[intro music]
Host – Dan Keller
Hello, and welcome to Episode Five 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 Dr. Anne Cross, who reflects on the past year in MS research. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.
Researchers have discovered that multiple sclerosis may have something in common with colon cancer; the Wnt pathway. It’s a genetic pathway important in development, stem cell maintenance, and cell differentiation. In colon cancer, the mutation of a mediator gene called APC causes the Wnt pathway to become overactive, leading to tumor formation. Now, researchers have discovered that a loss of function mutation of APC in the brain also leads to an overactive Wnt pathway, ultimately freezing oligodendrocyte progenitor cells in their undifferentiated state.
Next, what disease-modifying therapies should women start or stop before pregnancy? In our latest news synthesis, we discuss the difficulties many women with MS have in deciding when to stop DMT before trying to conceive. Since it can take months, and even years, for a woman to conceive, it’s important that she spend the least amount of time off medication as possible to reduce the chance of relapse. Some drugs may be worth taking during pregnancy anyway, but it’s up to the neurologist to do a risk-benefit analysis for each patient. Nevertheless, many women opt to go off of DMT altogether to reduce the risk of adverse effects on the fetus.
Finally, we would like to direct your attention to funding opportunities on the MSDF webpage. Under the Professional Resources tab at msdiscovery.org, you can find a listing of various organizations offering funding for research grants, fellowship grants, and more. Currently, there are several opportunities offered from ECTRIMS with deadlines this winter. There are also several deadlines for funding from the National MS Society coming up in August.
Now for the interview.
Interviewer – Bob Finn
This is Bob Finn. I’m here with Dr. Anne Cross of the Washington University in St. Louis. Dr. Cross will later today be giving a talk at the American Academy of Neurology meeting on what the year has been like in MS research. And, so, let me ask you briefly, what has the year been like? Has it been a good year, a bad year, an exciting year, a boring year?
Interviewee – Anne Cross
I think it’s been a pretty good year. There have been some mainly good things, a couple of bad things, some rather interesting and unexpected things, too. I guess some of the good things involve genetics research papers that have come out identifying genes that are associated with risk of developing MS. That’s been kind of exciting. Actually, there were 48 new genes that were identified and published this year by the International MS Genetics Consortium, which is a very large group of international researchers that have amassed probably close to 30,000 genetic samples from MS patients over the years that they’ve been in existence, which is about 10 years, plus close to double that of controls. And all these MS patient samples are from patients who were well characterized and submitted by, generally, MS specialists.
And that group did a study using something called the Immunochip, which is a genotyping array that was actually developed by a group of investigators who work on autoimmune disorders, so that array is very much weighted towards beings with immunologic function. So not too unexpectedly, all 48 of the newest identified genes all relate in some way to the immune system or are very closely linked to genes of immune function. But prior to that, the same group – the International MS Genetics Consortium – had identified about 50, a little over 50 genes that are associated with MS risk, and most of them were also related to genes of immune function. So I think together, all of this data certainly implicates the immune system, which we already knew, but I think things are certainly solidifying around that with the newest data.
MSDF
Let me ask you, if they’re using techniques that are specific for immunological genes, are they missing other genes?
Dr. Cross
They very well could be. The original studies that this group did which were published, the biggest study was published in the summer of 2011, did not do it in that fashion, though, they just did a genome-wide association study, and most of the genes that they identified were related to the immune system directly or indirectly. So, yes, I’m sure that some are being missed that aren’t related to the genes that are on this Immunochip microarray, but they’re trying to hone down a bit.
And some of the other things that were discovered were that, well, they identified 5 allelic variants; the particular allelic variant was over 50% of the time associated with risk of MS. And they also identified in this latest search – well, the strongest association was with a gene that has immune function called Vcl-10 – they actually in this latest search rediscovered the same 50 or so that they had discovered before, so they were actually mostly in this Immunochip microarray.
MSDF
So, aside from the genome-wide association studies, what else has been interesting in MS research this year?
Dr. Cross
Well, I think some of the clinical trials that have been published in the past year, and also that are just ongoing and aren’t published yet, have been interesting. This past week, Dr. Rhonda Voskuhl, who’s from UCLA, spoke and presented for the first time ever recent data from a study of estriol, which is a pregnancy hormone that was added to glatiramer acetate in women with relapsing-remitting MS, and that was compared to placebo pills added to glatiramer acetate. And the results were pretty positive, especially in the first year when there was an almost 50% reduction in relapse rate in the group that received estriol plus glatiramer. And, you know, that’s, of course, based upon longstanding data that we’ve known, that women with MS who have relapsing disease have a much decreased relapse rate during pregnancy. And then Dr. Voskuhl had done a good bit of work with estriol, in particular, which is a fairly safe pregnancy estrogen hormone compared to some of the others, but it’s not available in the United States right now.
