Saturday, 5 May 2018

A trial of a possible remyelinating drug in multiple sclerosis

Do you live in the UK? You may want to consider volunteering to participate in a very exciting remyelination trial.



Nerves within the brain and spinal cord are normally protected by a surrounding layer of a substance called myelin. In multiple sclerosis, the immune system of the body attacks this myelin, stripping it off the nerve fibres. This causes the nerves to malfunction, leading to your multiple sclerosis symptoms. Animal studies have shown that a group of drugs can stimulate cells in the brain to repair damaged myelin. This process is called “remyelination”. One of the drugs in this group is bexarotene, a capsule already used as an anti-cancer medication. We believe that bexarotene may also promote remyelination in people with multiple sclerosis, which could potentially reverse or alleviate symptoms. The purpose of this research is to assess whether bexarotene causes side effects in people with multiple sclerosis who are also taking disease-modifying drugs and also to assess whether it really can promote remyelination.

Participants in the trial take several capsules (which might be bexarotene or a placebo) a day for 6 months and remyelination is assessed by one MRI scan at the beginning of this six-month period and one at the end.

The trial centres are at Cambridge and Edinburgh.

Participants need to live reasonably close to these centres as frequent visiting (at times weekly) is required.

Participants should have relapsing-remitting multiple sclerosis, need to be able to walk, and should be taking a first-line disease-modifying drug (especially Tecfidera, etc.).

If you wish to be considered for the trial, please ask your GP or consultant to refer you to:

Prof Alasdair Coles
Department of Clinical Neurosciences,
Clifford Albutt Building, Level 4,
Cambridge Biomedical Campus,
Cambridge CB2 0AH

OR:

Dr Peter Connick
The Anne Rowling Regenerative Neurology Clinic
University of Edinburgh
Chancellor’s Building
49 Little France Crescent
Edinburgh EH16 4SB

43 comments:

  1. Can someone whose taken fist dose of Alemtuzumab apply after failing on tecfidera?

    ReplyDelete
  2. Participants should have relapsing-remitting multiple sclerosis, need to be able to walk, and should be taking a first-line disease-modifying drug.

    Why is it only people with RRMS are allowed onto this trial? Why not include a few people with advanced MS. Remember #ThinkHand. Yet another door closes. Shocker but not surprised.

    ReplyDelete
    Replies
    1. My guess? There should be something to repair. i.c. nerves should still be there

      Delete
    2. There is something to repair in progressive MS patients just less nerve supply/reserve in some tracts. Dalfampridine works in progressive MS which tells you they still have nerve supply/reserve intact.

      I would argue that a remyelinating agent would make a much larger clinical impact to a progressive MS patient than a RRMS patient, who still has the ability to endogenously repair.

      Delete
  3. If only it wasn't restricted to Cambridge and Edinburgh! I'd happily get on board with this...Should consider setting up a site in London.

    ReplyDelete
  4. Prof G,

    Please can you ask Prof C to amend his Twitter entry of 4 May which currently reads "trial of a demyelinating get therapy". I've got on already - MS.

    ReplyDelete
  5. Why not progressive Ms alongside this - every trial is exclusively for early stage. I still have nerves that need help!!?

    ReplyDelete
    Replies
    1. Pisses me off that it's never PPMS, 'Cinderella disease' is alive and not moving on any time soon!

      Delete
  6. "In multiple sclerosis, the immune system of the body attacks this myelin, stripping it off the nerve fibres"



    "We conclude that C3d1 microglial
    clusters in MS are not part of an acute attack against myelinated axons"

    GLIA 2017;65:264–277

    Now what?

    Obrigado

    ReplyDelete
  7. Are all of us with MS ok to start to feel some tentative hope and anticipation with regards to remyelination? Or is it actually a case of ifs, ands, buts and maybes, with the likihood of very limited application, for those who are RRMS, below EDSS 3 ??

    The professional expert view from the team will be very welcom.

