Multiple Sclerosis Discovery -- Episode 12 with Professor Gavin Giovannoni

[intro music]   Host – Dan Keller Hello, and welcome to Episode Twelve 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 Professor Gavin Giovannoni about the potential for finding a cure for MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Monocytes and microglia are hard to tell apart and as a result, their roles are poorly understood in MS. But we recently covered a paper that demonstrated separate roles for these macrophages in EAE. Using fluorescent tags, the researchers were able to determine that monocytes were directly attacking the myelin. Meanwhile, microglia arrived to the same area of myelin attack only to be shut down. The paper has major implications for future methods in studying MS as well as for the mechanisms of the disease itself.   We published another data visualization recently, titled the “MS Galaxy.” The visualization shows 250 authors of phase 3 clinical trials in MS, and how they are connected to each other. You can explore the galaxy by visiting msdiscovery.org and visiting the data visualizations section under the “research resources” tab.   Additionally, we published a different sort of visualization. This one is an animated video that synthesizes the current understanding of MS immunopathogenesis. Often in presentations, immunologists will toss up a confusing slide covered in shapes, arrows, and acronyms. ACTRIMS’ president, Dr. Suhayl Dhib-Jalbut, has taken that slide and broken it down into its component parts. It’s a wonderfully illuminating experience to listen to him go through the slide step-by-step. MSDF worked in collaboration with Dr. Dhib-Jalbut to make the video. You can view it in the data visualizations section of our website.   [transition music]   Now to the interview. Professor Gavin Giovannoni from Queen Mary University in London is one of the world’s most prolific and most visible MS researchers and clinicians. He is also on the scientific advisory board of MSDF. I met with him at the university to discuss the potential of a cure for MS. This is part one of the interview. Next week’s podcast will feature part two, in which Professor G, as he’s known, discusses the role of Epstein-Barr virus in MS.   Interviewer – Dan Keller Professor Giovannoni, let’s talk about the possibility of cure of MS. I suppose the first question would be what would you define as a cure?   Interviewee – Gavin Giovannoni Because MS is considered to be an autoimmune disease, we should really be able to destroy the autoimmunity by replacing the immune system, or rebooting the immune system, that’s the concept. And there are certain drugs that do that. Obviously, the most aggressive would be bone marrow transplantation, this autologous bone marrow transplantation. And the other one is a recent drug we’ve been using, alemtuzumab, which is a drug that targets leukocytes and depletes them and allows the immune system to repopulate, and when repopulated comes back clearly in a different way. And hopefully those two strategies will remove the autoimmunity. And those two strategies are very effective.   A significant proportion of the people who are treated with bone marrow transplantation or alemtuzumab go into long-term remission; I’m talking about remission 10, 12, 15 years in some of these patients. And if you follow these people up, there’s no evidence of inflammatory activity, so they don’t have relapses. And you monitor their MRI scans, you don’t see any new lesions; the lesions that are there are stable, scarred lesions. And also if you monitor the end-organ brain atrophy rates are not accelerated, their brains are shrinking in the same range as in normal aging. You know, looking at it at a superficial level, we can’t find any evidence of active MS.   Now the question is are those people just in long-term remission or are they cured? And so the definition of a cure then is how long would you follow these people up and say, alright, your MS has gone away. We’ve been debating this in the field for a while. And we think a reasonable definition would be 15 years after they’ve had the treatment, and that would give us sufficient time to study a population and compare them to what we would expect to happen in a natural history study or other treatments. And it’s looking like a significant number of these people are staying in long, long-term remission. So I’m hoping that a portion of them will be cured of the disease.   MSDF Now these are autologous bone marrow transplants?   Dr. Giovannoni Yes.   MSDF So what would prevent them from re-reacting to whatever caused their problem in the first place? I can see allogeneic transplant, you would have a sort of non-susceptible population of cells.   