“Success” Remyelination

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Here are additional results from a study with Bexarotene, which suggest some success. However, the trial is viewed as a failure. This is because the intended outcome aim wasn’t seen. You have to define this before the trialfinshes to stop you picking and choosing the positive outcome. However, it bodes better for the next study. However, Bexarotene is unlikely to be developed because it induces poorly tolerated side effects

Brown JWL, Prados F, Altmann DR, Kanber B, Stutters J, Cunniffe NG, Jones JL, Georgieva ZG, Needham EJ, Daruwalla C, Wheeler-Kingshott CG, Connick P, Chandran S, Franklin R, MacManus D, Samson R, Coles A, Chard D. Remyelination varies between and within lesions in multiple sclerosis following bexarotene. Ann Clin Transl Neurol. 2022 Sep 17. doi: 10.1002/acn3.51662. 

Objective: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response – measured by change in magnetisation transfer ratio – is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values).

Methods: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level.

Results: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions….Analyses detected significant treatment effects in WM lesions with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesions, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores.

Interpretation: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post-processing compared to WM lesions and markedly reduce sample sizes.

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MouseDoctor

20 comments

  • This is by far the worst title you could come up with. You can imagine my disappointment of seeing this headline in my RSS reading and then reading the piece.

  • The Bexarotene study reported c.2 years ago. It failed. The side effects were too bad for it to be used in a wider population. The term success can only be used if the treatment works effectively and with a good safety profile (and then is licensed for use).

    The follow up trial started in March 2022. Fingers crossed it will show efficacy and be safe. Given that the two drugs have a known safety profile, you would hope the dual therapy could be fast-tracked (if it shows efficacy). But the world of MS research is slow, so MSers might have to resort to buying the two readily available drugs from some dodgy pharma website. If you’ve got any spare metformin Mouse Doctor, I’ll give you a crate of real ale and an old Leeds Utd scarf.

    https://www-neurosciences.medschl.cam.ac.uk/jones-coles-group/ccmr2-trial-starts/

      • “Data-fracking is the fracturing of a dataset by the application of a pressurized search through as many datapoints as is necessary to find one that has the appearance of being positive. Typically, data is combined with cortisol and caffeine, and the mixture is injected at high pressure into statistical analyses to illuminate illusory correlations along which the appearance of success may migrate to a press release. The products of data-fracking tend to be more gaseous than substantive.”

    • Where do I start on this one

      1. Should we suggest that you donate your supply of Clozapine (PMID: 32050980; PMID: 31071102) as a remyelination/neuroprotective agent as you clearly have alot more personalities than Shirley Mason (Sybil Dorsett). https://en.wikipedia.org/wiki/Shirley_Ardell_Mason). Perhaps you think you are really Sid Dorsett [https://en.wikipedia.org/wiki/Sybil_(Schreiber_book)] but perhaps it is all fake too and you don’t need the meds…so give them away. However, your offer of drinks,etc have been made numerous times before and must say to the readers that this are all hot air:-(.

      p.s. You don’t listen as said many times before….I don’t drink real ale.. Maybe you don’t fit your percieved stereotype

      2. Bexarotene had known safety profiles (https://www.ema.europa.eu/en/documents/assessment-report/targretin-epar-public-assessment-report_en.pdf) when it was used. But agree side effects of are known. Clemastine is sedating anti-histamine, over the counter drug and there are plenty of people with MS who are taking metformin for type II diabetes. So you could ask is there benefit?
      Do you feel better on metformin, did you notice miraculous change? You can also ask is there remyelination in people with MS who have died whilst taking metforimn and had their brains donated to Brain banks. It happens

      Let’s hope there are fantastic results, but please note this is a phase II study and you are unlikely to get approval to use based on phase II data, there would probably have to be clinical benefit in at least one phase III and possible two phase III trials to get a clinical outcome before wide spread use ensues..

      If you live in the Cambridge area please consider volunteering for the trial., you can check it out in Sid’s link

      • MD,
        Why so horrible? I was being friendly.

        Regarding real ale. I sat behind you at an MS meeting and your pony tail definitely had a Side Pocket For A Toad real ale pong. I’m not 100% as I had to move away as your C&A jumper had a whiff of mouse droppings and a hint of Gregg’s Cornish pasty.

        Any news from the recent ‘At the limits’ meeting?

        • “I was being friendly”…..so was I 😉

          The At the Limits was filmed and I am guessing you will be able to see. I will provide the link when it is available.

          MS Star was presented…this is a multi-centre HSCT trial
          ProfK presented his trials
          Sir Jeremy presented the Octupus trial….however the selection of agents to be tested in the initial trial were still coated in secrecy.

          There was a presentation of repair by Dr Miron.

          I’m not going to discuss the microbiosome stuff as you can read it in Cell from a few weeks ago but genes associated with worse severity in MS have been identified, which is distinct from the immune genes related to susceptibility.

          BenJ gave a great talk

          The debate on value of cobnitive assessments verses biomarkers was interesting and the person doing the biomarker support element was beaten

          Aging was on the agenda

    • This is the problem of available drugs…is that they are adopted without evidence of efficacy or safety.

      As for cheeerier news…it is a long way from proven and one has to ask “how does a T cell modulatory agent up the nose work?” for a phase of disease where most immune modulation has not been good enough. Remember the information appears to come from a company source…they no doubt need investment for development…Turkeys don’t vote for christmas. Let’s hope it is good news.

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