Bexarotene for remyelination, the full article is now available

B

This study is now finally published. The initial findings were presented virtually at the last ECTRIMS and although the study was negative (i.e. the primary outcome was not met) it is still interesting to read the whole caboodle in the final article.

The road to remyelination has been a tough one, and this one in particular is underpinned by at least a decade of basic science preceding it. Bexarotene, a retinoic acid receptor agonist (with activity against the α, β, and γ isoforms) has the potential to promote remyelination. In the final study 52 participant were randomised 1:1 to bexarotene vs. placebo (dummy tablet).

Although, the study did not meet its primary endpoint, which was to show a difference in the mean adjusted submedian lesional magnetisation transfer ratio (MTR – an MRI marker purported to reflect remyelination) between bexarotene and placebo, it did on further data evaluation demonstrate a difference on lesional MRI in in cortical grey matter, deep grey matter, and the brainstem (see figure below). The primary outcome here is a summary score based on imaging assumptions of remyelination that may be taking place, whilst the latter is more selective of MS lesions in pre-specified territories. It is always tricking deciding on a correct primary outcome for work that has not been done before, and maybe trials that follow of this ilk may use predefined lesional analysis from the outset. They also looked at visual evoked potentials (an assessment of visual pathway conduction), which again was negative but I would say this was not the correct outcome for this study.

Figure: (A) Patient-level change in mean MTR (for submedian lesions) between baseline and month 6 by trial group (primary efficacy endpoint). The error bars represent SEs around the unadjusted group mean changes. The dotted line at 1·18 pu represents the target difference that the trial was powered to detect. (B) Adjusted bexarotene–placebo treatment differences in lesional MTR change, subdivided by baseline lesion MTR relative to the within-cohort median. The error bars represent 95% CIs. (C) Adjusted bexarotene–placebo treatment differences in lesional MTR change, subdivided by lesion location. The error bars represent 95% CIs.

Moreover there were no visible improvements in disability, and again the study was not powered to demonstrate this. If the initial findings had been promising I’m sure a larger study to check this would have been undertaken.

However, this is also a safety study, and unfortunately adverse events occurred more frequently in the bexarotene arm compared to the placebo arm; 159 event in total vs. 39. Things that would be considered problematic was that all 26 individuals on treatment became hypothyroid, with 24 starting thyroid tablets. The other was that supranormal elevations in triglyceride levels (a type of body fat) occurred in a majority of individuals on treatment with 6 displaying of readings of 10 mmol/l or more, which is in the familial hypertriglyceridemia range (normally high levels are between 2-6 mmol/l).

The final word from the authors was as follows: “We do not recommend the use of bexarotene in people with multiple sclerosis. Bexarotene was poorly tolerated and the primary efficacy outcome, which comprised an MRI endpoint untested in previous trials, was not met. Nonetheless, converging evidence from several other MRI and electrophysiological outcomes, in this trial not powered to detect a treatment difference in these outcomes, suggests that bexarotene might have a small biological effect, promoting remyelination in some demyelinated lesions.” Which, I have to agree with. But, the question remains whether it is worth tinkering away at more selective RXR agonists or dumping the project in entirety.

Abstract

Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study

Lancet Neurol. 2021 Sep;20(9):709-720. doi: 10.1016/S1474-4422(21)00179-4.

J William L Brown  1 Nick G Cunniffe  2 Ferran Prados  3 Baris Kanber  4 Joanne L Jones  5 Edward Needham  5 Zoya Georgieva  5 David Rog  6 Owen R Pearson  7 James Overell  8 David MacManus  9 Rebecca S Samson  9 Jonathan Stutters  9 Charles Ffrench-Constant  10 Claudia A M Gandini Wheeler-Kingshott  11 Carla Moran  12 Paul D Flynn  13 Andrew W Michell  5 Robin J M Franklin  14 Siddharthan Chandran  15 Daniel R Altmann  16 Declan T Chard  17 Peter Connick  10 Alasdair J Coles  5

Background: Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis.

Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18-50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed.

Findings: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene-placebo difference 0·16 pu, 95% CI -0·39 to 0·71; p=0·55).

Interpretation: We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies.

About the author

Neuro Doc Gnanapavan

17 comments

    • This is something we should put to the Cambridge and Edinburgh scientists and clinicians – they have been working on it the longest. There are other agents such as Lipoic acid which is going to go into clinical trial so watch this space.

      • J.K Rowling donated £10 million a decade ago to the Edinburgh myelination project and proclaimed that it was the most convincing undertaking when it came to advancing the restoration of the nervous system.

        Those who received the funding claimed at an MS Society event, I recall, that within a decade that we will have efficacious drugs to repair lost myelin, yet there remains nothing.

        Maybe we have to accept that our lifetimes will not cultivate what is sought.