    ReplyDelete
  8. Why is this trial looking at the safety of this drug when used with other disease modifying drugs, when surely if it is about remyelination why is it not also being tested on people who are not taking other drugs? i.e those with SPMS and PPMS? The side effects must be known as it is currently being used as an anti cancer drug and people such as myself should be given a chance.

    We are told that RRMS, PPMS and SPMS is the same disease so let’s test remyelination drugs on all people rather than just those with RRMS. Once again it seems that those of us with PPMS and SPMS are simply being ignored.
    This is not acceptable

    ReplyDelete
    Replies
    1. This is also our concern all the drugs for demilination seem to have possible side effects just taken a simple cannabis based tablet and it effected legs, presumably the commonsense approach is if you feel side effects to stop,May be more difficult if you are on a trial.

      Delete
    2. Why restrict the potential to gain yet more knowledge about how a drug behaves only to a specific part of the MS population. I understand the idea is to gain evidence in a scientific way, but we are desperate people, with not a lot left to loose. Can we inject a bit of compassion into the selection criteria.

      Delete
  9. Dr AC, the master of repurposing, strikes back.

    Instead of testing high dose Ω3 fat acid for repairing brain damage (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518659/) the focus is once given to a drug that has recently (2016) lost its patent.

    This is serious research, recycling existent drugs. Speechless.

    ReplyDelete
  10. Wow, excluding all progressive patients. There are > 1 million/2.5 million with MS in wheelchairs according to Dr.G. Probably much greater # if you account for the progressive phase of MS seeing as though 80% of RRMS will progress to SPMS in 15 years yet all trials geared to the artificial classification made by pharma for the RRMS stage of MS.

    If this is one disease, why are "card-carrying" neurology researchers not screaming from the rooftops that this is utterly unacceptable? It is time for revolution where the current research establishment is deposed and replaced by researchers that do not want to cherry pick RRMS to get a repurposed drug approved.

    It is time for innovation for remyelination, neuroprotective agents and neurorestorative products for all stages of MS that show a clinical difference, not just a statistical difference. I am not sure how Dr. AC or Dr.PC can look at themselves in the mirror. I am sure they will justify it saying the RRMS will show the best response and then all can share in the good fortune, which is never the case with any regulatory body using the faulty 3 classifications of MS system created by pharma. to make money.

    ReplyDelete
    Replies
    1. They "pharma" create separate classifications to get orphan drug status and thus charge astronomical prices. Hence it's only a treatable disease in the western world.

      Delete
    2. Re: "It is time for revolution where the current research establishment is deposed and replaced by researchers that do not want to cherry pick RRMS to get a repurposed drug approved."

      The amount of money generated by treating RRMS is so staggering that any change to the current MS paradigm will be difficult.


      Delete
    3. DrK has paper showing annual income of some countries verses cost of treatments

      Delete
  11. I trust medical professionals about as much as they trust their patients,so drug trials are definitely out of the question ! Plus you are not guaranteed to get the drug.

    ReplyDelete
  12. If it's such a wonderful drug why isn't pharma funding the trial and buy the rights to a rebranded version? Like anti lingo all hype and very modest effect!

    ReplyDelete
    Replies
    1. Phamra is not funding trial as there is no patent to protect the investment

      The problem with anti-LINGO is that is an antibody and 99.9% of it doesnt get into the CNS

      Delete
  13. "One disease"

    And 3 lessions types paterns

    :(

    ReplyDelete
  14. Thanks for all your comments.

    Thank you for the correciton of my tweets! It seems my spell checker keeps changing "remyelination" to "demyelination". I must remember to tell Mr Gates that "remyelination" is not a mistake....

    I understand why we are being challenged to include people with progressive MS. But there is a good scientific reason. We know the side-effects of this drug in cancer patients are quite significant... and we do not want to expose people uneccessarily to those risks, especially as we do not know whether the drug works at all. So we have designed a trial to use the minimum number of people possible. We suspect that the drug will have greatest effect in people with RR multiple sclerosis (because they have more axons left to remyelinate, as mentioned above). So, to reduce risk, we are just trialing the drug in people with RRMS. But, if the trial is positive, and the drug is reasonably safe, we will certainly suggest a trial in progressive MS.

