Thursday, 19 October 2017

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 ClinicalTrials.gov, 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...

64 comments:

  1. I indeed read this article early on and off I went to get the Rx filled. I was fortunate in that it did not fatigue me. I had an OCT before and after 3 months and indeed there was less inflammation. I continued on for another 3 months and then tapered off. Unfortunately, the researchers did not look at patients longer than 3 months. So my questions are whether you need to remain on the drug until the optic nerve returns to "normal" or a start will allow the immune system to do the rest. I am on a DMT and hope that any further damage would be held in check.

    It is exciting to see investigators looking at older not expensive drugs for novel means.

    Thank you for posting this article.

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    1. There is a thing call "regression to the mean" and says that if you look at things when they are active, if you look again it is likely to be less active and so one can't say the drug got rid of the inflammation but "time is healing". Indeed I do not think clemastine is a very good anti-inflammatory.

      As you say it is a shame that it was not longer than 3 months, but I am sure their will be a follow up....it this was a pharma trial there may be a duty to keep supplying the drug.

      Delete
    2. I suspect the optic nerve will not return to normal because there will be nerves lost and once gone they are gone. You can only remyelinate whats there. Therefore, we need to be realistic, if the drug was so spectacular we would not be talking about a 2,000th of a second improvement

      Delete
    3. Thank you for the reply. My thoughts much better said. I was happy for any improvement at the time but alas have not been tested again since.

      Delete
  2. Another exciting post.... and the floor is open with 7 questions!

    May I add an 8th one: would clemastine be OK as an add-on therapy to the current high-efficacy drug regimen (PIRT or maintenance)?

    Tony Fonda

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    1. Most definitely I would think in the trial the people were taking a DMT and it is surely the most sensible approach. Deal with the inflammation and then you can think about repair. Without it you are adding fuel to a fire.

      Delete
  3. This is great news; what do we know about the method of action?

    ReplyDelete
    Replies
    1. clemastine is a dirty drug but when they did the screen they pulled out a few that had similar mechanism of action

      Delete
  4. Great news

    More .........questions

    Could this be what team G have been talking about Ms treatment being immunosuppressant and another repair drug both working at the same time?
    In the study they make sure that the patients were rrms and had (very) stable disease
    How will this translate to real ms world?
    Could this repair mechanism works other that the optic nerve?

    Wil pharma be interest in this inexpensive few side efects drug?

    obrigado

    Luis

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    Replies
    1. Will pharma be interested in clemastine...I think the answer will be no.
      Clemastine is out of patent and I have yet to see a patent filed but the investigators. If they have, it should have been disclosed, if they haven't it will go nowhere fast.

      Although they looked at optic nerve the main effect you want to know is do MS brain and spinal lesions remyelinate and is their a clinical improvement.

      I am sure there will be follow-up and I don;t want to say too much in
      case Dr Green does a guest post.

      Delete
    2. Thank for reply

      Been digging ....found this (dont know if you allready had seen it)

      Peripherally derived FGF21 promotes remyelination in the central nervous system

      https://www.jci.org/articles/view/94337





      They said that after BBB disruption, peripheral tissue–derived factors can help Cns tissue remyelinate mainly FGF21, which is predominantly expressed from pancreas

      "Considering the relative kinetics of vascular barrier disruption and remyelination, it is conceivable that peripheral tissue–derived factors play a strongly supportive role during early regeneration mechanisms such as OPC proliferation, at a time when there is abundant extravasation of blood components into the CNS. "

      In this context, we found that FGF21, which is predominantly expressed from pancreas, is crucial for peripheral tissue–mediated OPC proliferation. The results of this study reveal an unexpected role of FGF21, which has been previously characterized as a metabolic regulator (42)

      They also sugest that if you have an aged peripheral milieu
      Your CNS repare after injury will be weaker than a young one


      Obrigado

      Luis

      Delete
  5. Ok let's buy into this. Let's say remylination has occurred due to drug and not because of the anti inflammatory effect of drug allowing body to naturally do the repair. So that implies, provided axons are still there, people in wheel chairs are going to start walking again?. That's my definition of remylinatiob!

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    1. What are you talking about? The patients are their own controls in the study.
      This is not the double-blinded randomly allocated usual stuff.

      Tony F

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    2. Not sure how this is relevant to the point I'm making. Just because it improves the conduction of the optic nerve by 2000 of a second doesn't mean it's remlynating or the body is naturally healing. So what that has to do with patients are their own control stuff!

      Delete
    3. From the paper.
      "The robustness of the findings were documented by the latency improvement observed in both groups of the cohort while on active treatment. Furthermore, the sustained clinical response in the first epoch provides evidence that the observed improvement was not due to a transient effect of medication on electrical conductance but rather reflects a persistent structural change induced by treatment."

