December 9, 2022

Over-the-counter antihistamine can repair myelin damage in chronic MS


Comprehensive results from a randomized controlled trial (RCT) suggest that over-the-counter antihistamine clemastine fumarate is safe and effective for treating chronic demyelinating lesions in multiple sclerosis (MS) Ö« – even in patients who have experienced symptoms of myelin degeneration for years.

Although preliminary results were presented at the American Academy of Neurology annual meeting last year, the full data from the ReBUILD trial has been published online October 10 in the Lancet.

The ReBUILD Phase 2 crossover study included 50 patients with relapsing MS, an average disease duration of 5 years, and chronic demyelinating optic neuropathy. The first group received oral clemastine fumarate twice daily for 3 months then placebo for 2 months, while the second group received the placebo for 3 months and the active treatment for 2 months.

The results showed that during the active treatment phase, the visual evoked potential (VEP) latency time was reduced from the baseline of 1.7 milliseconds per eye, the primary endpoint. In addition, this result remained significant throughout the study in the group that started with active treatment and then switched to placebo.

Although there were more reports of fatigue when participants took clemastine fumarate than placebo, no one reported serious treatment-related side effects. There was also no drop out during the study.

The investigators, led by Ari J Green, MD, head of the division of neuroinflammation and glial biology and professor at the University of California at San Francisco (UCSF), note that this is the first RCT to show the effectiveness of a remyelinating drug for this type of treatment.

Dr Ari J. Green

“Our results suggest that myelin repair can be achieved even after prolonged damage,” they write.

Dr Green stressed that the aim of the study was to demonstrate that this type of repair is possible. “And for me that was the most encouraging,” he said. Medscape Medical News.

Possibility of repair

While current treatments for MS block access to target tissues for immune cells or suppress inflammatory lesions, none completely prevent neuroaxonal degeneration – and no treatment is available to remyelinate the lesions, the researchers note.

Myelin in the central nervous system “is a specialized extension of the plasma membrane of oligodendrocytes and clemastine fumarate can stimulate the differentiation of precursor cells of oligodendrocytes [OPCs] in vitro, in animal models and in human cells, ”they write.

The United States Food and Drug Administration (FDA) first approved the drug, which crosses the blood-brain barrier, in 1977 for the treatment of allergies. While a generic form has been available over the counter in the United States since 1992, the FDA granted an investigational new drug exemption to investigate its use in the treatment of MS in 2013.

“We realize that even to get a diagnosis of MS, there has to be a pre-existing injury. But the key part that has never been addressed is the regeneration and repair of the damage that occurs, especially to the oligodendrocytes.” said Dr Green.

“The main goal of our program was to work on developing treatments that could help with this whole repair process. We really wanted to prove the concept that repair might be possible, and that was the hope of this trial.” , he added.

In the 150-day ReBUILD study, 50 patients with long-standing MS were recruited to UCSF between January 2014 and April 2015. At screening, baseline, and months 1, 3, and 5, electrodes were placed on the scalp of the participants above the occipital. lobe. The VEPs then recorded cortical responses to an alternate pattern of repetitive visual images.

“Almost all patients [MS] eventually exhibit demyelinating damage to the anterior visual pathway and the detection of prolonged VEP latency was used as supporting evidence to help confirm a clinical diagnosis, ”the investigators write.

The primary outcome was the shortening of the P100 latency time on full-field pattern-inversion VEPs from baseline. All patients had a VEP P100 latency of 118 milliseconds in at least one eye, showing pre-existing neuronal transmission deficits.

VEP improvement

The first treatment group (n = 25; 76% female; mean age, 40.2 years) received 5.36 mg of clemastine fumarate twice daily for 90 days, followed by 60 days of corresponding placebo. The second group (n = 25; 52% female; mean age, 40.0 years) started with placebo for 90 days, then switched to active treatment for 60 days.

“The different length of the two epochs was intended to help determine whether a difference in effectiveness was based on the variation in exposure time,” the researchers explain.

Combined, the groups achieved the primary outcome while taking clemastine fumarate, reducing the latency time by 1.7 milliseconds per eye (95% confidence interval [CI], 0.5 – 2.9; P = .005).

Post hoc analysis using a delayed treatment model showed a reduction in VEP latency time of 3.2 milliseconds per eye (95% CI, 1.8 – 4.7; P = .0001).

In addition, an improvement in latency greater than 6 milliseconds was shown in 16% of group 1 and 26% of group 2 during the active treatment phase vs. 3% and 6% of each group, respectively, during the placebo phase.