Dr. Giovannoni Yes. I mean, we don’t really know the pathogenesis of autoimmunity in the sense where’s it driven from. I mean, there’s lots of epidemiological evidence in the MS field it probably starts in utero, actually. There’s evidence for parental origin, and migration studies, and monthly birth defect, etc., to suggest that something’s happening in utero. And there’s probably something happening in early life that imprints the autoimmune phenotype or the susceptibility to get autoimmunity. And then, obviously, there’s some trigger that occurs that happens later in life. And I would imagine that that rebooted immune system that we say the autoimmunity is gone would probably still be susceptible because you’re repopulating from a susceptible background, but maybe that trigger won’t come again.   I mean, one of the things people have got to realize is we’re not trying to say this is a cure in everybody who gets this treatment, it’ll only be a proportion of people, and those are the people who don’t reactivate. I mean, we need to learn a lesson is what’s triggering their reactivations if they’ve been in long-term remission. Is it an environmental agent, infection, or something like that? So I wish one knew where the autoimmunity is being triggered from, we don’t know.   MSDF What sort of experiments are going on now? Is this just registries, or do you have multiple strategies? It seems like you have to do very, very long-term follow-up.   Dr. Giovannoni Alemtuzumab was developed in Cambridge and they’ve been using the drug now since 1992, and they’ve got an open-label extension study that they’ve been following up, and they’ve just published a 12-year follow-up data about a month ago in the JNNP. And of that open-label study, about just over 50% of the population are stable. Then there’s obviously the clinical trial programs, and there have been relatively large phase 2 and two phase 3, and those have all gone into open-label extension and those people will be followed up indefinitely, and we’ll probably get data from that.   The bone marrow transplant, it’s a little bit more complicated because most of the development has been done by academic units, so there are registers. And there is a larger phase 3-type study happening in the US at the moment. The registers follow these patients up long-term, so we’ll see what happens. But the cohorts that have been treated early with the disease are doing extremely well. The majority of them, provided they get through the bone marrow transplant, their disease goes into remission and their brain atrophy rates after year 1 are within the normal range, no relapses at MRI, no new MRI activity. So it’s looking very promising.   The problem with bone marrow transplants, it’s quite a risky procedure. For some people it’s a risky procedure, for others it’s not, which is one of the things we find out. If you go to the community and you ask people with MS, when you say to them your chances of dying from the procedure – because in very good bone marrow transplant units now, the mortality rates are between 0.5 and 1% – a lot of people with MS will take those risks. I mean, it’s up to them, they’ve got the disease. The difficulty we have is which patients do you offer those aggressive therapies to.   MSDF Does the feasibility of bone marrow transplantation go down with age?   Dr. Giovannoni I mean, if you train in MS is that all these therapies really work early in the disease. I think the reason for that is the longer you’ve got MS, the more damage is left behind, and that primes that nervous system to degenerate. So when they’ve used bone marrow transplantation in secondary progressive disease and people have really got quite a lot of disability, the induction part of the chemotherapy – the chemotherapy itself is neurotoxic, so they tolerate the induction therapy very poorly. And although the bone marrow transplant switches off the inflammatory component of the MS, that damaged central nervous system is still there and they continue to progress. We think they may progress at a slower rate, we don’t know that, so it doesn’t really stop the secondary progressive phase of the disease when it’s been used in that, which is why most people who do bone marrow transplant now are shifting towards early MS when there’s much more to protect.   And the other issue is there’s a big theory evolving in the MS field that a part of the progressive phase of the illness is premature aging. I’m not talking about premature aging across the whole body, but premature aging within the central nervous system. We know now that any inflammatory or chronic inflammation triggers aging pathways, and that may just drive some part of the progressive component to the disease. And if that’s the case, then we’re not going to be able to modify with anti-inflammatory therapies the strategies that target aging.   MSDF Is this total bone marrow ablation as you would do in any other transplant for curative purposes in oncology, or is it something less than that?   Dr. Giovannoni Well, it depends who you speak to. I went into detail with this in terms of wanting to set up a bone marrow transplant program here about 15 years ago, and I opted out because the risks then were too high. So some people say you really need myeloablative therapy and some people say you don’t need as much as myeloablative; less, you know, these partially ablative ones. So there’s two schools of thought; some want to go for the aggressive and some go for the less aggressive. The Canadian group have used really aggressive induction therapy with myeloablative therapy, and they had, unfortunately, one death and some serious toxicity. So there again is a tradeoff between which one you go for, and I think the results will show over time.   