ECTRIMS 2021. Too old to remyelinate.. Bexarotene trial result

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We know that the Bexarotene trial failed because the drug was not tolerated. However there were glimpses that the supporting pre-clinical biology found by Prof Franklinstein from Cambridge was active. Now the clinical bobs have had a look at the data abit more closely and suggest that there is a problem with age. You asked for some ECTRIMS news so here is some

Older people do not repair as well. This is worrying that those in their 40s and over did not repair that well. This does not make good reading except that it sets the stage for a metformin trial as a rejuvenating agent.

This approach is set to go and studies will be occuring in the UK and would have occured if COVID-19 did not get in the way

I am hopeful for this. Why?

This is based on the information surfacing from COVID. As you know when COVID appeared having diabetes was a risk factor for doing badly. Likewise the biggest risk factor for doing badly was age…hence us old follks getting offered the Jab first.

I thought one of the problems of age was senesence of the immune system and your macrophages would be less good at attacking the SARS-CoV-2 virus. Prof Franklinstein had again shown that old macrophages were a problem with repair. If you dont clear up the debris from damage you can’t repair. So if you take metformin it makes the macrophages young and the old beasties repair better.

So if this is the case you would expect diabetics who take metformin to do better. This was my prediction and the subsequent data appeared to support that view

Li Y, Yang X, Yan P, Sun T, Zeng Z, Li S. Metformin in Patients With COVID-19: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2021 Aug 19;8:704666. 

So maybe hope for us oldies that it is possible to repair

C.E McMurran1, T. Mukherjee1, JW.L Brown1,2,3, A.W Michell1, A.J Coles1, N.G Cunniffe1
1University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom, 2University College London, NMR Research Unit, Queen Square Multiple Sclerosis Centre, London, United Kingdom, 3University of Melbourne, Clinical Outcomes Research Unit (CORe), Melbourne, Australia

Introduction: Therapeutic enhancement of remyelination is a promising strategy to prevent axonal degeneration and progressive disability in people with multiple sclerosis (MS). Remyelination becomes less efficient with advancing age in animal models, and much preclinical research is focused on interventions to reverse cellular hallmarks of ageing in remyelinating lesions. However, the same has been harder to demonstrate for patients with multiple sclerosis.
Objectives: To examine data from a completed clinical trial of a bexarotene, a retinoid-X receptor agonist, to see whether remyelination – as measured by visual evoked potential (VEP) latency and magnetisation transfer ratio (MTR) – varies with patient age.
Aims: To determine whether the response to a remyelination-promoting drug declines in older patients.
Methods: We carried out a post-hoc linear regression analysis of the Cambridge Centre for Myelin Repair trial One (CCMR One, ISRCTN14265371) to investigate the effect of patient age on treatment response. CCMR One was a double-blind, placebo-controlled phase 2a trial (n=52) that demonstrated the ability of bexarotene to improve neurophysiological and radiological markers of remyelination in people aged 25-50 with relapsing remitting MS.
Results: For eyes with chronic optic neuropathy (baseline latency >118ms), bexarotene shortened the full-field VEP P100 latency maximally in younger patients.  P100 improvement in the treatment group diminished by 0.45 ms/year (95% CI 0.03 to 0.88, p = 0.044) such that bexarotene gave no significant benefit over placebo in patients aged 42 and older (α = 0.05). There was a similar age-related decline in deep grey matter remyelination, as determined radiologically by MTR (0.34 pu/year, 95% CI 0.04 to 0.64, p = 0.028), with no significant treatment effect in patients older than 42 (α = 0.05). In the other two brain regions sensitive to bexarotene, remyelination did not significantly decline with age (cortical grey matter: -0.08 pu/year; 95% CI -0.18 to 0.01, p = 0.09; brainstem: 0.01 pu/year, 95% CI -0.07 to 0.10, p = 0.73).
Conclusions: These results provide evidence that bexarotene promotes remyelination best in younger patients, reinforcing the need to address the age-associated decline in remyelination capacity to develop successful remyelinating therapies that work across the lifespan.

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MouseDoctor

4 comments

    • The fact that it actually reduced lesion volumes rather than just slowing growth sounds almost too good to be true… I wonder if this is real repair or just pseudo-atrophy caused by a reduction in microglia-driven inflammation.

  • Plenty of talk over the years about metformin trials, but nothing.

    I think the octopus trial is going to trail it, maybe in combination with ALA etc.

    However there doesn’t seam to much enthusiasm in this blog about those trials as the trail is just to find classes of drugs that may work, people with MS may never be given the drugs even if they are found to work.

    Then all people with MS will hear is, ‘well the trail wasn’t designed to well’ etc, whether it’s the octopus trial or another. Then the wait just goes on and on and on and on

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