The low contrast letter acuity (LCLA) was the primary functional secondary outcome. Although patients showed an improvement of 0.9 letters per eye when taking clemastine fumarate, this was not statistically significant (P = .085). In a post-hoc, delayed-treatment analysis, the suggested improvement was 1.6 letters per eye (P = .02).

No MRI measurements, including new and enlarged T2 lesions, showed improvement or worsening with active treatment in crossover or ad hoc analyzes. There were also no significant changes on the expanded disability status scale, the 25-foot timed walk, or the 6-minute walk test.

No serious adverse events occurred, but fatigue worsened considerably, as measured on the Multidimensional Fatigue Rating Scale, with or without active treatment (P = .02).

A first step?

“To the best of our knowledge, this is the first time that a therapy has been able to reverse the deficits caused by MS,” Dr. Green said in a press release. “It is not a cure, but it is a first step towards restoring the brain functions of the millions of people affected by this chronic and debilitating disease.”

Lead author Jonah Chan, PhD, professor of neurology and vice-chief of the division of neuroinflammation and glial biology at UCSF, first identified clemastine fumarate as a possible treatment for MS in 2013 Still, “people thought we were absolutely crazy” to start the ongoing trial, he said in the same statement.

“They believed that it was only in newly diagnosed cases that a drug like this could be effective. Intuitively, if the damage to the myelin is new, the repair change is strong,” Dr Chan said. . “In the patients in our trial, the disease had lasted for years, but we still saw strong evidence of repair.”

Dr Chan added that the disappointing MRI results highlight that MRI is a weak tool for this type of measurement. “We still do not have imaging methods that have been shown to be able to detect remyelination in humans,” he said.

Overall, “we not only saw an effect on our primary outcome, but there was even modest evidence of functional recovery on the part of the patients. This tells us that the repair process may have a functional benefit for patients, ”Dr Green said. Medscape Medical News.

That said, questions remain as to how long the window can be left open for repair. “Damage that is a decade or more old may not be as repairable. What we hope to have added is the feeling that the window of time is at least longer than immediate,” said Dr Green. .

“I would say the main takeaway for clinicians is this: the era of medically induced brain repair may be upon us.”

He cautioned, however, that the study treatment was not a wonder drug and was associated with fatigue, which is already a problem in MS. And although it is available over the counter, “it should only be taken with the advice and guidance of a healthcare practitioner or in clinical trials.”

Not clinically significant … yet

In a accompanying editorial, Jeffrey A. Cohen, MD, Neurologic Institute at Cleveland Clinic, Ohio, and Paul J. Tesar, PhD, Department of Genetics and Genome Sciences at Case Western Reserve University School of Medicine, Cleveland, Ohio, note that the positive results from the study were remarkable.

“However, the average improvements detected by VEP and LCLA in this short trial were modest and probably not of a clinically significant magnitude,” they write.

In addition to the short duration of the trial, they note that the dose was higher than what is commonly used to treat allergic symptoms in clinical practice.

However, testing the treatment for a longer period or at higher doses “could be difficult due to the side effects resulting from the interaction of clemastine fumarate with a variety of G-protein-coupled receptors,” write Dr. Cohen and Dr. Tesar.

“The sparse mechanistic data on human OPCs and the inability of many potent M1 muscarinic receptor antagonists to stimulate OPC differentiation in vitro suggest a lingering uncertainty around. [the drug’s] mechanism of action to promote remyelination and the need for further studies, ”they add.

In summary, “while clemastine fumarate is unlikely to be the final answer in the search for repair-promoting drugs to treat multiple sclerosis, the ReBUILD trial represents a milestone in this quest”.

The study was supported by the University of California at San Francisco and the Rachleff family. Dr Green says he has received grants from the National MS Society and the US National Institutes of Health, other backers from MedImmune, as well as grants and other backing from Inception Biosciences. He also declares to have received other supports apart from the submitted work of Mylan, Sandoz, Dr Reddy, Amneal, Momenta, Synthon, JAMA Neurology, and Bionure. A full list of disclosures for other study authors can be found in the original article. Dr. Cohen has received consulting fees from Adamas and Celgene “for the development of symptomatic and disease therapies” for MS and as co-editor of Multiple Sclerosis Journal – Experimental, Translational and Clinical. Dr Tesar reports on fairness as co-founder of Convelo Therapeutics and develops screening strategies to identify remyelinating compounds.

Lancet. Published online October 10, 2017. Full article, Editorial

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