To be honest with you, now that we’ve got alemtuzumab which is a licensed therapy, it’s going to be hard to justify using bone marrow transplant when we’ve got a less toxic monoclonal antibody available. It’s also got safety issues, but I think those safety issues are manageable with monitoring. So I think it’s going to be very hard in the current climate to justify bone marrow transplantation when you have alemtuzumab as a licensed drug.   MSDF Is chemotherapy in itself a reasonable treatment?   Dr. Giovannoni They’ve been tried in the past. I mean, the mistakes we made would say cyclophosphamide, which is an alkylating agent, is that when the trials were done we did them in an era when we didn’t know how to do MS trials. So they were done prior to MRI monitoring, they tended to be doing advanced MS, and the trials were underpowered. I think if we had to do cyclophosphamide in the modern era, we would have done the trials differently, and I’m almost certain they would be effective. We have mitoxantrone which is a chemotherapy agent; that’s got a license in quite a few countries. It’s unfortunately a topoisomerase inhibitor and it’s associated with translocations and causes leukemia. And that’s pretty common actually. The registries that have been tracking are reporting the incidence of mitoxantrone-related leukemia at about 1:150 to 1:200, and I think that itself takes that drug out of practice, to be honest with you. And it also is dose-related treatment; you can only give it for a certain number of infusions because it causes a cardiomyopathy, and it’s also linked to premature ovarian failure. There’s a lot of the issues about using that drug in clinical practice, and most centers now have stopped using mitoxantrone.   MSDF Does this lead into the idea of aborting MS so you don’t get into a progressive phase, all these strategies?   Dr. Giovannoni Yes. We all talk about secondary progressive disease. I’ve stopped using the term secondary progressive disease in isolation. I say clinically progressive disease because the progressive phase of this illness is present from the very beginning of this disease. So when people present with their very first clinical attack, a significant number then will already have had brain atrophy and cognitive impairment. And if you monitor people at every stage of the disease, there’s this progressive brain atrophy occurring. So we think the pathological substrate for progression is there from the outset.   What makes somebody transition into the progressive stage clinically is when the brain reserve runs out. So what stops the progressive phase manifesting is the fact that we’ve got reserve capacity and we compensate. And once that’s run out, people enter the clinically progressive phase of the disease. So I talk about progression being there from the outset; at some point in time you’ll present with secondary progressive MS, and I think it’s system-related.   This is one of the other concepts I’m trying to get across is that progressive disease is not just progressive disease. I mean, most people present initially with the motor system and the lower limbs or their bladder involvement, and then it gradually spreads to their arms, their cerebellar systems, etc. I call it asynchronous progressive disease, and I do this because I really want to give people with progressive MS hope that if you’ve got progression in one pathway, we may be able to treat you and prevent it from becoming clinically progressive in the other pathways.   So this is where we need to rethink our trials, because all of our outcome measures in clinical trials are based purely on lower limb function and mobility. If we wait for people to become progressive in that system, then use that system as a readout, we might miss an important therapy. So what we probably should do is say, well that system’s in the progressive phase, let’s focus on preventing the other systems from entering the progressive phase, those systems that have got reserve capacity. If we change our thinking like that, we’ve got a much greater chance of getting a drug licensed for progressive disease than we have at the moment.   MSDF Because you can choose various endpoints to look at and show that it’s having some effect somewhere?   Dr. Giovannoni Yes. The idea would be to stop or prevent people entering the progressive phase in the other systems. Once somebody’s in the clinically progressive phase in a particular neuronal system, it means that they’ve lost reserve capacity. And that reserve capacity is what predicts recovery. So somebody who is really progressing along that pathway is extremely vulnerable and probably prime to continue to progress. That’s going to be very difficult to show an effect in that pathway. And that’s what we’re doing right now. We’re saying let’s take people with progressive MS that are having walking difficulties, let’s put them in a trial and try and slow down that walking problem. And I think that’s the wrong strategy. I think we should be changing our way we do trials.   