Remyelination here we come…well almost. Bexarotene trial ECTRIMS

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The basic science gives the tools for the clinicians to try and find treatments and Prof Franklinstein (Robin Franklin) from Cambridge and Prof ffffffffffrench-constant from Edinburgh hunted for molecules that may affect switches from precursors cells to full myelinating cells. They came up with a target that is triggered by the retinoid X receptor (RXR) gamma. Prof Franklin tried to get companies making retinoic acid receptor drugs to target the receptor that had been developed for cancer, but had no success so they used what was available which was bexarotene https://en.wikipedia.org/wiki/Bexarotene. This trial tests this idea.

Bexoratene is a anti T cell cancer agent and it has side effects.

If you remember, I said some time ago that this target is expressed all over the body and therefore you would have to expect side-effects if this was to be used long-term. This is a problem for the remyelination targets that they have found so far. They are largley signalling molecules that are present all over the body. There is nothing specific for oligodendrocytes. So as an agent hits them, it targets other things. However, you may not have to treat for ever, if it is a switch factor and as a proof of concept you don’t have to treat for ever. I was clearing-out a fridge yesterday and came across a box of cis retinoic acid, which we were going to use, following discussions with Robin, to test this idea in chronic EAE, where chronic old lesion would be present. It never got funded. The experiments cost too much to do on a whim. However to date animal experiments show they can repair stuff that is naturally going to repair anyway. The experiments where you try and repair an old chronically demyelinated lesion have never been done.

In addition, since the early discovery about RXR, it has also been found that age is key and unless you revenate the system these agents don’t work as well as they can. The Cambridge group (Franklinstein and Bjorn Neumann) showed that metformin would act as the revenating factor so that they could be Bjorn again and some of the drugs they discovered work much better with a combination. This would be the case here

However, great science is only one part of the equation. Next you have to have a great trial design that is capable of showing an effect. Because if the trial doesn’t work it could be because the drug was wrong or importantly the trial design was wrong. In my opinion in so many times, the trial design fails. I know this from personal experience. This is why I rant about it so much.

This trial design by ProfC from Cambridge no doubt with the help of the gang from Edinburgh and Queen Square was really rather neat because we know in the animals that if you demyelinate, you can remyelinate it, but it was not known to what extent you can remyelininate chronic lesions. It is also good to see that they were on a DMT too. So rather than look for a clinical effect the trial that was designed to see if they could spot repair using MRI and electrophysiology. Now remember last week I said the Magnetic transfer ratio may detect things other than remyelination. The eletrophysiology will be reported later today.

I am sorry to say it is negative and failed based on the end points selected. In trials you have to say what is going to be the positive result to stop you cherry-picking the best results. But there are positives.

First of all there were alot of side effects and this led to people dropping out of the study. This suggests that it may be the end of the road for this agent. and this view is supported in reports from the media. When the size is rather smal,l as exploratory studies often are, they suffer if there are drop outs. This happened with the lamotrigine trial. It caused side effects, people dropped out or stopped taking their drugs and the trial failed. NDG showed that if people took their drug, there was evidence for a positive effect. However the SH1 stuck and the trial was seen as a failure. Likewise, this happened with THC. If you looked at the less-disabled people who progressed in the trial…the trial was a success. It is seen as a failure. We have tried to resurrect this and it was canned. However, the studies get remembered as a failure and you throw the baby away with the bath water.

In this trial there was a suggestion that some lesions responded by MRI and importantly there was positive news when they looked at the eye. Where there was evidence of demyelination seen by a slowing speed of transmission of the nerve signal, there was evidence of repair. If MRI was not the endpoint but electrophysiology we may have been talking successs.

So it seems there is some evidence of repair and this is great news because it informs on how positives can be obtained from future studies. However, it shows again that trial design is key to translating the basic science. It also suggests that some lesions may not respond. This does not surprise me as chronic astrocytic lesions have proved difficult to repair. However, if we are to have a drug then it is going to have to have a positive effect on clinical outcomes. Again stressing that trial design is key. However it supports the idea that basic science can be translated to benefit

We will have to see if selective RXR agonists are developed (see below). It will depend on the side effect profile and also if the SH1 sticks. As we have seen with lamotrigine, the positive data is not remembered and people may view this as a failed trial. I see positives, and I know that more studies are planned of combinations, to well done to the guys for giving it ago. We know from history that you have to have tail-blazers who may not completely succeed but this is on the road to unleashing a trial design that will show efficacy as the next stage to producing a remyelinating agent.

