Summary: UCSF researchers reveal a common over the counter antihistamine appears to accelerate neural signaling and restore nervous system functioning for some multiple sclerosis patients.
In a remarkably rapid translation of laboratory research findings into a treatment with the potential to benefit patients, UC San Francisco scientists have successfully completed a Phase II clinical trial showing that an FDA-approved antihistamine restores nervous system function in patients with chronic multiple sclerosis (MS).
In light of previous laboratory studies of the antihistamine compound at UCSF, the researchers said, the drug most likely exerted its effect by repairing damage MS had inflicted on myelin, an insulating membrane that speeds transmission of electrical signals in the nervous system.
The drug tested in the trial, clemastine fumarate, was first identified as a candidate treatment for MS in 2013 by UCSF’s Jonah R. Chan, PhD, Debbie and Andy Rachleff Distinguished Professor of Neurology, vice chief of the Division of Neuroinflammation and Glial Biology, and senior author of the new study. First approved by the U.S. Food and Drug Administration (FDA) in 1977 for allergies, the drug has been available over the counter in generic form since 1993.
The researchers said that the Phase II results, published online on Oct. 10, 2017, in The Lancet, are the first in which a drug has been shown to reliably restore any brain function damaged by a neurological disease in human patients.
“To the best of our knowledge this is the first time a therapy has been able to reverse deficits caused by MS. It’s not a cure, but it’s a first step towards restoring brain function to the millions who are affected by this chronic, debilitating disease,” said the trial’s principal investigator, Ari Green, MD, also Debbie and Andy Rachleff Distinguished Professor of Neurology, chief of the Division of Neuroinflammation and Glial Biology, and medical director of the UCSF Multiple Sclerosis and Neuroinflammation Center.
Chan and Green are co-directors of the UCSF Small-Molecule Program for Remyelination, and both are members of the UCSF Weill Institute for Neurosciences.
The new results are particularly notable, Chan said, because patients in the trial had suffered from MS symptoms caused by injury to myelin for years. “People thought we were absolutely crazy to launch this trial, because they thought that only in newly diagnosed cases could a drug like this be effective – intuitively, if myelin damage is new, the chance of repair is strong. In the patients in our trial the disease had gone on for years, but we still saw strong evidence of repair.”
MS Affects Millions Worldwide
MS is an autoimmune neurodegenerative disorder that affects nearly 2.5 million people worldwide. The disease strikes when the immune system attacks myelin, layers of fatty insulating membrane that surround nerve fibers. Unlike the rubber insulation around wires, however, myelin helps electrical signals in neurons move faster and more efficiently. As myelin damage continues over the course of the disease, neurons progressively lose their ability to reliably transmit electrical signals, resulting in progressive loss of vision, weakness, walking difficulties, and problems with coordination and balance.
Current MS treatments aim to prevent the immune system from doing further harm, but none have been shown to repair damaged myelin. In both his 2013 research and in subsequent studies with a mouse model of MS, however, Chan and colleagues had demonstrated that clemastine fumarate promotes myelin regeneration and restores neural function, promising preclinical results that inspired the new study, known as the ReBUILD trial.
Because the visual system is often one of the first and most prominent parts of the brain to be affected in MS, and because there are well-established tools to measure the speed of neural transmission in the areas of the brain devoted to vision, the research team used a method known as visual evoked potentials, or VEPs, to assess clemastine’s therapeutic effects in the trial.
The five-month Phase II trial enrolled 50 patients with relapsing but generally long-standing MS whose VEPs reflected preexisting deficits in neural transmission. The researchers showed flickering patterns on a screen to participants, and used electrodes placed over the brain’s visual areas at the back of the head to gauge how long it took for the flickering signal presented to the eye to generate an electrical response that could be detected by the electrodes. The time from presentation of the pattern to the detection of the VEP is a measurement of how long it took for the signal to travel via nerve fibers from the retina, at the back of the eye, to the visual areas at the back of the brain.
To enhance the power of their study, the researchers used a “crossover” design: they divided the patient population in two and gave the drug, blinded to both participant and researcher, to one group, and a placebo to the other for 90 days; then they switched between the two groups, giving a placebo to the first group and the drug to the other for the next 60 days. This “flip-flop” technique gave the researchers the ability to compare patients to themselves – a form of control that increased the statistical power of the study by nearly an order of magnitude, Green said.
During the periods when each group was taking the drug, the neural signal from the eye to the back of the brain was significantly accelerated over the baseline measurements taken before the patients began the study. The effect persisted in the group that had switched to placebo, suggesting that durable repair of myelin had been induced by the drug.
‘First Step in a Long Process’
Although the research team could not directly observe evidence of rebuilding of myelin in trial participants using magnetic resonance imaging (MRI), Chan and Green said that this reflects a weakness of current MRI techniques as a tool for this purpose rather than evidence that myelin regeneration did not take place. “We still don’t have imaging methods that have been proven to be able to detect remyelination in humans,” said Chan.
That myelin increases the speed of neural transmission is one of the most well-established concepts in neurobiology, and combined with the clear evidence from Chan’s preclinical research showing that clemastine fumarate promotes myelin formation, myelin regeneration is the only plausible explanation for the VEP results, the authors said.
“This is the first step in a long process,” Green said. “By no means do we want to suggest that this is a cure-all. We want to ground-truth myelination metrics – we’re designing the crucible that’s going to be used to test any future method for detecting remyelination.”
Funding: The work was funded through generous support from the Rachleff Family.
In addition to Green and Chan, authors (all at UCSF) include Jeffrey M Gelfand, MD, MAS; Bruce A Cree, MD, PhD, MAS; Carolyn Bevan, MD; W. John Boscardin, PhD; Feng Mei, PhD; Justin Inman; Sam Arnow; Michael Devereux; Aya Abounasr; Hiroko Nobuta, PhD; Alyssa Zhu; Matt Friessen, PhD; Roy Gerona, PhD; Hans Christian von Büdingen, MD, PhD; Roland G Henry, PhD; and Stephen L Hauser, MD.
Source: Devika Bansal – UCSF
Image Source: NeuroscienceNews.com image is credited to the NIH.
Original Research: Full open access research for “Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial” by Dr Ari J Green, Jeffrey M Gelfand, MD, Bruce A Cree, MD, Carolyn Bevan, MD, Prof W John Boscardin, PhD, Feng Mei, PhD, Justin Inman, BS, Sam Arnow, BS, Michael Devereux, BS, Aya Abounasr, BS, Hiroko Nobuta, PhD, Alyssa Zhu, BS, Matt Friessen, PhD, Prof Roy Gerona, PhD, Hans Christian von Büdingen, MD, Prof Roland G Henry, PhD, Prof Stephen L Hauser, MD, Prof Jonah R Chan, PhD in The Lancet. Published online October 10 2017 doi:10.1016/S0140-6736(17)32346-2
Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial
Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis.
We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298.
Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5–2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported.
To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage.
“Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial” by Dr Ari J Green, Jeffrey M Gelfand, MD, Bruce A Cree, MD, Carolyn Bevan, MD, Prof W John Boscardin, PhD, Feng Mei, PhD, Justin Inman, BS, Sam Arnow, BS, Michael Devereux, BS, Aya Abounasr, BS, Hiroko Nobuta, PhD, Alyssa Zhu, BS, Matt Friessen, PhD, Prof Roy Gerona, PhD, Hans Christian von Büdingen, MD, Prof Roland G Henry, PhD, Prof Stephen L Hauser, MD, Prof Jonah R Chan, PhD in The Lancet. Published online October 10 2017 doi:10.1016/S0140-6736(17)32346-2