    We are hoping to recruit 50 people for this trial, and we are half way there. If we can recruit the final 25 quickly, we will have a result by the end of next year, from which everyone will benefit.

    Alasdair Coles

    P.S I actually trust my patients a lot!

    ReplyDelete
  15. Am I correct is saying this new study is going to be a 2b study?
    And that bexarotene has already had a study for MS?
    What were the outcomes of this previous 2a study?

    2015 2a trial at Addenbrookes:
    A trial to determine bexarotene's safety and tolerability and its ability to promote brain repair in patients with multiple sclerosis

    http://www.isrctn.com/ISRCTN14265371

    ReplyDelete
    Replies
    1. Prof G,
      I would have thought there would be more discussion on this blog about this previous trial of bexarotene for MS in 2015.

      The previous 2015 trial must have been positive??

      Delete
    2. I am not convinced their was an earlier trial

      Delete
    3. The 2015/16 bexarotene MS trial details are on the UK Clinical Trials Gateway.

      Primary Trial Contact

      Mrs Arti Gulati

      Scientific Title

      A randomised placebo-controlled study of the safety and tolerability of a retinoid-X receptor agonist's ability to promote remyelination in people with relapsing-remitting multiple sclerosis already on interferon-beta therapy: a phase 2a trial

      EudraCT Number

      2014-003145-99

      Delete
    4. Mrs Arti Gulati works for Cambridge University, Department of medicine, details on the university website.

      Perhaps Prof Coles has spoken with Mrs Arti Gulati the primary contact of the original 2015/16 2a bexarotene MS trial.

      I would be interested to know the outcome of that trial or if the trial was shelved then why.
      I'm sure many of us with MS would interested to know.




      Delete
    5. Still ongoing according to this.
      https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-003145-99

      Delete
  16. There are other medications that have excellent remyelinating efficacy data in animal models with a much more benign side effect profile than bexarotene. Why not give miconazole a go for example?? Cheap as dirt and not many side effects even when taken orally (there are many studies on oral administration of miconazole from the 70s to 90s before the newer antifungals came out). Clemastine has shown some effect but it has way to many side effects such as drowsiness, fatigue and anticholinergic effects that can lead to dementia in the future.

    ReplyDelete
    Replies
    1. Why not give miconazole a go for example

      Evidence?

      Delete
    2. The compounds screened in this study were obtained from a drug library maintained by NIH’s National Center for Advancing Translational Sciences (NCATS). All are approved for use in humans. NCATS and Dr. Tesar have an ongoing collaboration and plan to expand the library of drugs screened against OPCs in the near future to identify other promising compounds.

      Dr. Tesar’s team found that two compounds in particular, miconazole (an antifungal) and clobetasol (a steroid), stimulated mouse and human OPCs into generating myelin-producing cells.

      Next, they examined whether the drugs, when injected into a mouse model of multiple sclerosis, could improve re-myelination. They found that both drugs were effective in activating OPCs to enhance myelination and reverse paralysis.

      “Off-label use of the current forms of these drugs is more likely to increase other health concerns than alleviate multiple sclerosis symptoms. We are working tirelessly to ready a safe and effective drug for clinical use,” Dr. Tesar said.

      https://www.nih.gov/news-events/news-releases/drugs-activate-brain-stem-cells-may-reverse-multiple-sclerosis

      Delete
  17. I think the neurologists in Cambridge need to communicate better. Professor Robin Franklin, who's there as well, thinks Metformin is the best bet for remyelination - it should be included in the trial. Watch the video below and see why.
    https://stopms.mssociety.org.uk/annual-lecture.html

    ReplyDelete
    Replies
    1. Yet prof Franklinstein doesn't test his theories in an inflammatory model such as EAE. Maybe he doesn't think it'll work under these conditions?