      Delete
    4. Thank u for your reply. Just playing devils advocate. We all been down this path with anti lingo and then have our hopes crushed. Regardless of the bell curve response observed.

      Delete
    5. Have you read the ECTRIMS titles
      "P718 - Predictors of an opicinumab treatment effect and identification of an efficacy subpopulation: a post hoc analysis of the SYNERGY study
      S. Sheikh, Cambridge, US"

      This implies that anti-LINGO works, but this is a subgroup.
      What is it?
      I would guess that fresh lesions will repair easier than gliotic old lesions but we have to wait until 25th for the rest of the abstract becomes visible.....exciting

      Delete
    6. in comments from last years blog financial analyst asked Biogen about clemastine and anti-lingo

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

      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....

      "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."

      http://multiple-sclerosis-research.blogspot.com/2016/04/aanremyelination-reality-will-biogen.html

      Delete
    7. 15-love

      My reply would be....spin doctor.....so much for the in vitro test because we put B11B-61 into an animal and human and virtually none of it got in the brain but with clemastine loads gets in the brain we know this because it causes brain associated side effects... so as i often say in vitro smeetro, in Vivo Veritas.

      The animal rights wants us to do test tube tests before using animals. I hate to say this but there is so much meaning less science done this way because it has no relevance to what occurs in the body.. Bad science.

      15-40

      I think there is a poster at ectrims on the pharmacokinetics of anti lingo. Because they are pumping so much protein to get some brain penetration that the trials lack control when the placebo gets nothing.

      It is obvious that you need to develop a CNS penetrating small molecule to do the job of the antibody

      Delete
    8. Let's see the effect in the responder group we may be pleasantly surprised. Are the results good enough to do another trial.......

      Delete
  6. One of the things that I have learned from this blog is the importance of prioritizing brain health in multiple sclerosis. According to the anti-choligernic burden scale (www.agingbraincare.org), clemastine is rated as having "definite anti-choligernic effects," which have been linked to cognitive decline in the elderly generally (https://www.ncbi.nlm.nih.gov/pubmed/25621434) and individuals with MS specifically (https://www.ncbi.nlm.nih.gov/pubmed/25877263). Unfortunately, this issue is not mentioned anywhere in the paper published in the Lancet. Personally, having selected a highly effective DMT based on its efficacy in normalizing rates of brain atrophy, I would want to see additional evidence and analysis regarding the cognitive side-effects of clemastine before taking it. I hope that the investigators will look at this issue in their phase III trial.

    ReplyDelete
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    1. Interesting.

      "Personally, having selected a highly effective DMT based on its efficacy in normalizing rates of brain atrophy"

      Which DMT is that?

      Tony F

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    2. Alemtuzumab is the DMT I was referring to, based on the data from the extension studies published this past summer.

      In the extension data for CARE-MS I, the median yearly BVL improved over years 2-4, remaining low in year 5 (years 1-5: -0.59%, -0.25%, -0.19%, -0.15%, and -0.20%). In the extension data for CARE-MS II, the median yearly BVL remained low throughout the extension (years 1–5: −0.48%, −0.22%, −0.10%, −0.19%, −0.07% (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595276/).

      These BVL rates fall within the normal range for adults over the age of 35: http://www.jung-diagnostics.de/uploads/Schippling%20et%20al.%202017.pdf

      Delete
    3. So it's the same question I've been asking myself:
      how would Clemastine be used in the treatment of MS if it has an anticholinergic effect?
      Is she a 1st or 3rd generation anticholinergic?

      http://www.alzheimers.net/3-23-15-memory-loss-and-medication/

      Delete
  7. What a wonderful new!

    But I keep wondering: is Clemastine or will it be a reality for progressive MS, SP and PP?

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    Replies
    1. Has research with Clemastin up for ALS

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994328/

      Delete
  8. I'm not keeping my hopes high. It might just turn out to be like biotin.

    ReplyDelete
  9. Cannabis protects your brain. Read US Patent 6630507 ....

    ReplyDelete
    Replies
    1. Yes we know, read https://www.ncbi.nlm.nih.gov/pubmed/25537576 where we show it in animals and humans...unfortunately

      read https://www.ncbi.nlm.nih.gov/pubmed/23856559
      Neuros have messed it up..trial perceived to have failed and no one will go near this to show the mistakes

      As to the patent it is about cannabidiol and if we look at the data most of the optimal effects were between 10 and 100 micromolar. I hate to say, I think this is meaningless. cannabinoids are very fat soluble and so it is like putting cells into a sea of butter. 10 micromolar of these type of compounds do all sorts of weird things to cells and it is probably way above the levels occurring in human use.

