AAN:Remyelination a reality, Will Biogen say Bugger?

#MSresearch suggests #Remyelination

The resuts are out on tuesday. 

Title: Positive Phase II Double-blind Randomized Placebo-controlled Crossover Trial of Clemastine 
Press Release Title: Over-the-Counter Drug May Reverse Vision Damage Caused by Multiple Sclerosis 

Objective: To assess the efficacy of clemastine fumarate for remyelination in patients with multiple sclerosis (MS) and chronic optic neuropathy. 

Author(s): Ari Green, MD; Jeffrey Gelfand, MD; Bruce Cree, MD, PhD, MCR; Carolyn Bevan, MD; WJ Boscardin; Feng Mei; Justin Inman; Samuel Arnow; Michael Devereux; Aya Abounasr; Matt Friessen; Roy Gerona; Hans Christian Von Buedingen; Roland Henry; Stephen Hauser, MD; Jonah R Chan 

Background: No reparative therapies exist for the treatment of MS. Clemastine was identified as a robust potential remyelinating agent using the in-vitro micropillar screen (BIMA) developed at UCSF. Following in-vivo validation, an FDA IND  (Investigational new drug = the agreement to test in humans) exemption was granted to investigate clemastine for the treatment of MS. Visual evoked potentials (VEPs) are capable of measuring conduction speed for electrical signals through the visual pathway and serve as a putative biomarker for remyelination. 
Design/Methods: We conducted a phase II randomized double-blind placebo-controlled crossover trial comparing twice daily oral clemastine to placebo in 50 patients with MS and chronic demyelinating optic neuropathy. The study period was 150 days (21week= 5months).The pre-specified primary efficacy end point was change in latency delay on VEP. Trial outcomes were analyzed using mixed effects multivariable linear regression models. 
Results: Enrolled patient’s average age was 40.1 years, EDSS 2.1,  (So not much established disability) and disease duration 5.1 years. Retention was 100% through the course of the study. There was a reduction of the primary efficacy endpoint of VEP latency delay of 1.9 ms/eye (95% CI [.66, 3.1]; p=.003) for the period on treatment. A strong trend for improvement of the principal secondary endpoint of low contrast visual acuity (LCVA) was also observed (p=.089). Clemastine treatment was associated with mild worsening of fatigue on the multidimensional assessment of fatigue (p=.017). 
Conclusion: In MS patients with chronic optic neuropathy, clemastine improved VEP latency delay and demonstrated a beneficial trend for the secondary endpoint of LCVA. This is the first RCT documenting efficacy for a candidate remyelinating agent in MS. 

This study stems from the work of Jonah Chan a scientist who developed a really neat screening method to look for myelinating-promoting compounds and at the top of their list was clemastine. Jonah is unable to do anything without the aid of a clinician and he teamed up with Ari Green to do the study.

If we think of the nervous system, there are few nerves that can be studied. The most accessible nervous aspect is the visual system and this was used to see if they could detect repair. Without it demyelinated nerves will transmit at a slow pace, but with myelin it will be much quicker. So the latency (speed t
hat the nerve impulse reacts to the stimulus)  is made faster after clemastine. This suggests that clemastine is inducing remyelination just as occurs in animals

Assessment of Clemastine Fumarate as a Remyelinating Agent in Multiple Sclerosis (ReBUILD) NCT0204029

There is no mention of what happened in EDSS, which was another endpoint in trial, so what next?

Assessment of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis (ReCOVER) (ReCOVER a study of n=30 which is too small to take us further forward quickly.

So this appears to be very good news. There is evidence that we have a remyelinating agent for MS. Yes, there are more studies to be done but this is the first small molecule to do this in MS. 

Unfortunately, the UCSF press release appears to fuel what will probably happen now. This because clemastine is a over the counter drug and  a twice a day course, costs a few cents.  Be careful!...but with in a few days of the press release of high dose biotin...people were rattling with the thirty low dose biotin pills a day, even before the data was actually presented. This won't be different I suspect .

This approach needs more studies, but will this happen?

I had a quick check and did not see a UCSF patent on clemastine, (but if they did, it would have surely have holes in it as previous studies have already pointed at such a target), although the technology was protected? 

So now we have the usual problem. What happens next? 

Maybe it is time that something happens differently and academic discoveries are not left to rot.!  

So will the MS Socieites/NIH get behind this and get it developed or at least tested properly in sensible numbers or will we see the usual and they steer clear of an anti-pharma approach. This will be a good test case to see what can be done.

Biogen have their trial on anti-LINGO ongoing, but this still has someway to go. Could they charge $50,000 or more for something compared to a few dollars if clemastine makes it? 

Are they saying bugger... a small molecule that can break our biological strangle hold on MS....or are they laughing to themselves and thinking it will go the way it normally goes as there is no way  it will ever be developed. 

Is there a histamine blocker-clemastine me-too up the UCSF sleeve or some other company's?

If this result is real and benefit is there to be had surely we need to move this forward yet another case to look at the idea of repurposing drugs. Is it just something that we pay lipservice to.

Maybe ProfG can comment on the work when it is presented.