      Delete
    2. "It should be included in the trial".

      Its too late the trial protocol is done and the trial is recruiting you can't change the protocol.

      The idea is that age of oligodendrocytes is a central brake to repair and the new Cambridge work suggests that drugs like metformin block that brake and rejuveniate the oligodendrocyte.

      Therefore you need a remyelinating drug plus the metforin, so when the remyelination trial finishes and if it is not great the view is that you need to re-do the trial with a combination.

      Unfortunately SH1 sticks and if the current trial fails to excite it will fail to excite funding to go for round two.

      Question also is, given there must be loads of pwMS with type 2 diabetes who take metformin. Have they noticed any change?

      Probably not miraculous a there would be anecdote...Therefore we need to bear this in mind when we here the hype.

      Delete
    3. Your own words suggest pwMS and diabetes would need to take bexarotene or clemastine as well as metformin to see an effect. That might explain why there are no anecdotal reports of improvement when starting on metformin.
      I still think the doctors working on MS at Cambridge should communicate better with each other.

      Delete
    4. "Question also is, given there must be loads of pwMS with type 2 diabetes who take metformin. Have they noticed any change?"

      Hype is ccvsi/chiropractic most posts from 2011-13 then nothing http://www.thisisms.com/forum/chiropractic-treatment-f50/

      There are studies on Metformin:
      For the current study, 20 patients received metformin (850-1500 mg/d), 10 patients received pioglitazone (15-30 mg/d), and 20 untreated patients served as controls. The groups were similar in age, sex, BMI, disease duration, relapse rate, and treatment status, and were followed up for a mean 26.7 months.

      After 6 months of treatment, patients treated with either drug therapy showed a significant decrease in the number of new or enlarging T2 lesions (metformin, 2.5 at baseline to 0.5 at 24 months; pioglitazone, 2.2 at baseline to 0.6 at 24 months). Gadolinium-enhancing lesions also decreased (metformin, 1.8 at baseline to 0.1 at 24 months; pioglitazone, 2.2 at baseline to 0.3 at 24 months)

      Ultimately, both metformin and pioglitazone appear to have beneficial anti-inflammatory effects in MS, and should be explored further, study authors concluded.

      https://www.neurologyadvisor.com/multiple-sclerosis/metformin-pioglitazone-anti-inflammatory-effect-in-ms-patients-with-metabolic-syndrome/article/485829/

      Delete
    5. "Prof Franklinstein sewed a young and and old mouse together to show that young blood could help old bods repair. This was shown to be due to the macrophages/microglia clearing up the myelin debris. In a gene search they found that the RXR gene appears in remyelination. In this study they show that the RXR gene pathway is decreased with aging but you can stimulate them by stimumlating the RXR receptor....go figure. If you remove RXR the young mice do not clear the debris up. They showed that bexarotene allowed old mice to remyelinate and they are aiming to do a trial in Cambridge with bexarotene. Hope it is aiming to repair newly demyelinated lesions as they have yet to show this approach works in chronic demyelinated lesions and if it is working at the level of clear up them maybe treating relapses and showing better recovery is the name of the experiment."

      http://multiple-sclerosis-research.blogspot.com/2015/10/remylinating-trial-on-wayheres-why.html

      Delete
  18. Unfortunately live in North Shropshire nearest centre Stoke On Trent,
    Understand Tamoxifen is an option work done by Cambridge.

    ReplyDelete
  19. Would treatment with Cladribine preclude participation? I am not sure if it qualifies as a first line therapy or not.

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  20. I have multiple sclerosis was diagnosed Sept 2016 I can walk and I am on copaxone injections 3 times a week I tried tecfidera and my body wouldn't accept it. Is there any info on people testing it now? And of I decided to try it would I be accepted I have RRMS just asking for future reference thanks

    ReplyDelete

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