Multiple Sclerosis Discovery -- Episode 40 with Dr. Raj Kapoor

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Raj Kapoor who discusses a clinical trial of the epilepsy drug, phenytoin, for MS. But first, a few updates on the latest developments at MSDF.   We posted an essay by Dr. Katie Lidster of the National Centre for the Replacement, Refinement, & Reduction of Animals in Research, a U.K.-based scientific organization. In her essay, she points out that Dr. Kapoor’s phenytoin study was made possible by the prior development of a refined mouse model of MS that is more humane than experimental autoimmune encephalomyelitis, which results in paralysis. To find Dr. Lidster’s article, go to msdiscovery.org and click first on News and Future Directions and then on Essays and Opinions.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of April, we added 9 new trials, we updated information on 28 trials, and we've added 42 other pieces of information.  The drugs with important additions and changes are alemtuzumab; BAF312; BIIB033, which is also called anti-LINGO-1; daclizumab; dalfampridine; dimethyl fumarate; fingolimod; glatiramer acetate; interferon beta-1a; interferon beta-1b; laquinimod; mitoxantrone; natalizumab; phenytoin; rituximab; RPC1063; and teriflunomide. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   According to our curated list of the latest scientific articles related to MS, 42 such articles were published last week. We selected two of them as Editors’ Picks. One is a review of the role of microRNA in MS. The other is an analysis of the cost of MS drugs in the U.S. This study reports several startling facts. For example, first-generation MS drugs, which cost $8000 to $11,000 annually when they were first released, now cost $60,000 a year. And disease-modifying therapies cost two to three times more in the in the US than in comparable countries. This study ties in nicely with our interview with Dr. Kapoor. Phenytoin has been off patent for many years and is dirt cheap. Good news for MS patients? Maybe not. Paradoxically, phenytoin’s low cost may mean that it will never be fully developed for use in MS. To see our curated list of recently published papers, go to msdiscovery.org and click on Papers.   [transition music]   Now to the interview. Dr. Raj Kapoor is a neurologist at the National Hospital for Neurology and Neurosurgery in London, England.   Interviewer – Robert Finn Hello, this is Bob Finn. I'm at the American Academy of Neurology meeting Washington, D.C., and I'm talking with Dr. Ray Kapoor, who's presenting a very interesting study on a trial of phenytoin – also called Dilantin – in optic neuritis. Dr. Kapoor, welcome. So my first question is why phenytoin and why optic neuritis?   Interviewee – Raj Kapoor So phenytoin we use because it works as a sodium channel blocker, and this is based on years of experience and validation in animal models over the years about how neuroprotection could be achieved in MS. And it turns out that sodium channels are quite important for neurodegeneration in the setting of inflammation. And work in London that we've done, work in Yale has validated animal models that say that if you block sodium channels you can achieve neuroprotection. So why phenytoin? Well that comes down to why optic neuritis? We wanted to test sodium channel blockade in a relapse. And optic neuritis has a lot of advantages because you can study the visual system in so many ways. So why phenytoin? Because we think there's a window of opportunity, and a relapse degeneration occurs pretty rapidly. You need to treat quickly to switch off the mechanisms of neurodegeneration. And phenytoin has the advantage that we can load it very quickly and achieve therapeutic levels. So we have here a model of neuroinflammation and neurodegeneration, which we can study using multiple techniques. And we have a drug that we can load and inhibit those mechanisms quickly.   MSDF I find it fascinating that optic neuritis, which is one of the many symptoms of multiple sclerosis, can be used as a model for multiple sclerosis itself.   Dr. Kapoor The important thing there is it's part of the model. And the key is that we have – in MS – two processes going on. We have inflammation flaring up and leading to relapses like optic neuritis; and then, there is perhaps an allied or even a second process going on, which is the slow grumbling degeneration that leads to progression of disability. Now, we've studied both, but what we're focusing on in this study is that acute process that leads to relapses, you know, attacks which occur from time to time. I mean they're quite important in themselves because they don't always recover. We know that with every attack – even if there's apparent recovery – there is underlying damage to the nervous system. So to protect the nerves in any case is self-serving; it's a good idea. But what we are hoping is that this may even be a key to preventing progression, and that would really be a worthwhile target.   MSDF So you say you chose phenytoin because of its effects as a sodium blocker. What's the connection between sodium and neurodegeneration?   Dr. Kapoor What we found many years ago was that in areas of inflammation there can be nerve damage. And the inflammation drives nerve damage through a number of pathways, but one of them is that it actually indirect leads to sodium accumulation inside the nerve fiber, the axons. This has been well worked out in ischemia, as well. So sodium enters axons; it can't leave through the normal sodium pump because they're metabolically inhibited by the inflammation itself. And the sodium exchanges with calcium. So there's a sodium/calcium exchange in the membrane of nerve cells, and if you load them with sodium then sodium has to get out and gets out by driving the influx of calcium, and that's dangerous; that kills axons. So the whole process can be inhibited by inhibiting sodium entry. Now there's another thing that's very important, which is in acute inflammation one of the things that drives it is microglia, activated microglia release chemicals such as nitric oxide, which in themselves drive the whole inflammatory damaging cascade. But it turns out – and this is work from Yale – that actually the microglia themselves have sodium channels, and that their functioning can be inhibited by inhibiting those same channel. So what phenytoin is doing is it's actually inhibiting not only the cascade that damages the axons but is actually inhibiting the cells which are driving the inflammation and causing the damage in the first place.   MSDF Now, is there any indication that phenytoin may be working in this way more centrally than the optic nerve?   