Q: Hi Nick, thanks for talking with us. Could you tell us a bit about remyelination?
Absolutely. Perhaps the best starting point is to say that MS is primarily a disorder where the protective myelin lining of nerve cells becomes damaged. We know that as demyelination, as you mentioned.
Regeneration or repair of myelin is possible and we all have stem cells in our brains and spinal cords that are able to migrate to areas of damage and start this process. Unfortunately, this repair fails in the majority of people living with MS. Remyelination or remyelination treatment is important because it's a therapy that might be able to enhance the repair process and allow recovery of some function.
Q: If there was a drug that could remyelinate, what would we expect it to do for people with MS?
The rationale for remyelination therapies are two-fold and this relates back to the two main functions of myelin as well as the cells that make it, known as oligodendrocytes.
The first function of the myelin lining is that it allows information to be sent along nerve fibres in a reliable fashion. The second, and often underappreciated, role of myelin is to insulate and protect the underlying nerve fibre itself.
It's the demyelinated area of the nerve that leads to its vulnerability and eventually, degeneration. So remyelination therapy, we believe, will have two key effects. The first is that it will allow nerves that have been damaged by MS to recover function, hopefully reducing MS symptoms. The second is that by remyelinating nerve fibres, they will be protected from degenerating, therefore reducing progressive disability in MS.
Q: So if somebody already had progressive MS, would remyelination therapies help them as well?
We believe so but there is a caveat to the question of how these therapies will affect progressive MS. In order for remyelination to occur, you need to have an intact nerve cell because the oligodendrocyte cell has to recognise it and appropriately put the myelin around that cell.
In progressive MS, some nerve fibres have already degenerated and that is what gives rise to the progressive disability. While I think remyelination certainly will be effective in people with progressive MS, we do not know just how effective it will be yet.
Q: Another word that we sometimes hear is neuroprotection. What's the difference between remyelination and neuroprotection?
Neuroprotection is just an umbrella term for a treatment that protects nerve cells from degenerating. There are several possible ways of achieving neuroprotection or protecting the nerves, one of these is remyelination.
Q: Recently we've heard some news about the Bexarotene trial which has been going on in Cambridge. Could you give us a summary of the outcome of that trial?
Yes, so the Bexarotene trial, otherwise known as the Cambridge Centre for Myelin Repair trial number one (CCMR1) gave us some really exciting results.
The trial actually goes back to over a decade ago when one of the laboratories in Cambridge noted that if you target a particular part of the cell, the RXR-gamma, it can enhance remyelination in animals. While there is no drug that targets that precise area, there is one called Bexarotene that is a treatment for a rare type of skin cancer that targets the RXR-gamma along with a few other areas. We tested this in the CCMR1 trial to determine whether the remyelination that was seen in animals also occurs in people with MS.
Fifty two people with MS were involved in the trial, with half receiving Bexarotene and half receiving a placebo. By using MRI scans to look at the structure of the nerve fibres and visual evoked potentials (a test which measures how long it takes the brain to respond to messages sent by the eyes), we were able to see that Bexarotene did lead to remyelination. The results did depend on how damaged the nerves were and also where the damage was within the brain. The remyelination appeared to be greatest in the grey matter regions compared to the white matter regions of the brain.
The disappointing side of the trial was that the drug itself caused several side effects. It caused everyone that received the drug to develop underactive thyroids. Although they did recover after stopping the drug, people experienced fatigue and reduced energy levels as a result. It also led to elevated levels of fats in the blood, the triglycerides, and while these are recognised side effects of Bexarotene, they occurred slightly more frequently in our trial compared to the people who had received the drug for cancer.
Our conclusion was that this was a really important trial of remyelination but we first need to develop a drug capable of doing that without the side effects that we came across.
Q: That's still an exciting outcome. What other trials are happening in this field?
There have been a few other trials. The Bexarotene trial (CCMR1) has been the first to show positive evidence of remyelination from both the brain scans and the visual evoked potentials (VEPs).
Out of the other trials, I think perhaps the most noteworthy was the rebuild study which used an antihistamine known as Clemastine and showed a small beneficial effect on the VEPs.
There are several other trials being undertaken at the moment including another using Clemastine which is being tested on people who have had recent episodes of optic neuritis.
There have also been trials using a drug known as Opicinumab as well as one in America and Canada using nano crystalline gold which is a very interesting way of promoting remyelination.
Q: So clearly a happening field which is very exciting! Another trial that we've heard about is focused on another repurposed drug called Metformin, can you tell us about that?
CCMR2 as it will be called, focuses on Metformin, an anti-diabetes drug which can promote remyelination in animals in a similar way to Bexarotene. Where Metformin varies is that it tells the stem cells in our brains to be in a position to respond to the signals telling them to start the repair process.
We think this drug will be best given as a combination treatment alongside Clemastine. While Clemastine acts as a signal to tell the stem cell to commence repair, the Metformin allows that stem cell to be in a position to respond to the Clemastine so it's almost a synergistic effect of the two.
I think what's exciting is that Metformin is an anti-diabetes drug that's widely prescribed so we know it's safe. Generally speaking, it will also be very tolerable for people living with MS that happen to have diabetes too.
The plan for the trial is similar to the last study that we've done. It will involve 50 participants with relapsing remitting MS but all must be on a disease modifying treatment. The reason for this is that we want to make sure the inflammation of MS is controlled so we can study the repair process happening on account of the Metformin and Clemastine in isolation. Again, we're going to be using both the brain scans and eye tests to see if the drugs are having a beneficial effect compared to those on placebo.
Q: If trials like this are successful for relapsing remitting MS, do you think that there will be trials for people with progressive MS as well?
Yes, absolutely. Treatments for progressive MS are the greatest unmet need that we have in the MS community at the moment.
In relapsing MS, more nerve fibres will be in a position to be remyelinated so we should be able to measure a biological effect in a clinical trial with a smaller number of participants. That isn’t to say that the drugs are not going to work in progressive MS, it just means that it would be harder to demonstrate in a clinical trial with a small number of participants. That's because, in order to show that this drug works, we're using combinations of MRI scans and VEPs rather than seeing if it's improving disability, for example.
It all comes back to what the objective of the clinical trial is. Most of these trials are seeking to demonstrate whether the drugs have a biological effect in humans. If the answer is yes, they need to be tested in large clinical trials which will undoubtedly include people with progressive MS. For this comparatively small trial, we think it's best to do that in a small number of people with relapsing MS first.
Q: If these trials are successful, how long do you think it will be until we see drugs that promote remyelination on the market?
The question of how long is hard to answer. However, the benefit of ‘repurposed’ drugs, which covers things like Metformin, the diabetes drug and Clemastine, the antihistamine, is that they're already licensed so we know they're safe for people. If they're shown to be effective in clinical trials then there aren't perhaps as many barriers to their being introduced to the MS community as with a completely new drug that's not been tested before in people.
Unfortunately, the trials that I've mentioned do take some time. For example, I don't anticipate that the CCMR2 trial will have results for a couple of years and the Covid-19 pandemic has delayed things significantly for us too. However, we do hope to be starting this in the first quarter of 2021.
As mentioned, there are also some unanswered questions as we don't know exactly who's going to benefit most from these drugs. We hope everyone, but don't know that. We don't know when they should be given, whether it be continuously, at impulses or just after relapse. We don't yet have all the answers, but the positive news is that there are people working on them.
Despite these challenges, it's now looking increasingly likely that a remyelination treatment for MS is a matter of when, rather than if. It really is an exciting time for the MS community, I feel.