        • Same old same old, maybe remyelination isn’t biologically possible.

          Or maybe it can be achieved safely, just we’re not near that stage yet.

          But making claims it can be done, with clearly no evidence or clue that it is morally wrong

        • There are systematic problems with the way MS researchers as a whole think about and investigate remyelination IMO. For one, many trials are done on “progressive” patients who are not on any treatments to control inflammation, which, as Prof G would say, makes no biological sense. For another, increasing rates of remyelination may not actually matter or make a difference because it’s not just myelin that is damaged and/or destroyed, it’s the underlying axons. When people recover from an MS attack, it’s usually because of rewiring around the damage, not remyelination. To actually repair damage, you would probably have to first apply something promoting axonogenesis, and maybe those new axons would just remyelinate naturally anyway. So is it even clear that remyelinating drugs would be necessary once there is something to remyelinate? Are people with MS walking around with brains full of denuded axons, or are they walking around with brains full of destroyed axons?

          • There’s another problem, which is that the initial experimental studies are done in chemical models of demylination, whch actually bear very little relation to MS. Something we have been banging on about for a long, long time but which fell on deaf ears.

  • Remyelination since I was diagnosed almost 20 years ago was always seen as the holy grail of MS therapies. I’ve lost count of the failed attempts – anti-lingo antibody was the most disappointing as the early trial results looked so promising. The Bexarotene trial was a complete failure – it is dangerous to give to patients, it failed to meet it’s primary efficacy outcome, and “converging evidence from several other MRI and electrophysiological outcomes, in this trial not powered to detect a treatment difference in these outcomes, suggests that bexarotene might have a small biological effect.” Sometimes you have to call a spade a spade!

    I suspect that the toxic environment in the CNS plays a big role (+ the issue of whether there are axons that can be saved ie they are not too far gone.

    I think the approach must be (a) highly effective anti-relapse drug early on, (b) a treatment that gets rid of the cause of the toxic environment in the CNS (which I think is the aim of the Sizomus trial), and (c) once the first two have delivered, a remyelination drug (but perhaps if the CNS has been cleaned up natural repair might take place).

    • So add on therapy trials for neuroprotection trials have been something we’ve done in the past – not successful as yet but probably can be explained by under recruitment etc. MD/MD2 probably have comments to make about this.

      • >So add on therapy trials for neuroprotection trials have been something we’ve done in the past – not successful as yet
        But didn’t the optic neuritis trial with phenytoin in 2016 have a statistically significant effect on saving nerves? And didn’t the PROXIMUS trial in 2019 show a statistically significant effect on reducing progression with oxcarbazepine? Why haven’t these results been taken further or translated to the clinic?

        • I will add that Lamotrigine has managed to make it into the OCTOPUS trial (there were promising data on the timed walk and neurofilaments). I agree with you Phenytoin needs to be taken forward as a Phase 3 study – needs funding. PROXIMUS (oxcarabazepine) also needs to be taken forward as a Phase 3 study – needs funding. To explain why there are these huge gaps, there are a few centres with the staff resource and experience to run these types of study. What happens is always that groups are working on other ideas at the same time as the one they’re currently testing so these naturally roll over, but it means that at least five years can lapse between projects. Scientists are salaried from grants, and so this perpetuates the roll over of ideas of new and the submission of new grants. A Phase 3 study would set you back £5-6M; very few groups have the clout to secure this level of funding, in fact it normally takes a few years of lobbying and applications to achieve this.

  • There may been zero urgency on clemestine trial. Also metformin. Or a clemestine/metformin trial and others

    Loads of talk and no action. Then when I trail does come around it takes years to get any results and nothing happens even then.

    Just a merry go round, keeping people in a job

      • Yes along with lipoic acid, lipoic acid and metformin and niacin. To start. And clemestine to follow

        However by the sounds of things this will not lead to anything with people with MS in the short or medium term, it’s for the drug companies to make similar compounds if found successful in the octopus trail.

    • Clemastine is a terrible agent to investigate really. Even 10mg amitriptyline a day reduces the IQ of someone with MS by 7 points on average, ultra-high doses of an ultra-powerful anti-cholinergic like clemastine would probably be way worse.

      Metformin is apparently going to be trialed “soon” (soon is a relative term in the MS world) but it looks like they are going to do it in progressive patients with aren’t on anti-inflammatory = failure.

  • Sadly, my doubts about this approach have been confirmed and I’m not surprised the drug was poorly tolerated.

    • This is a terrible idea. Fibrinogen is a critical component of the clotting cascade and meddling with this just because it is something that has been observed is silly and dangerous. There are drugs out there for this already, but used for specific clotting disorders and are not without serious side effects!

Translate

Categories

Recent Posts

Recent Comments

Archives