Dr. Kapoor It's very unlikely because the mechanism that we've testes is really something well characterized as inflammation within the optic nerve. And we are measuring the damage and the effects of treatment by actually imaging the retina looking at retrograde degeneration from the optic nerve lesion. So I think it's very unlikely given the timescale – you know, we're treating within a couple of weeks of onset, we're having a readout within six months – that it's doing anything other than what we're asking of it, which is a readout of what's going on in the optic nerve and retina.   MSDF If I understand you correctly, even if this is working exactly the way you want it to be, it's not going to be doing anything for people with central damage. Is that correct?   Dr. Kapoor Well I think the thing to understand here is it may do in MS where damage is happening everywhere. This is really a proof of concept. We've tried our very best to isolate the damaging process and to work out whether the theory works. So yes, there may be more general implications, and we think there probably are. But it's important to note that really what we're doing here is choosing a very clearly defined model to test the hypothesis.   MSDF Now one of the advantages of phenytoin is that it's generic; it's dirt cheap. But is that a liability, as well?   Dr. Kapoor Yeah, this is a very important point. So we're talking here about this whole issue of repurposing drugs. And we think that there may be many different drugs on the shelf which may have a role in treating diseases like MS. Now for us that was an advantage. This is an investigator led study, and it was funded by charitable means from the National MS Society and UK MS Society. So that's an advantage because the drug is really cheap. But of course, in terms of development, the commercial reality is that there's very little money in this. And so to take this further, it makes it harder not to have a drug that makes money.   MSDF So what's the solution to that problem?   Dr. Kapoor We don't know. I mean there are lots of ways that we're taking this forward. I mean you may know that there is a thing called the Progressive MS Alliance, which is an international body of MS societies, which is trying to work its way through questions exactly like this establishing industry relations. And it may be that they're a scope for industry to step in. And governments step in sometimes. I mean in the U.K. we have a trial running at the moment which is using funds from government to do a moderately sized Phase 2/Phase 3 trial of neuroprotection. So I think, actually, this all depends on the results. If the results are good, then we hope that either through industry or through government or, indeed, through charitable means there may be a way through. Just to get back to your question, I think that, you know, repurposing is a problem because clearly the commercial angle is far less prominent.   MSDF Is one possible solution to find a drug that's still under patent?   Dr. Kapoor Indeed, that would be a remarkable thing to do. But of course, a trial in the beginning would then need commercial collaboration. But certainly that's an angle.   MSDF So assuming that your research is confirmed and extended and phenytoin proves to be truly neuroprotective, when in the course of MS is it likely to be useful?   Dr. Kapoor So by definition, phenytoin is going to be useful for relapses. The idea that relapses sometimes leave damage and that a drug like phenytoin or phenytoin itself prevents some of that damage speaks for itself. The real question, though, comes down to whether progressive MS is also driven by similar mechanisms. We did a trial of lamotrigine, which is another sodium channel blocking anticonvulsant, and published the results about five years ago now. And that trial was reportedly negative for its primary outcome, which was brain atrophy; could we reduce the rate of loss of brain volume. I suppose what we've done is to go back to that trial and look at positive signals there because after all the question is do sodium channel blockers prevent progressive MS or prevent progression? And in fact, it turns out that there was some remarkable positive signals in that trial. So I have the knowledge that phenytoin should be useful for relapsing MS. But I also have a hunch that it may be useful for progressive MS, as well.   MSDF Now there's a flipside to the fact that phenytoin is so easily available, and that is that physicians listening to this podcast or to other news reports may consider prescribing it off-label. How would you counsel somebody considering that?   Dr. Kapoor I think it's difficult for somebody to use phenytoin in that way because the way the trial was designed was to treat people in a very narrow window after the onset of a relapse. Now people may say well, you know, the next time I see a patient who has a relapse, you know, can't walk or the vision is affected I will immediately prescribe phenytoin. The difficulty I have there is that this remains a very attractive study but hasn't proved the point. And phenytoin is not without its side effects. You know, I'm always somebody who's evidence led, and so I would counsel against using drugs without even further evidence. This is one Phase 2 study after all. I think the temptation will be there nevertheless.   MSDF And if a physician falls to that temptation, what should he or she look for?   Dr. Kapoor Well again, this is the point. We have shown a concept works. You know, we have shown that phenytoin, by a number of measures, prevents nerve damage. I think the difficulty – and I need to be very clear about this – is that with acute optic neuritis where vision generally recovers we didn't see better recovery with phenytoin. So again, perhaps another answer is that if I treat somebody with a relapse with phenytoin I'm not really sure that I may be protecting nerves, but am I producing a better outcome? So that may be another reason to say let's wait for a better drug or a better trial.   MSDF That's a very good point. So is there anything I haven't asked that I should have asked, or anything you'd like to add?   Dr. Kapoor No, I think that really the way I want to convey the result is that it's a robust result. I mean what I'll be presenting is that on a number of measures the drug worked. I think it worked with a modest amount of success. I see this is opening a door. I don't see this as the final answer to a problem. You know, if you think about it, we've been looking for a long time for a neuroprotective drug in MS and a strategy. And I think this is opening a door, which I think needs to be opened a lot wider.   MSDF Dr. Kapoor, thank you very much.   Dr. Kapoor Thank you.    [transition music]   MSDF Thank you for listening to Episode Forty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected].   [outro music]