Claire: What research is being done to reduce neurodegeneration for MSers? And maybe you can elaborate on what research is being done on neurodegeneration for the MS community.
Dr Anna Williams, Neurologist: Yes. So I think there’s sort of two ways of looking at ways to reduce neurodegeneration. And one is just, is to say, well the nerves are degenerating, let’s make them better. So actually something for the nerves themselves. And the other one is to say well, if we put the myelin back on, then that will make the nerves better. So we’ve got the sort of the remyelination arm and then the actual direct on the nerves arm. And we’ve talked about the remyelination arm a little bit. We can try and keep the nerves from dying, and really that’s quite similar to all of the research and things like stroke and Alzheimer’s disease, Parkinson’s disease, because all of those are neurodegenerative diseases and people are trying to keep the nerves alive. Motor neurone disease is the other one.
So there is a trial actually going on between Edinburgh and London at the moment called the SMART trial and what it did was it looked at all the literature on mouse and rat, and it said okay, if we give mice and rats these drugs, do their nerves not degenerate so fast. And it took the top few of those and then what they’ve done is taken three of those. So there’s one drug that’s currently used for motor neurone disease, there’s one drug that’s currently used for high blood pressure and one drug currently used for depression. And in mice or rats it helps nerves survive, and so they’re trying those against a placebo, clearly. So we’ve got – it’s called SMART because you’re trialling three drugs at the same time against a placebo, so that’s going to be smart and quicker. And the idea is that these are people who are secondary progressive, have secondary progressive MS and they’ll be doing measures like MRI scans and how far people can walk and looking at eyes, and you can now measure the nerves in the eyes, and to see whether they are not getting worse so quickly as you would expect, as we said before. So that’s a trial looking directly at whether they can keep the nerves alive, so ignoring the myelin.
And the myelin side of things, there’s actually currently a trial which we’re not involved in in Edinburgh, but it’s a Biogen trial with an infusion of something called anti-LINGO-1, and that’s the first year. It’s just the name of the molecule. But it’s the first treatment that aims specifically to improve remyelination, so it’s quite an exciting trial for that one. And the idea is it’s trying to make these oligodendrocytes make the myelin quicker. So it’s trying to get them maturer so that they can make myelin. And so that’s started. And I think it’s interesting to look at the time zones of this, because it’s called anti-LINGO because LINGO is a molecule that was discovered to stop oligodendrocytes making myelin. That was discovered ten years ago. It’s taken a while, so ten years they discovered it and then they had to try and find something that inhibited it, because that isn’t good because that inhibits maturation, so you need to inhibit that. And then they need to make sure that it’s safe. And then they went for the phase 1 trials, which are the safety in humans, and now this is the phase 2 trials to actually say well, does it work, with all the caveats that, how do you measure it. But they’re doing exactly what we talked about, looking at people, looking at scans and looking at eyes.
Claire: So how long for both of those things that you talked about to actually get to market and be of use to people like myself?
Dr Anna Williams: Yes. Well, I think that’s why I was sort of giving you the timeline because it’s, from discovery of the molecule to the phase 2 clinical trials, the one that says does it work, is ten years. Now, the trial will be two years, then they’ll need to, if it works, do a bigger trial, because this is fairly small still. So we’re probably talking of another five years before it would get into common use, if it works. Now, that doesn’t mean that the next molecule will take 15 years, because I think what will happen, you sort of have to start somewhere and then you make mistakes about, you know, is this the best way to measure it, is this the best way to do it, and what will happen is, the next one that comes along, it will be a bit quicker because it will be able to use some of the information that they found on the first trial to use on the second one and on the third. So I don’t think it’ll be as long, but it’s still long, because you still have to check that it’s safe. If you’re going to put someone on this for 30 years, you do want to make sure that it’s something that’s not going to cause you more problems than you solve. So I think it’s not unreasonable to say ten years between target discovery, a molecule discovery and actually in the clinic. Now that’s different from… so the SMART trial, those three drugs are actually already used, so we know that they are safe, or at least we know what’s wrong with them, we know the safety issues of them. And so if that works, that will go into clinical use much quicker. And so there’s a lot of enthusiasm for using drugs that we already have, but in a different way.
Claire: When you say much quicker, sort of a year or, you know?
Dr Anna Williams: No, because the trial, the problem with progression is it’s slow and so you have to measure it over a fairly long period of time to see if there’s differences. So the SMART trial is a two-year trial, so it would be two years plus a little bit of time to analyse results and get it into clinical use if it works. And I think that would be under five years, probably a bit less, if it works and if it works enough. But again, these are cheaper drugs as well, so high blood pressure pills, they’re already there, they’ll be off patent and therefore they’ll be cheaper and therefore licensing probably will take less time because the cost benefit analysis would be different. So I think – it’s called repurposing – it’s just using drugs for a different purpose, drug companies and doctors are quite enthusiastic with these. But, what we don’t know is if any of our drugs that we’ve already got actually improve remyelination. They might. There have been a few studies out recently that have shown – in mice – that some of the drugs that we use for things like Parkinson’s disease and even some of the antifungals seem to improve the way that oligodendrocytes work. So that might be a way of shortening the time, is to try those, because they’re drugs we know, and see whether that helps. But we’ve still got the measuring problem. That’s not going to go away. Hopefully someone will solve it quickly and find a better way of measuring remyelination.
Claire: And are those timelines sort of pretty fixed, or if there was unlimited money available, could that be sped up?
Dr Anna Williams: I don’t think unlimited money will solve everything, because safety trials, you have to do them for a certain length of time. You know, you can’t just do them for a week if you’re going to put somebody on it for 20 years. You’ve got to do it for at least a reasonable length of time in a different animal. And so there is… you know, if we had unlimited money we couldn’t get a drug into use tomorrow, there’s still going to be a limit, a time that we’ll have to have to make sure that things are safe. Although I sort of understand people’s enthusiasm to get new drugs out fast, that’s really important, but also you’ve got to get new drugs out safely. There have been a variety of drugs over the years that have come out and then had to be withdrawn again because we’ve discovered that they’re actually unsafe, and so one has to be a bit careful. Have to temper enthusiasm with common sense. And so somewhere in the middle would be good. Yeah, so it might shorten it a bit, unlimited money, but not completely down to tomorrow, there’ll still be a limit, a time where you’d have to just check things are safe, I think. And also, you know, the trials have to go for a couple of years. It’s different from the relapsing ones, because if people are having ten relapses in a year, then you could do a six-month trial and say, well it’s halved them, that’s fine. But with progression, things go slowly and so usually it’s two years as a minimum as a trial, otherwise you can’t see differences. And what we don’t want to do is dismiss drugs that don’t… say, oh well, it doesn’t work, when actually it might if you just give it long enough. Enthusiasm with common sense, I think.
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Dr Anna Williams is Professor of Regenerative Neurology at the Centre for Regenerative Medicine. She has published multiple works focused on MS and its treatment. Her recently research has focused on T Cells effects in myelin and brain lesions. She gained her PhD at the university of Edinburgh.