Sunday, 17 April 2016

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.

34 comments:

  1. Mouse Doctor, right now Biogen are gearing up to work their lobby machine and crush this thing to dust. Numbers are small, trials not rigorous enough, results not meaningful etc bla bla bla Any guesses who wins in the end? :-)

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  2. TC said

    I was left aghast when I found out that they (Biogen) would get a share of profits from ocrelizumab. That's like free money and will help them make up for some of the losses from Tysabri. And guess what Roche would do? They will just charge a lot more for ocrelizumab. And this arrangement is only for US sales. MS drug prices are already very high in the US, this will only make things worse. I hope the various MS societies get behind the Clemestine research. Academia vs pharma. Let's see who wins.

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    1. Yes biogen has a share in ocreluzimab, just as other companies have a share in a number of other MS drugs. This perhaps speaks to reasons why drug pricing seems more of or a cartel rather than true competition.

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  3. How large is the reported effect of clemastine (VEP latency delay of 1.9 ms/eye)?
    If this is significant, I am pretty sure there will be a startup developing the compound and its relatives. I am also pretty sure Biogen will look for small molecule alternatives to anti-LINGO, if it's not doing this already.

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  4. Thank you MD so much for this enlightening review. The clemastine trial is very optimistic. I can see by the authors of the abstract that there are some major heavyweights involved from the neurology world, like Dr. Stephen Hauser.

    I really hope (but doubt) that pharma has some ounce of moral fibre and does not try to squash or cash in on the clemastine studies and that it is recommended soon to MS patients. Hopefully, it will just make pharma move more quickly in terms of it's remyelinating studies, as this is one of the greatest unmet needs in MS patients currently.

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    1. I suspect that if Pharam can't cash in then there will be no development...remeber rituximab off label was morphed into Orcrelizumab

      Hofefully....one day this cynical view will be proved wrong

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    2. If only the cold pharma fish could feel what a drug for remyelination would do for so many people, before the dollar signs start rolling before their eyes. Could feel what it is to suffer this disease. Could think about, for example, the tragic loss to the world of the genius of Jacqueline Du Pré. Would mankind only put humanity and scientific knowledge before profit. One might wish that there was a higher perspective. But no, there's no app for that. I don't believe I will see anything for progressive MS in my time. Not because there isn't anything in the pipeline, but because of these constructs and delusions of man - politics, economics and ego.

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  5. . . . why there needs to be an ACT UP for MS, especially PPMS.

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  6. As you stated people were buying high doses of biotin after the paper was out. There will be a same effect with clemastine. Since it is an OTC drug what will prevent people from purchasing? The cat is out of the bag.

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    1. Try to actually find some of the stuff. It has virtually disappeared from store shelves and online vendors like Amazon over the last year or two. What little supply there is, runs at a very hefty price per pill.

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  7. Pertaining to the study, they looked at reduction in VEP latency delay as a measure of myelination. Does RNFL thickness using OCT correlate with myelination or is it used to measure neuro degeneration?

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    1. RNFL thickness essentially measures neurodegeneration/protection.

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  8. Is the dosis of Clementine used in the study known?

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    1. "Outcome measures will be assessed at three and five months after taking a baseline at the beginning of treatment. Fifty patients will be treated for a total of five months in the crossover study. For the first three months, patients will receive either a 4 mg Tavist (clemastine fumarate) tablet or placebo twice daily, and for the following two months, patients will receive the alternate treatment (placebo or Tavist)."

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    2. 4mg tablet twice daily. From the official trial page.

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  9. How is dimethyl fumarate related to Clemastine fumarate if at all?

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  10. Dr G, MouseDoctors!
    What's your opinion about Tisch MS Neural progenitor cell research which also targets regeneration?

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    1. The data is being presented today but reading the press release it says donate, donate and donate and once we get your cash we will do the next trial so donate!

      They say “Repair and regeneration is possible. We have a patient who no longer needs her cane, one who has transitioned from a motorized scooter to taking steps with a walker"

      We I see the data I can comment more

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    2. Hmmm, Tisch or Tosch? Sounds faintly snake oily to me but let's see the data.

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    3. I'm a patient there. They are not selling snake oil, but they believe that study is important to try. They were dissed by the MS Society, but gearing up for Phase II with Cornell, a very good NYC MS Center.

      We'll see. If we diss pharm and then say these independent research outlets are "snake oil salesman" it's not very productive.

      The Tisch Center's clinical center, the IMSMP, is truly excellent with patients, who travel from all over the world to see the neurologists there. They do much of what Dr. G promotes as best practices on this site. (I am a patient at multiple major MS centers, so I have some personal basis for comparison too.)

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  11. I think pharma has already started to counter this. I think they started doing so not long before the Phase II was even started. You can't find clemastine in any real quantity anywhere in the U.S. now, as far as I'm aware. Small quantities (16 pills for $25.00 or so) can be purchased online, but that's about it.

