With thanks to Medscape, a fascinating piece of research about antihistamine and remyelination which will also be applicable to children on the Snowdrop programme who have myelination issues.
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A common antihistamine available over the counter has shown evidence of remyelination in patients with multiple sclerosis (MS) in a double-blind, placebo-controlled trial.
The study showed that clemastine — at a dose just a little higher than that approved for allergies — reduced the transmission delay in the optic nerve seen in patients with MS and chronic demyelinating optic neuropathy.
"We are extremely excited about these results," lead author, Ari Green, MD, medical director, University of California San Francisco (UCSF) MS Center, commented to Medscape Medical News. "Our main message is that it appears to be possible to repair injury to nerve cells in MS by remyelination. We have been taught that the brain can't repair itself, but our results suggest that this is not true. This could have consequences for many other neurodegenerative diseases as well as MS."
The results were released April 12 in advance of their presentation at the upcoming American Academy of Neurology (AAN) 2016 Annual Meeting.
The phase 2 crossover study — which is said to be the first randomized controlled trial documenting efficacy for a candidate remyelinating agent in MS — compared twice-daily oral clemastine to placebo in 50 patients with MS and chronic demyelinating optic neuropathy. The study period was 150 days.
The primary efficacy endpoint, latency delay on visual evoked potential (VEP; the time for transmission of signal from the retina to the visual cortex), was reduced by 1.9 ms/eye for the period on treatment with clemastine (P = .003).
Dr Green explained that VEP records the speed of transmission in the optic nerve from the visual stimulus to the processing of the image in the visual cortex of the brain.
"Good myelination of the nerve enables the signal to travel faster. For example, in an unmyelinated fiber, the signal would travel at a speed of 1 m/s. In contrast, a myelinated fiber would transmit the signal at about 100 m/s, 100 times faster. Demyelination as seen in MS-related optic neuritis can delay transmission by 30 to 50 ms. Clemastine seems to restore some of this loss."
The researchers also looked at a functional endpoint — low-contrast visual acuity — and saw a strong trend for improvement, but this did not reach statistical significance (P = .089).
In terms of side effects, clemastine treatment was associated with mild worsening of fatigue on the Multidimensional Assessment of Fatigue scale (P = .017).
Reflection of Nerves Throughout the CNS
Dr Green said that although this study just focused on the optic nerve, it probably reflects what is going on throughout the central nervous system. "We are using vision as a method of testing the principle of remyelination. The optic nerve is an obvious place to start as it is logistically practicable. We believe, however, that it should reflect nerve condition generally and acts like a surrogate marker for the rest of the CNS [central nervous system]."
But he urged caution to patients with MS. "I do not want to make false promises, and I am not advocating that MS patients take clemastine on the basis of this one study. But if they chose to do so, they should have the supervision of a physician and preferably enroll in a clinical study."
Clemastine was identified as a potential remyelinating agent in a screening program developed by a UCSF team led by Jonah Chan, PhD, using precursor cells of oligodendrocytes (the cells that make myelin).
"These oligodendrocyte precursor cells are present in the brain but don't seem to mature and make oligodendrocytes," Dr Green explained. "We are looking for agents which stimulate the precursor cells to differentiate into oligodendrocytes and produce new myelin to repair the damaged neurons. Chan et al tested many different existing drugs and found that clemastine did just that."
The researchers have identified a specific muscarinic receptor at which clemastine is acting to bring about this effect. "It is probable that the drug is only partially saturating the receptor, so we may not be seeing the full effect," Dr Green said.
But because clemastine also acts at many other receptors, his group is looking into developing new agents that act specifically at this receptor, which may be more appropriate for myelin repair. "We also know that there are other nonmuscarinic receptors that appear to bring about similar results, so there are a few possibilities under investigation," he added.
"The screening method has identified the biology. Now we have to fine-tune that biology," Dr Green commented.
Biogen is also developing a compound known as anti-LINGO, which has shown evidence of remyelination. Dr Green noted that the anti-LINGO study recently reported involved patients with a current episode of optic neuritis. "So they showed an acute action, whereas patients in our study had not had a recent episode of optic neuritis and so we have shown evidence of benefit in the chronic phase."
Commenting on the study for Medscape Medical News, Lily Jung Henson, MD, chief of neurology, Piedmont Healthcare, Atlanta, Georgia, said, "This is really exciting preliminary news. The results seem to suggest that clemastine may be effective in remyelination, for which we have no therapies."
She cautioned that larger studies will be needed with patients treated for longer periods of time for confirmation. "As clemastine is an anticholinergic, it will be interesting to see if it causes any worsening of some MS symptoms, such as cognitive difficulties, urinary hesitancy, or constipation," she added.
The study was funded by the University of California, San Francisco.
American Academy of Neurology (AAN) 2016 Annual Meeting. Emerging Science Abstract 008. To be presented April 19, 2016.
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