      This one of the reasons there is so much guff written in the cannabinoid pharmacology field. I log it an then forget it as it is not worth remembering. However I do accept that cannabinids can be anti-oxidant

      Delete
  10. Exciting news for PwMS in wheelchair who have lost the use of hands and feet. If Clemastine can relmyelinate spinal cord even to a small degree, it might make a huge difference to the quality of life. I appreciate Mouse Doctors comment that it is only possible if the nerves are there.

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    1. I suspect there is more than nerves just being there. I suspect not all nerves remyelination. All the evidence points to gliosis as a problem and there is no experimental evidence that this type of demyelination is affected.

      Delete
    2. Hi MD, just trying to make sense of your last comment, sorry if I'm way off. Are you saying scar tissue is preventing remyelination ?
      Regards as always

      Delete
    3. Hi Andy

      Yes scar tissue prevents remyelination,
      The animal models used to say clemastine works do not have this scar tissue and so whether the drug works here is unknown.

      If is us lazy scientists trying to get results in a few weeks, the gliosis takes much longer to develop and the models used don't have this issue as they repair even without giving drug

      Delete
    4. I read something like this the other day come out of Mayo Clinic i think (cannot find now blast) re TM and clemastine. In that not likely to be as effective as in ON. My ms is all spinal.
      Am I wrong in not feeling enthralled by this? Not sure what a 2000th of increase will have on actual symptoms, but knowing if it would be neuro protective would be brilliant.
      Do you think it might be? I would have guess if there is more Myelin there is less chance of axon death?
      -Bee

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    5. It shows us how easy it is to do a trial and not easy to get support to do animal work, so the human trial is done before the proper animal studies are done. If it had failed we would be blaming the animal work

      Delete
  11. If clemastine does something to a muscarinic receptor, what does that tell us about MS? Why doesn't dipenhydramine do the same thing (promote remylination?)

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    Replies
    1. The muscarinic gives you the side effects. I think the histamine receptors are the common link with the remyelination signal

      Delete
    2. benztropine another remyelinator is and M! muscarinic and also an anti-histamine

      Delete
  12. I had a few large lesions on my spinal cord - which was seen on MRI between 2011-2014. It was bad and the neuro was surpirised than I was walking about. My symptoms were one sided leg spasticity and footdrop along with leg/arm numbness and continual l'hermittes. In 2014 I started B12 weekly therapy and slowly the numbness and l'hermittes disappeared. In 2016 I had an MRI and the lesion was no longer seen. As this was unusual the scan was repeated on a 3T scanner and they still could not find it as a normal signal was reported. I have been told the axon has remyelinated. The remyelination has solved all my sensory symptoms but I am told the axon was damaged due to the nerves being exposed for so long. Remyelination can not repair nerves. So if someone is in wheel chair due to demyelination only then they could get up and walk after remyelination. Once I believe nerves are damaged then currently there is nothing that can be done. It is quite funny as a few years ago I had to give up using the vibration plate as it would set the l'hermittes into overdrive if I was on it for 30 seconds. Now I can use it for a long time and there is no sign of the l'hermittes. several years ago I had more than 5 lesions and as of last year there is only one tiny brain lesion. I think than I am stuck with the foot drop until there is a cure for that damaged axon under the newly remyelinated cord.

    ReplyDelete
  13. B12 as in vitamin b12? What was dosage? Was it biotin by Medicova? Did the Neuro think B12 caused your lessions to remylinate?

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    1. Biotin is vitamin B7, not vitamin B12. Biotin is the potential remyelinator MD1003, I don't think vitamin B12 has been discussed as a potential treatment.

      Although, interestingly, pernicious anaemia (the inability to absorb vitamin B12) does cause nerve damage if left untreated, leading to ataxia as one of its symptoms.

      Biotin is not "by" anyone, it's a vitamin, not a drug, so is available even in high doses from several sources, vitamin B12 is available at a health food shop near you. Or on prescription, but I believe that's becoming very difficult to obtain.

      Delete
    2. Thanks JoH. Just that post before mine said he/she took b12 injections and all their spinal lessions disappeared. So wondering if that's why. Heard of biotin. Thanks again for your clarification.

      Delete
    3. There is a bit of work suggesting that there's a relationship between b12 and MS, although it's not well studied.

      https://www.ncbi.nlm.nih.gov/pubmed/15896807

      Delete
    4. Yes, sorry, I realised the connection to vitamin B12 with the previous post after I'd published but before my comment was visible. And I wasn't aware of any connection before this that any relationship was being investigated between pernicious anaemia and MS. My gran had PA. Very interesting!

      Delete
  14. Joanna I did the same when my releapse, I went through with the treatment with Vitamin B12, or by mouth or by injection.