    The generics here are made by Sandoz - which is really just Novartis, and I think it goes without saying that they don't want a generic that used to cost pennies a pill cutting into big pharma's current and future plans to hold the MS community hostage.

    I used to use Clemastine for my allergies. Heck I used it for my dog's allergies. Starting about two years ago, the supply dried up very, very quickly. Now I can't get it for myself, or my dog (vet tried to order more for me, but said he couldn't procure any either).

    That being said, I had a decent stockpile on hand for my allergies when I learned about this Phase II kicking off. I checked the trial's dosage, and upped my daily clemastine dosage to the amount they used in the trial (was only 1 more pill per day). In the 11 months that I took it at that dose, from the time I started until I the time I ran out of pills, my MS did far better than it has done since. I paid for my own bloodwork at 3 month intervals during that time, and everything came back normal. I also did not experience the sleepiness that some folks get from taking clemastine (then again, I never have had that issue with it at any dose). Call my experience a fluke, or whatever you prefer, but I've expected this trial to come back positive for some time now, based on my own experiences.

    I think it's very unlikely that we'll see a ready supply of clemastine again. If it is available in your market, and you want try this experiment yourself, I suggest you buy as much of the stuff as you can before it gets pulled. Expect pharma to do everything they can to keep it out of the public's reach until they have a more dangerous, patentable treatment that they can use as a substitute. One that allows them to keep a gun to the head of everyone who has been unfortunate enough to come down with this cash cow of a disease.

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    1. There is a bunch of generic clemastine from India, Egypt Eastern Europe, etc where I live. I think even if novartis will withdraw clemastine from US market, arbitrage would happen and other producers, who is not involved in any MS drug development would pick up.

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    2. While I worry that you're overly optimistic, I hope you're right about other producers picking it up, for all our sakes!

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  12. FYI Quote from medscape

    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." i.e. 2ms

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  13. Thanks for that. my uneducated guess is that 2 m/s will not be clinical relevant to those who suffers from ON, or?

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    1. Perhaps not, but if things improve (or even just stabilize), rather than decline, that is a major milestone, regardless of how small the improvement is, right? Especially considering that the historical backdrop of MS symptoms (ON, or otherwise) is virtually always a long term trend downward, not up.

      Add to that the well-established long-term safety of the drug, and the affordability . . . I think this may be the biggest news of the week!

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  14. Hello. Today in a investors meeting of Biogen, one financial analyst has made the this question. I transcrip the whole question and answer. I would thank you also you expert opinion about it.
    Financial analyst:
    Christopher Raymond - Raymond James & Associates, Inc.

    Hey, thanks for letting me slip in here. So just a question on anti-LINGO. So at AAN, there was some interesting data on clemastine. That agent seems to have at least some sort of similarity in terms of mechanism to LINGO in terms of impacting the oligodendrocyte differentiation at least. Wondering, Al, if you had any thoughts – is there any kind of read-through we should be thinking about, with respect to that agent and the results there? Thanks.

    Alfred W. Sandrock, Jr. - Executive Vice President, Neurology Discovery & Development Center, Neurodegeneration Therapeutic Area and Chief Medical Officer

    Yeah, so we've – the clemastine came from this micropillar assay that was developed in San Francisco, where they have oligodendrocytes wrapping myelin essentially around tubes. And what they found was that there were a number of antimuscarinic compounds that work, benztropine, as well as clemastine. We've actually tested clemastine in our oligodendroctye differentiation assay here, and in our hands it's less potent than BIIB-61, our oral compound that we have in early clinical trials, and it's also less effective overall in a side-by-side comparison in our hands.

    Nevertheless, I did look at the data. Crossover designs like the one that they did are probably not the best approach for looking at disease-modifying therapies, because when you switch from clemastine to placebo, I don't expect that the – if it is causing myelination, how would the placebo patients look? They would continue to get the benefits from the clemastine that they had received in the period prior. So nevertheless they did show a modest effect on latency of the conduction between the retina and the brain, and we're keeping a close eye on that. I think that these are all early-day experiments in reparative therapies, and I believe we have established one of the best ways of looking at this in our anti-LINGO program, both in acute optic neuritis, as well as the MS program.

    Best regards,

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    1. "and I believe we have established one of the best ways of looking at this in our anti-LINGO program"

      By that he must mean the amaturish way in which they designed their anti-LINGO trial (missing most of the therapeutic window). Why am I not surprised that their tests found that their own "pipeline products" are much better? Talk about conflict of interests. Sounds like the same ole market spin designed to protect profits, not patients.

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    2. goodthing is they talk about a small molecule version of anti-LINGO

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    3. "Crossover designs like the one that they did are probably not the best approach" . . . and . . . "They would continue to get the benefits from the clemastine that they had received in the period prior."

      So what they're saying is that the drug may have actually produced more of a therapeutic effect than was noted, because the placebo group would have had a higher-than-actual amount of remylenation once the two groups were crossed over? Did I understand that right, MD?

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