ACTRIMS 2024: An antihistamine may speed MS disease progression
Despite early promise, clemastine appears to worsen disability in some adults
The antihistamine clemastine accelerated disease progression by more than five times in some adults with progressive multiple sclerosis (MS) who received it in a Phase 1/2 trial, new data show.
Joanna Kocot, PhD, a neuroscientist at the National Institutes of Health (NIH), showed that this effect is at least partly triggered by the activation of pyroptosis, an inflammatory form of cell death that contributes to further neurodegeneration and disease progression.
While previous clemastine studies had suggested that it could be used to repair myelin, a protective covering around nerve fibers that becomes damaged in MS, the new findings may halt additional studies of the antihistamine, or at least prompt the selection of MS patients least likely to experience pyroptosis activation, Kocot said.
The results were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024, which was held Feb. 29-March 2 in Florida and virtually. Kocot’s presentation was titled “Clemastine Fumarate Accelerates Accumulation of Disability in Progressive Multiple Sclerosis by Enhancing Pyroptosis.”
Early hope, new concerns
Clemastine showed promise as a treatment for multiple sclerosis in a previous Phase 2 trial, ReBUILD (NCT02040298), which enrolled people with relapsing forms of MS. Data demonstrated that clemastine significantly increased the speed of nerve impulses and had some ability to repair myelin in these patients.
Kocot and other NIH researchers also tested clemastine as part of TRAP-MS (NCT03109288), an ongoing Phase 1/2 clinical trial that is simultaneously evaluating multiple experimental MS therapies to accelerate treatment development. Eligible participants were those who continued to experience worsening disability independent of lesion activity.
Nine adults with a diagnosis of MS enrolled in the clemastine fumarate arm and received 8 mg of the oral medication daily, either alone or in combination with the patients’ current disease-modifying therapies.
Treatment with clemastine was stopped, however, because three (33.3%) of the patients experienced an accumulation of disability that was more than five times greater than that observed before the treatment.
Notably, the TRAP-MS clinical trial is also testing other medications — such as the antidiabetic pioglitazone, the muscle relaxant dantrolene, and the antifibrotic pirfenidone — but none of the 55 patients on those medications triggered safety protocols to stop treatment.
Breaking down the problem
To better understand the mechanisms through which clemastine accelerated disability in that subgroup of patients, the researchers measured the levels of about 7,000 proteins in spinal fluid samples collected before and after clemastine treatment.
They identified some changes in proteins involved in purinergic metabolism, a process by which cells make the buidling blocks of DNA, and activation of myeloid cells, which are immune cells.
“In search for an explanation for these unexpected results, we identified a paper which showed that clemastine is [a modulator] of P2RX7,” Kocot said.
P2RX7 is a purinergic receptor that triggers inflammatory responses in myeloid cells. This receptor normally needs energy to activate a series of inflammatory signaling events, but clemastine modulates it in a way that requires less energy to do the same job.
This shift ultimately means the P2RX7 is more active and prone to activate inflammatory mechanisms in the presence of clemastine. Among these inflammatory mechanisms, the receptor can also activate a protein that forms holes in the cell’s membrane, causing the cell to burst open and die. This form of cell death, driven by inflammation, is pyroptosis.
This mechanism of action was confirmed in lab-grown myeloid cells, where treatment with clemastine increased the release of a pro-inflammatory molecule called IL-1 and increased a marker of cell damage called lactate dehydrogenase. However, the effects of clemastine disappeared in the presence of a P2RX7 inhibitor.
Additional analyses by Kocot and her colleagues showed that, among all human cells, P2RX7 is found at particularly higher levels in oligodendrocytes, cells responsible for making and repairing myelin in the brain and spinal cord. P2RX7 was also elevated in oligodendrocytes and myeloid cells from MS patients compared with healthy controls. In patients, it was particularly evident in regions of lesions with chronic active inflammation, indicating it may be contributing to nerve cell damage through pyroptosis.
The research showed that measures of how much pyroptosis was happening were significantly higher in MS patients than in controls and people with progressive MS than relapsing remitting disease.
Also, patients who received clemastine had a significantly greater annual increase in pyroptosis scores than in those on a placebo, and “patients [with] elevated pyroptosis scores accumulated disability much faster,” Kocot said.
She suggested that pyroptosis of oligodendrocytes may at least partly explain why progression continues to occur in MS patients who have no evidence of inflammatory lesions.
Note: The Multiple Sclerosis News Today team is providing coverage of the ACTRIMS Forum 2024, which ran from Feb. 29-March 2. Go here to read the latest stories from the conference.
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