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    Replies
    1. I give myself a B12 injection weekly. way back at the start of this neurological journey I went to a functional doctor who tested my B12 - her said it was low and I started to take supplements. On reading a heard a low B12 can cause nerve damage. He said that it does not cause demylination on the spinal cord which is what I had. But he did say tHAT b12 could help with fatigue I was instructed to have one injection every 4 months. To be honest I did no notice much difference but when I was tested by the fucntional doctor I was still low on B12 even though I was having the injections. The fuctional doctor told me to ask for more frequent B12 injections sO I got them weekly. After about 6 months numbness & l'hermittes gradually disappeared as did the fatigue. The when I had an MRI the cord MRI report said Normal. Neuro was surprised so the MRI was repeated o a 3T machine. Again the cord was normal. I have been told it has nothing to do with the B12 just a coincidence that the myelin has recovered. My legs were numb for a solid 2 years before I started the B12. This numbness went very gradually as did the l'hermittes.

      Delete
    2. Careful excess B12 caused lung cancers in men.

      "Lung-cancer risk among men who took 20 milligrams of B6 daily for years was twice that of men who didn’t. Among people who smoke, the effect appeared to be synergistic, with B6 usage increasing risk threefold. The risk was even worse among smokers taking B12. Using more than 55 micrograms daily appeared to almost quadruple lung-cancer risk.

      There was no apparent risk among women—which is not to say it doesn’t exist, only that it wasn’t apparent."

      https://www.theatlantic.com/health/archive/2017/08/b12-energy/537654/

      "This is dictated by a 1994 law called the Dietary Supplement Health and Education Act (DSHEA).

      “The law was created by industry lobbying to keep the FDA away from regulation, so the industry self-regulates,” said Brasky. But he deferred and said he hoped this article wouldn’t be about regulation.

      “I don’t want to pick a fight with the vitamin industry for any reason.”

      So that falls to me. There are legitimate and important uses for B-vitamin supplements, but the emerging evidence suggests we’re best to treat them more like pharmaceuticals than like panaceas to be shoveled into us in pursuit of energy, metabolic fortitude, “cardioprotection,” “bone wellness,” or whatever way in which we’d like to be better.

      The enduring theme in health is that more doesn’t mean better. What’s healthy for one person may be unhealthy for another. The fact of a product being sold without a prescription does not mean it is exempt, or that it’s good or even harmless. Any ingested bioactive substance will come with risks and benefits."

      Delete
  15. Does anyone know why the exclusion criteria included anyone taking Fampridine?

    ReplyDelete
    Replies
    1. Maybe because potassium is involved in remyelination.

      Delete
    2. "Maybe because potassium is involved in remyelination."

      So if one eats a 2 or 3 a day banana diet..remyelination will
      be going on ?

      Is this mostly diet hype..?
      https://livelovefruit.com/healthy-brain-foods/

      "Bananas are a great brain food. For one, they help lift depression due to their high tryptophan content (a protein that the body converts into serotonin), which helps you relax and improve mood. Secondly, they are remarkably high in potassium (same with medjool dates!) which is a mineral that helps send oxygen to the brain and thus makes you feel more alert. They are also rich in B vitamins which are very important in calming the nervous system and protecting the myelin sheath around our nerves."

      Delete
    3. The reason why fampridine is excluded is probably because if speeds up the nerve conduction, which is what they were aiming to measure as a remyelination.

      Dietry potassum and nervous potassium are not the same thing

      Delete
  16. I'll try nettle tea instead I think.
    https://clinic.deeatkinson.net/dees-blog/herbal-alternatives-to-anticholinergic-drugs

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  17. But if the effect is not due to the solely anti cholinergic effect which is likely, then the herbs are going to do nothing but a placebo and if they dont have the anticholinergic side effects which they don't then they are not providing enough stimulus

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    Replies
    1. Very nice tea at least. And it won't give me added dementia.

      Delete
    2. MD, This is my concern too about the dementia.

      Delete
  18. Is clemastine fumarate related to dimethyl fumarate?

    If so, could dimethyl fumarate help with remylination too?

    ReplyDelete
    Replies
    1. If fumarates are changed into fumaric acids by our bodies, might it be fumaric acids that are helping?

      Delete
    2. Is fumarate.....answer "no" it is called a fumarate because of part of its chemical structure.

      Delete
  19. Interesting...
    Clemastine inhibits IL-6 secretion and easily crosses the BBB

    https://www.ncbi.nlm.nih.gov/pubmed/21807405

    ReplyDelete
  20. New anti Lingo phase 2 trial. For people in early phase of disease. Who likely to remylinate anyways and then claim anti lingo is effective. Another dud drug biogen is trying to hood wink and charge thousands to recap trial costs. If so confident in anti lingo, why not go to phase 3?

    ReplyDelete
  21. I read the anti-lingo drugs did not work, therefore no phase 3 study.

    ReplyDelete

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