MSDF
You mentioned that there were some disappoints.
Dr. Cross
At least for me, and probably for a lot of MS patients, the biggest disappointment was the failure of the FDA to approve a drug called alemtuzumab, which is a humanized monoclonal antibody against an antigen that’s on pretty much all the mononuclear cells of the immune system. And the US FDA failed to approve it, although, I believe, 32 countries and counting have approved it at this point, including Canada and Mexico and all of the countries of Western Europe, Australia, Brazil.
MSDF
Have there been any interesting developments on the remyelination front?
Dr. Cross
Yes, yes, yes. In fact, I hope to speak about that today. There are studies in early-phase trials right now of anti-LINGO-1, which is a humanized monoclonal antibody against a molecule called LINGO-1, which is found only in the central nervous system – at least that’s what the data says so far – and it’s expressed by oligodendroglial cells, or the cells that make central nervous system myelin. And, for whatever reason, it’s involved in inhibiting remyelination in the central nervous system. So the monoclonal antibody that inhibits it then enhances remyelination. And in mouse models it looked very good, and it also led to less injury to axons, or nerve fibers, so it had more than just a remyelinating effect. And it’s now in phase II studies in relapsing-remitting MS and optic neuritis patients. At least the relapsing-remitting MS study is fully enrolled, and so we’ll be looking forward to those results.
So another potential remyelinating agent is a little bit behind anti-LINGO-1. It’s called recombinant human IgM22, and it was developed from a natural IgM antibody that was discovered at Mayo Clinic that binds to a surface antigen on oligodendrocytes – the cells that make central nervous system myelin – and it enhances myelination in mouse models of demyelination, and, in fact, in some studies, just a single dose of that led to longstanding remyelination in the mouse model. So that’s in dose-finding studies in human beings at the present time, and hopefully will move forward from there.
Other exciting things, at least to me, are studies of stem cells that can be differentiated into different types of cells. And, at this point, you can actually take human skin cells or human fibroblasts and revert them back to stem cells; they’re called induced pluripotent stem cells. So you can actually take a person’s skin and do that, and then you can differentiate it forward into whatever cell type you want, really, these days; I mean, you can differentiate them into neurons. And in MS, we’re very interested in differentiating them into oligodendrocyte precursor cells – cells that form the cells that make central nervous system myelin.
And a study that I plan to talk about this afternoon took such cells and made them into human oligodendrocyte precursor cells and put them into the central nervous systems of mice who had a genetic mutation in myelin basic proteins, so they are essentially unmyelinated. And these mice die very soon after being born, much earlier than normal, and they put these human cells in. They had to immunosuppress the mice so that they’d accept the human cells. But these cells actually made myelin, and it was functional myelin at least from the standpoint of wrapping around fairly normal-looking nerve fibers, axons, from the mice, and forming compact, normal-appearing myelin. So that particular group, they’re from New York State and they’re affiliated with several other medical centers, and they plan to get this into humans pretty soon. Their first project, however, is going to involve fetal stem cells first, because that was easier to get approved and moved forward on, and so I believe they’re already funded to do a three-center – all in New York State – stem cell study injecting such cells into the central nervous system of people with secondary progressive MS.
MSDF
Now some patients aren’t waiting for the studies, I understand, but what is your point-of-view about that?
Dr. Cross
It depends on where they’re going and what they’re doing. I personally think there’s some shoddy research, some charlatans you might call them, out there who are taking the money and presenting false hopes to patients that I certainly disagree with. And I have one particular patient I know who went to another country and had stem cell therapy done in what she described as a very dirty environment. And luckily nothing bad happened to her from this experience, but nothing good happened either. I’m hoping that she’ll be able to get into some of these well-done, scientifically valid, protocol-driven studies that seem to have some promise.
MSDF
Any other interesting areas of MS research in the past year?
Dr. Cross
I think the unexpected finding that I plan to talk about is an association of salt – sodium in particular, the sodium component of sodium chloride – in the development of a particular type of pathogenic T-cell that at least is related to the mouse model of MS called experimental autoimmune encephalomyelitis. These are Th17 cells and they’ve been shown to, at least in some models, cause the EAE model for MS. And it was found that if you increase the salt intake of mice that had been induced to develop this model and compared them to mice who weren’t getting extra salt in their diet, that the mice who got extra salt got disease earlier; they had a more severe course, they didn’t recover as well, and they had histologically when you looked at their central nervous systems, more cells infiltrating and just more damaging. So that was kind of interesting and quite unexpected, I would say.
