Remyelination....a reality

Good news from repair studies! 

A few years ago Jonah Chan and his team developed a neat screening assay to show myelination (making myelin) by myelin-forming cells (oligodendrocytes). 

They did a screen of many drugs and pulled out one of the best called clemastine. This was shown to stimulate myelin formation and in animal models it helped to speed up the remyelination process.

Clemastine is old type of anti-histamine (anti-itch) that has fallen out of favour, because it induces fatigue and drowsiness. It is used for drying you up when you have a streaming eyes or nose. 

Now they have done a trial in MS and claim that it causes remyelination.

This was seen by an increase in nerve impulse conduction speeds because demyelination slows them down, so if you remyelinate the nerve impulse speed increases.

So in this study people took a placebo for 2 months and then the drug for three months, or the drug for 3 months followed by the placebo.

The nerve impulse speeds increased by 2,000th of a second.

So the trial worked.

Here's the abstract:

Green et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial.Lancet. 2017. pii: S0140-6736(17)32346-2.

BACKGROUND: 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.

METHODS: 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 were randomly 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. The trial is registered with, number NCT02040298.

FINDINGS: 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)  Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported.

INTERPRETATION: 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.

So there you have it: a positive effect, moving ideas from animals to humans, so great news!

But before you rush down to the chemist (if you have not done this already) here are a few questions to consider: 

1. What are ProfG, DrK, NDG and Dr MnM going to say when you say "Give me clemastine"? 

It is licensed for use in humans. It costs a few pence, so NICE isn't going to waste any sleep over this one. 

2. What is Biogen going to do with anti-LINGO, costing thousands if clemastine does it?

3. What are the MS charities going to do next?
     Another trial? Then What?

4. Why was there no-dose response?

Because the dose used is massive, compared to what's usually prescribed. So will a repeat study be needed before it can it be prescribed off-label as the 5.36mg dose used in the trial, is twice that normally used (2.68mg). No wonder the participants got fatigue. 

5. If you get fatigue are you going to take the drug, long-term?

6. Do you even need to take it long term or just as a pulse therapy? 

7. (Importantly) are the results clinically meaningful?

Questions, questions questions.

More from the Neuros will be forthcoming...