MSDF My impression has been that when someone enters the secondary progressive phase, there seems to be an acceleration. But from what you say about loss of reserve leading to progression, it sounds like it’s just the same slope but without the remissions.   Dr. Giovannoni Yes. We think the mechanisms are different though. There is some evidence what I call a therapeutic lag. This is complicated. Let me explain what a therapeutic lag is. When you’re in the progressive phase of the disease, we think the progression that’s occurring this year or next year has been primed by inflammation that’s occurred over the two years. So there’s a lag between the inflammatory component which damages those nerve fibers, and then they dive over the next few years. It probably damages them and they’re probably surviving and functioning but compromised, and that process then runs its course.   So I think what we really need to do is if we do clinical trials and switch off inflammation now, you’re not going to see an effect of an anti-inflammatory drug in the next two years, we have to look in year three, four, and five. And there is data now from extension studies supporting this. So I actually think we also need to change our trial design in progressive MS if you’re going to look at a progressing pathway; not to look in two years, we’ll be looking at year three, four, and five.   The current crop of trials are kind of doing that. What they’ve done is instead of having a fixed time point of two years, most of them are event-driven, so when they have enough events they will stop the trial. And the event-driven trials looks like they’re taking the follow-up into year three and sometimes year four. So we may get enough power to see if that works in the current crop of trials in progressive MS. But I really do think that we need to go to probably five years in progressive MS trials to get a readout that we can trust, based on our understanding of the progression of the disease.   MSDF So can you enumerate or summarize what you think trials should look like? What one would choose as endpoints, definitions, anything else that would be different from how they’re doing it today?   Dr. Giovannoni Yes. So if we’re going to continue to use the gold standard, which is EDSS, this expanded disability status goal which has a lot of psychometric problems – it’s got a flawed seeding effect, it’s not linear, it’s got a high inter-rater. . – with all those problems, we’ve still got this damn gold standard, EDSS. If we’re going to use the EDSS and we’re going to focus on mobility, then we’re going to have to do 5-year trials. And know that there’s a therapeutic lag, forget about expecting to see a result in year two and look at year three, four, and five. In addition to that, I think we need to actually then develop new outcome measures that assesses the systems that aren’t affected, like upper limb function, cognition, cerebellar, eye movements, etc., and look for differences in those systems on active treatment versus placebo. We’ve changed the question. In other words, we’re trying to prevent those systems from being damaged relative to the system that is damaged. And I think then we may get an answer. And I’m almost certain anti-inflammatory strategies that I’ve been told not to work in progressive MS will work.   MSDF If you look long enough.   Dr. Giovannoni If we look long enough or we change the way we define the outcomes. Because I do think that those other systems that aren’t progressing clinically will be more responsive in a shorter period of time; they’ve still got reserve capacity. And that reserve capacity really predicts recovery. We’ve seen this now in early MS is if somebody has got a low disability score and you treat them with a powerful anti-inflammatory, be it natalizumab or alemtuzumab, a significant number – 30 to 40% - actually improve in function. And that’s because they’ve got reserve capacity; they have the ability to recover function. I think if you can choose pathways that have got reserve capacity and you treat with anti-inflammatories, those pathways may have an ability to recover or improve, and you’ll see the difference between the treatments much earlier. It’s just an observation that needs to be taken into clinical trials.   MSDF Locking the barn door while the horse is still in.   Dr. Giovannoni Yes. This is like any other disease. There’s no point in treating a disease after you’ve missed the boat. If you speak to rheumatologists or nephrologists, it’s much better to protect the kidney and the joints before they’re damaged. The same concept needs to come into the MS field. You need to target the organ before it’s damaged, because prevention is much better than trying to promote recovery.   MSDF Very good. We appreciate it. Thank you.   [transition music]   MSDF Thank you for listening to Episode Twelve 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]