Two different groups of investigators sort of came up with that at the same time; I’m sure they were speaking to each other about it, that the studies came out right together. It certainly would be a modifiable environmental thing if it proves to be true, and perhaps even a little bit simple. And there is actually a scientific reason behind why this might occur. Well, there’s a response in the body by something called p38 MAP kinase in response to, like, many different stresses, but including among them osmotic stress which increased salt could cause. And that pathway that p38 MAP kinase is involved in eventually can lead to the induction of a particular kinase that is key to the development of Th17 cells. So it sort of all, you know, fits together.
There are certainly some things that don’t fit with that. I think that certain areas of the world, for example, have very high salt intake and yet have low MS rates, but it may be that there’s this environmental factor. There probably are many different environmental factors that’s going together with a genetic predisposition, and those together are probably leading, perhaps, to MS. In any event, this will have to be proven by other groups, but if the association is true, it would certainly be modifiable.
MSDF
So looking ahead into the next year of MS research, what are you particularly looking forward to seeing?
Dr. Cross
I’d like to see more data come out on some of the other oral agents; there are a couple that are in the pipeline that are being looked at that perhaps have other mechanisms of actions from what we have now. I’d like to see other studies funded for estriol so that perhaps it could come to the United States and be an adjunctive therapy probably for women with MS and probably pretty safe. I’m really hopeful – I’m not sure if it’ll be in the next year – that we’ll see some good data coming out from these scientifically valid stem cells projects to help people with progressive MS, and help people who have longstanding disability to recover some function; those are the people that really, really need help in the MS world right now.
MSDF
Well, Dr. Cross, thank you very much.
Dr. Cross
Thank you.
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Thank you for listening to Episode Five 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 nonprofit 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 editor@msdiscovery.org.
[outro music]
[intro music]
Host – Dan Keller
Hello, and welcome to Episode Four 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 Dr. Michael Racke about the potassium channel Kir4.1 and its potential role in MS. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.
Researchers at the University of California San Francisco have developed a new remyelination assay that allows high through-put drug screening. The assay takes advantage of oligodendrocyte’s tendency to wrap myelin around anything axon-shaped, such as plastic fibers and microscopic glass pillars. The assay has already identified several FDA-approved drugs as candidates for remyelination therapies, including an over-the-counter antihistamine now in phase II clinical trials.
In another article, we report on a new study that sheds light on the ameliorating effect of ultraviolet rays on inflammation and disease progression in mouse models of MS. In the study, MS patients sat in a therapeutic UV chamber for five sessions a week for six weeks. Even after one session, the patients had an increase in dendritic cells and regulatory T-cells. In follow-up studies with EAE mice, the researchers uncovered a possible mechanism by which these regulatory T-cells migrate to the central nervous system.
In addition to covering the latest in MS research, the MS Discovery Forum also curates news stories from around the web in our twice-weekly Research Roundup. Last week we wrote about the findings in phase III trials of daclizumab, a legal dispute between drug companies Acorda and Actavis, and a new collection of immunology papers from the journal PLOS. We also posted some social media advice as well as the amusing hashtag #yomanuscipt. Our favorite tweet: Yomanuscript is so bad the null hypothesis rejected it. Check out Research Roundup under the news brief section in the News and Future Directions tab on our website.
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Now to the interview. Dr. Michael Racke is the Chair of the Department of Neurology at the medical school at Ohio State University. He’s here to discuss the latest findings of the potassium channel known as Kir4.1 and its implications for MS. MS Discovery’s Executive Editor, Bob Finn, spoke with Dr. Racke.
Dr. Racke, welcome.
Thanks.
So what is Kir4.1?
Dr. Racke
So Kir4.1 is a what’s called a potassium inward rectifying channel that’s expressed on the end-feed of astrocytes and also on oligodendrocytes. And so it’s important for trying to adjust the right concentration of potassium in and outside of a cell.
MSDF
And what is its relationship to MS?
Dr. Racke
Well, there’s been a lot of interest recently. There was a paper published in the New England Journal now almost a year and a half ago, I believe, from Bernhard Hemmer’s group that showed that about 50% of MS patients have antibodies directed against this potassium channel, Kir4.1.
MSDF
And is that a lot more than people without MS?
Dr. Racke
Right. So when they looked at healthy individuals or looked at patients with not just neuroimmunologic diseases but also other non-inflammatory diseases, the number of antibodies directed against it was very low, on the order of magnitude of like 3%.
