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. Voxel-level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, 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 (which require voxel level analyses) and markedly reduce sample sizes
A trial of a possible remyelinating treatment in multiple sclerosis
Nerves in the brain and spinal cord are normally surrounded by a protective layer of a
substance called myelin (similar to the plastic insulation of an electric cable). In multiple
sclerosis (MS), the immune system attacks the myelin, leaving nerve fibres (similar to
the metal wire in the cable) unprotected. This causes nerves to malfunction, resulting in
multiple sclerosis symptoms. Over time, unprotected nerve fibres die, leading to the
progressive phase of MS. To avoid this happening, we are trying to promote
remyelination – the process by which myelin is regenerated.
Metformin and clemastine, two drugs that are already licenced for diabetes and hay
fever respectively, have recently been found to work together to promote remyelination
in animals. We believe that this combination may also promote remyelination in people
with multiple sclerosis, which could potentially reverse or alleviate symptoms. The
purpose of this research is therefore to assess whether metformin and clemastine
really can promote remyelination in people.
Participants in the trial take several capsules twice daily for 6 months. There is a 50%
chance (much like flipping a coin) that these will contain metformin and clemastine. The
other half of participants will receive “dummy drugs” called placebos. Neither the
participant, nor the trial doctor, knows which treatment they are taking. Remyelination
is assessed by an eye test and an MRI scan at the beginning of this six-month period
and again at the end.
Finally, our trial of metformin and clemastine is ready to start… or it will be when the placebo is manufactured early next year!
Check this website for further details near the time.
Published in Lancet Neurology today, is our complete description of the bexarotene trial. It is a mixture of good and bad news!
Sadly, we concluded that the drug has too many side-effects to take further as a treatment for people with MS. And the trial did not hit the “primary endpoint” that was pre-specified as a measure of “success”. However, there is clear evidence that bexarotene has a small effect to promote remyelination. The next step is to see if chemists can create a better drug. Bexarotene works on all the subtypes of the retiond X receptor, but the remyelinating action probably comes from the gamma subtype, whereas the alpha and beta subtype are responsible for the side effects.
You can read more here.
Trial shows myelin repair in humans is possible
Critical to stopping MS
New research presented at the MSVirtual2020 conference has shown that bexarotene, a drug developed to treat cancer, is able to repair myelin in people with relapsing MS. This is a breakthrough that scientists say is critical to their goal of stopping MS.
Professor Alasdair Coles from the University of Cambridge, who led the research, said: “The lessons we’ve learned are incredibly exciting, as we now have further concrete evidence that remyelination in humans is possible. This discovery gives us confidence that we will stop MS, and will swiftly be taken forward into further studies trialling other potential new myelin repair treatments.”
Important lessons learned
In the trial, vision tests and some types of MRI scans showed that bexarotene could repair myelin.
Participants in the trial did experience some serious side effects, including an underactive thyroid gland and high levels of fats in the blood. This means bexarotene won’t be taken forward into a Phase 3 study.
But the lessons we’ve learned from this trial will now be taken forward into new clinical trials.
Co-investigator Professor Siddharthan Chandran from the University of Edinburgh added: “We now understand much more about myelin repair and are in a significantly better position to measure remyelination in clinical trials. While this work was taking place, further lab research identified new and more tolerable treatments that could repair myelin, and we look forward to these being tested in trials imminently.”
A new trial for myelin repair
Promising results from laboratory studies in October 2019 showed the common diabetes drug metformin could repair myelin in rats. We’re proud to announce we’re funding a new Phase 2 clinical trial to test metformin in combination with clemastine (an antihistamine). 50 people with relapsing MS will take part.
It’s hoped that together these treatments will be safe and effective at repairing myelin in people living with MS, and could provide a way to prevent disability progression in the condition.
This new clinical trial will be led by Professor Alasdair Coles. It will build on our current understanding of myelin repair, which has been furthered by the bexarotene clinical trial and the work of Professor Robin Franklin and his team at the MS Society Cambridge Centre for Myelin Repair. In studies in mice, they discovered that metformin was able to mimic the effects of fasting and return cells to a “more youthful state”, and encourage the re-growth of myelin.
Professor Robin Franklin said: “Metformin is one of the most exciting developments in myelin repair we have ever seen. Our findings last year shed light on why cells lose their ability to regenerate myelin, and how this process might be reversed. We’re very proud to have done this work and thrilled to see our discovery taken forward so quickly.”