Maybe this is where the ATTACK MS trial of ProfK could really benefit. There the lesions are new and have a chance of repairing and the Sponsors could do an extra arm of natalizumab plus a remeylinating agent.

LB01.02 – Phase 2 clinical trial evidence that a retinoid-X receptor agonist promotes remyelination in people with relapsing-remitting multiple sclerosis. Brown et al.

Background

Retinoid acid X receptor [RXR] gamma agonists promote oligodendrocyte progenitor cell differentiation and remyelination following experimental demyelination.

Objectives

To assess the safety and efficacy of bexarotene, a non-specific RXR agonist licensed for cutaneous T-cell lymphoma, as a remyelinating therapy in people with relapsing remitting multiple sclerosis.

Methods

In a double-blind, placebo-controlled, phase 2a trial (Cambridge Centre for Myelin Repair: CCMR-One), participants aged 18-50 years with relapsing remitting multiple sclerosis, stable on dimethyl fumarate for at least 6 months, were randomised to bexarotene 300mg/m2 or placebo for 6 months. The primary efficacy outcome was change in mean lesional magnetisation transfer ratio (MTR) for lesions whose baseline MTR was below the median lesional MTR for that patient. The secondary efficacy outcome was change in full-field visual evoked potential (VEP) latency in eyes with electrophysiological evidence of optic neuropathy (baseline latency >118ms). We analysed by intention to treat.

Results

52 patients were randomised 1:1 to receive six months of bexarotene or placebo. Two placebo patients withdrew before receiving study drug and one bexarotene patient withdrew consent during the trial. All bexarotene patients experienced adverse effects, notably central hypothyroidism (26 [100%]) and hypertriglyceridaemia (24 [92%, mean maximum of 6.79 mmol/L ,SD 4.4]; as well as rash (13 [50%]) and neutropenia (10 [38%]). Two discontinued placebo because of adverse events and five discontinued bexarotene because of rash [2], neutropenia, triglyceridaemia and mood disturbance. The primary efficacy outcome was negative (mean submedian lesion MTR change was 0.25pu in the bexarotene group versus 0.09pu in the placebo group, p=0.54), but in an exploratory, lesion-level analysis, though treatment difference in submedian lesions was too small to achieve significance, it was statistically significantly greater than in supermedian lesions (p=0·007). This suggests that bexarotene has a biological effect on MTR and that this effect is dependent on baseline lesional MTR. This interpretation is supported by the finding that bexarotene treatment reduced full field visual evoked potential latency compared to placebo in the 52 eyes with delayed VEPS at baseline, by 4·66 ms/eye (95% CI -8·38 -0·93; p=0·014) and in all eyes, by a per-protocol analysis, by 4.02ms/eye (P=0.015).

So some people seemed to respond well, but most did not

Conclusions

Despite a negative primary efficacy outcome, evidence from both magnetisation transfer ratio imaging and visual evoked potentials suggest that a retinoic X receptor agonist, bexarotene, promotes remyelination in people with multiple sclerosis. We have also a heterogeneous response of MS lesions to a drug promoting remyelination. Although bexarotene’s safety profile precludes its widespread use, these data support efforts to develop a selective RXR-gamma agonist.

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MouseDoctor

8 comments

  • Thanks for this detailed and balanced post MD. After seeing online yesterday The Guardian headline ‘MS treatment a step closer after drug shown to repair nerve coating’ I was hoping you might provide us with the info we need to know.

    Enjoy the rest of your weekend.

  • Since the patients were stable for at least six month on Tecfidera, am I correct to conclude that the remylination occurred in old lessions?

  • Comparing bexatrone and metformin, doesn’t metformin have a better profile for tolerability/safety? 100% thyroid problems and hypertriglycerides doesn’t sound great.

  • Strange why some of the top scientist would spend all that time and money, testing a repurposed cancer drug that already had so many side effects making it unusable for vast majority! Are they taking the biscuit?

  • Could you provide some more information on safety / tolerability? Why is safe enough to be already approved as a treatment for cancer but not safe enough to continue trials as a treatment for MS?

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