MSDF
So what does this mean for our research in MS?
Dr. Racke
You know, for a long time people have been interested in what are the potential targets, and this would represent a little bit different target than the typical myelin proteins that one has thought of as being targets in MS. It’s also kind of interesting because of another molecule, aquaporin 4, that is expressed in the same place in the astrocytic endfeet that’s been the antibody target for neuromyelitis optica. And so I think as we begin to see responses against some of these other molecules, it’s interesting to see whether they result in in demyelination and whether that can be a new avenue for therapeutic intervention.
MSDF
Just within the last week, another study came to a quite different conclusions regarding the prevalence of Kir4.1 autoantibodies in MS. How do you resolve the discrepancy?
Dr. Racke
There was data presented yesterday to suggest that one of the differences may actually be differences in glycosylation of Kir4.1. It turns out that eukaryotes—and humans are eukaryotes obviously—glycosylate proteins, and that very often glycosylated protein looks very different to the immune system than an unglycosylated protein. And since a lot of these studies take an unusual cell type and then try to over-express to your 4.1 on its surface and then see whether an antibody recognizes it, it may not be the same type of glycosylation that’s actually seen within patients with MS.
MSDF
There’s a lot of research going on now on Kir4.1. What more needs to be done in this area before Kir4.1 becomes a therapeutic target?
Dr. Racke
Right. Well, so, for example, if you look at neuromyelitis optica, that if you did plasmic change in those patients, then very often those patients are benefited. So it’s as though if I take away those antibodies the patient does be better, so those antibodies are pathogenic. When that’s been done in MS, the data, it’s sort of been, I don’t want to say controversial, but in some sense it is. And then there have been studies, for example, done from the Mayo Clinic that looked in at certain types of demyelinating events where it seemed like plasma exchange did work, then there were larger studies that were done and it didn’t seem to work. And if, in fact, it’s, say, a pa a patient population where really only one-third to half of the patients have the pathogenic antibody, then if I do that study and say I’m going to do it to everybody, it may not have enough power to suggest that there’s efficacy for everybody. But I think it gets back also to this idea of what a lot of people talk about in personalized medicine, right, and the idea may be that you would be able to identify patients that perhaps had an antibody to Kir4.1, and then perhaps they would be more amenable to therapeutic interventions that targeted antibody synthesis in the blood.
MSDF
Do you think that interventions targeted at Kir4.1, would that would it work much the same way as other as existing therapies in decreasing the number of relapses in re relapsing-remitting MS?
Dr. Racke
For example, if you look at things like interferon, natalizumab, the way those therapies are trying to work isn’t against the specific antigen, right. What they’re really trying to do is just interrupt the disease process. And I think the difference is going to be there have been some studies where people were trying to target the specific epitopes to either myelin basic protein – the altered peptide ligand studies were like that – and there’s studies now also where people have solubilized MHC molecule that has a myelin peptide on it. And those are specifically trying to target the immune response against a very specific antigen. Now I have to say that most of those things haven’t really worked very well, and I think part of the reason is that the human immune response is complicated enough, but by the time a person has had several attacks in MS, they probably are making an immune response against a number of myelin antigens, and so if I target just a single antigen it may not work.
And that may also end up being true in in terms of Kir4.1, that it’s just going to be another thing. But, I mean, if there’s enough similarities between it and some of the things that we’ve seen with neuromyelitis optica in aquaporin 4, like I say, there the plasma exchange and targeting the B-cell response in many instances has been quite beneficial to pa patients, right. And so I think that’s going to be an important next step to not just demonstrate that it can be part of the target that happens in multiple sclerosis, but whether inhibiting that response to that target actually has therapeutic benefit.
MSDF
You just outlined one area of research on Kir4.1 that needs to go forward. What are some others?
The other issues have to do with trying to understand exactly the cell-type specificity in terms of glycosylation, trying to understand why is it that this particular channel is a target in MS, then are other channels also targets in MS. This sort of opens up a whole other ballgame in terms of diversity of targets that could potentially participate in MS pathogenesis.
MSDF
Is there anything else you’d like to add about Kir4.1 that we haven’t already talked about?
Dr. Racke
I’ve been in this field for 20 years, and realistically this has been the first new antigen that really has come up. And that’s sort of interesting in and of its own right. I think the other thing, obviously, for those people who are interested in things like molecular mimicry, this gives you another molecule to begin to look at in terms of its sequence homology with infectious agents. I mean, the people who are interested in, you know, viruses like HHV-6 and Epstein-Barr viruses, and those that they think that have an important role potentially in MS pathogenesis, how might infections with those agents affect Kir4.1 expression. That’s going to be another area that’ll be of interest to the research community in MS.