A major milestone in our plan to stop MS
By 2025 we plan to be in the final stages of testing a range of treatments for everyone with MS.
Dr Emma Gray, our Assistant Director of Research, said: “Finding treatments to stop MS progression is our number one priority, and to do that we need ways to protect nerves from damage and repair lost myelin. This new research is a major milestone in our plan to stop MS and we’re incredibly excited about the potential it’s shown for future studies. We look forward to what comes next.”
We have just [August 2020] recieved these emails from two students who did work experience with us last year:
“I hope life is treating you well in the midst of this pandemic, and that work is not too stressful. It’s been a while since we last spoke and I’ve been eager to see how you are doing and to let you know how life is going for me! I’ve recently attained a spot on a medicine course at XXXX, and upon reflection realised that this would not have been possible without the generosity of you and your colleagues by offering me an amazing week of work experience in 2019! I truly can’t express my gratitude and the memories that I made along with YYY are some that I’ll cherish forever. Thank you so much for the amazing work you do, and for inspiring me to take a leap in medical world.”
“Just to let you know that I have got the grades I needed to study medicine in XXXX! Term starts for me on the 7th of September. After a very stressful few days, I got my results emailed out to me this morning, which were somehow 4 A*s. I’m still in shock but its slowly beginning to sink in! Thank you so much for all your help and guidance. The work experience was such an amazing opportunity and was such a great week. Having that more in depth view of medicine was so helpful at the interviews because it gave me so much more to talk about. Also, I still have no idea what area of medicine I want to go into but I’ve got a while to decide yet! Hope you are keeping safe and keep in touch”
Advice on the use of disease modifying therapies during the COVID pandemic has been issued by the Association of British Neurologists here.
The EMA has made the sensible decision to lift its previous temporaray restriction and allow alemtuzumab to be used first-line in the treatment of MS. But, because of the new sawety concerns noted last year, the eligibility criteria are more stringent. So:
Alemtuzumab should now only be used as a single disease-modifying therapy in adults with relapsing‑remitting multiple sclerosis with:
- highly active disease despite a full and adequate course of treatment with at least one disease-modifying therapy or
- rapidly evolving severe disease defined by 2 or more disabling relapses in one year, and with 1 or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared to a recent MRI.
And its use is contraindicated in:
- evere active infections until complete resolution
- uncontrolled hypertension
- history of angina pectoris, myocardial infarction, stroke or dissection of the cervicocephalic arteries
- coagulopathy, on antiplatelet or on anti-coagulant therapy
- concomitant autoimmune diseases other than multiple sclerosis
Read the full advice here.
The EMA and MHRA are worried about the safety of alemtuzumab and today [12th April 2019] announced a temorary restriciton on alemtuzumab prescribing. They have not revealed new side effects. Rather I supsect the steady drip-drip of serious, and often very rare, side effects has broken their confidence in the liberal licence that alemtuzumab currently enjoys. They cite these concerns:
- immune-mediated conditions, including autoimmune hepatitis (with damage to the liver) and haemophagocytic lymphohistiocytosis (overactivation of the immune system which may affect different parts of the body);
- problems with the heart and blood vessels occurring within 1–3 days of receiving the medicine, including bleeding in the lungs, heart attack, stroke, cervicocephalic arterial dissection (tears in the lining of the arteries in the head and neck);
- severe neutropenia (low levels of neutrophils, a type of white blood cell that fights infections).
They are conducting a detailed review and, have suggested that:
“ during this review, [alemtuzumab] treatment in new patients should only be initiated in adult patients with highly active relapsing remitting multiple sclerosis (RRMS), despite a full and adequate course of treatment with at least two other disease modifying treatments (DMTs), or in adult patients with highly active RRMS where all other DMTs are contraindicated or otherwise unsuitable. Patients being treated with Lemtrada who are benefitting from it may continue treatment in consultation with their prescriber.”
Personally, I think it is appropriate to raise these concerns. Alemtuzumab can cause serious side effects. Patients and neurologists need to take these seriously and weigh them against the severity of disease. But I think that it is excessive to ask patients to fail two disease modifying drugs before being able to access the benefits of the drug. We will see what the final opinion is!