with fatigue, authors reported no serious adverse events overall.
Click here for more coverage of ACTRIMS 2024.
REFERENCES
1. Kocot J, Kosa P, Ashida S, et al. Clemastine Fumarate Accelerates Accumulation of Disability in Progressive Multiple Sclerosis by Enhancing Pyroptosis. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. CE2.3.
2. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489. doi:10.1016/S0140-6736(17)32346-2
