Clemastine fumarate linked to accelerated disability progression in MS

Key takeaways:

• Researchers added a treatment arm to an ongoing study of nine patients with MS who were given clemastine fumarate.
• The treatment was halted when three patients experienced exponential disability progression.

WEST PALM BEACH, Fla. — Treatment with clemastine fumarate was linked to accelerated disease and disability progression due to pyroptosis in a small cohort of individuals with multiple sclerosis, according to a presenter at ACTRIMS 2024.

“Disease-modifying therapy significantly inhibits mass lesional activity; however, the problem is that patients continue to progress through non-lesional activity including demyelination,” Joanna Kocot, PhD, DSc, a visiting fellow in the National Institute of Allergy and Infectious Diseases at the NIH, told attendees.

Since clemastine fumarate, an over-the-counter antihistamine, has demonstrated remyelinating potential in MS, researchers sought to examine its disease-arresting properties.

Kocot and colleagues added a clemastine treatment arm to the ongoing TRAP-MS clinical trial, which aimed to identify cerebrospinal fluid (CSF) remyelination signatures and to collect safety data on the use of clemastine in 64 individuals with MS progressing on disease-modifying therapies by non-lesional activity.

Nine individuals with MS had at least one clinical follow-up visit (scheduled every 6 months) on clemastine. CSF was collected before treatment initiation as well as 6 months after, with approximately 7,000 CSF proteins quantified by DNA aptamers. Mechanistic studies were subsequently performed on THP-1 cells, THP1-Gasdermin-D knock-out cells, primary human monocyte-derived macrophages and iPSC-derived oligodendrocytes.

The clemastine arm of the study was halted after three patients’ disability increased five-fold compared with their 18-month baseline progression slopes.

None of the remaining 55 patients treated with other TRAP-MS therapies triggered safety criteria, providing evidence for clemastine toxicity, the researchers wrote.

Kocot and colleagues also reported that those given clemastine increased C-reactive protein/ESR levels and gained weight, indicative of pro-inflammatory status. This was corroborated by CSF proteomic profiling, increased purinergic/ATP signaling and enhancement of immunogenic cell death, including pyroptosis.

Further, the researchers wrote that clemastine caused injury to the central nervous system by enhancing pyroptotic cell death in macrophages/microglia and in oligodendrocytes, which have highest P2RX7 RNA levels from all human cells. These toxic effects of clemastine were blocked by P2RX7 antagonists.

“Clemastine enhanced disability accumulation in patients progressing by non-lesional MS activity by potentiating intrathecal P2RX7 signaling and pyroptosis,” Kocot said.