MSDF
Well, Dr. Racke, thank you very much.
Dr. Racke
You’re welcome.
[transition music]
Thank you for listening to Episode Four 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 nonprofit 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 editor@msdiscovery.org.
[outro music]
[intro music]
Host – Dan Keller
Hello, and welcome to Episode Three 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 investigators Daren Austin and Susan Van Meter of the pharmaceutical company GlaxoSmithKline, who will discuss results from the MIRROR trial of ofatumumab, a human monoclonal antibody already FDA approved for leukemia. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.
First, a complementary approach to treating MS. A new study lends support to the prevailing theory that the immune system’s ancient complement system drives persistent axon damage between MS relapses. The complement system consists of proteins that can activate innate and adaptive immune responses, but have a poorly understood role in autoimmune diseases. The new results suggest that anticomplement therapies might help prevent damage to axons. Clinical trials are in the early planning phases, but one of the study’s authors cautions that even if this approach proves valuable, it would be used in addition to and not in place of therapies targeting inflammatory T-cells.
In a second article, we report on a study suggesting that inhibiting a common cytokine called granulocyte macrophage colony stimulating factor – GM-CSF – might be a new therapeutic target to treat MS. Studies have shown an association between the cytokine and MS flares. A newly described class of T helper cells produce GM-CSF, and inhibiting that production might be helpful in preventing flares.
Finally, we’d like to call your attention to our blog series called “MS Patient, Ph.D.” There are numerous blogs and other websites where people with MS talk with other people with MS. And there are also a few, including our own MS Discovery Forum, where MS researchers and clinicians talk with other researchers and clinicians. But we can’t think of any sites where people with MS who have a scientific bent communicate directly with researchers and clinicians. That’s what MS Patient, Ph.D. is all about. It’s a place where two articulate people struggling with MS, both of them Ph.D. biologists, present their points of view about their disease and about the state of MS research. You’ll find some of their opinions provocative and controversial, and we hope you’ll join the discussion. In our two most recent posts, Griselda Zuccarino-Catania discussed the snake oil treatments touted as MS cures and relates that to the recent testimony before the U.S. Senate Committee by Dr. Mehmet Oz. And Emily Willingham discusses conflicting evidence on whether exercise is good or bad for people with MS.
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Now, onto the interview. Here at the 2014 annual meeting of the American Academy of Neurology, we caught up with Dr. Daren Austin of GSK in London. He’s presenting the MIRROR study, which is a randomized, placebo-controlled study doing dose-ranging on ofatumumab in subjects with relapsing-remitting multiple sclerosis.
Interviewer – MSDF
What led you to implicate B-cells? We often think of T-cells as a target in multiple sclerosis.
Dr. Austin
Well, there’d been previous work using other anti-CD20 therapies in immune inflammation diseases that have shown efficacy. Most notably the first was rituximab in rheumatoid arthritis and subsequently rheumatoid looking at multiple sclerosis, so the precedence for anti-CD20 modulation as a target for inflammatory diseases was known before we came to design this study. What wasn’t known before we designed the MIRROR study was how much modulation of B-cells would generate what level of clinical benefit. The primary objective of this study really was to look at how best we could administer ofatumumab, which is an anti-CD20 monoclonal antibody, to modulate B-cells and then modulate clinical disease.
MSDF
How’d you go about it? Can you describe the study and also what you found?
Dr. Austin
Well, the study was a randomized, double-blind, parallel group study looking at relapsing-remitting multiple sclerosis patients who had to have evidence of disease activity, i.e., they they would be requiring therapy. What we did was we took what we knew about the pharmacology of ofatumumab – and we’d previously conducted both an intravenous study in in multiple sclerosis patients, so we knew the drug could be efficacious in suppressing MRI lesions, and we took what we knew about the clinical pharmacology of ofatumumab; and, namely, that it is an extremely potent depleter of B-cells. We began by by hypothesizing that there was a link between the level of B-cell suppression and the level of MRI lesion suppression. From that we produced some some predictions. And our predictions led us to suggest that extremely low doses given relatively infrequently could be beneficial. We produced a transimulation before we conducted the trial, and we proposed a range of doses and dosing frequencies. So the first dose level was was placebo, the next level was a 3 mg dose that was given once every 12 weeks. The next dose level was 30 mg given once every 12 weeks. The next dose level was 60 mg given once every 12 weeks. And, finally, because we knew that a dose of 200 mg was efficacious over 12 weeks, we gave 60 mg every 4 weeks to give a cumulative dose of 180 mg. So we explored a dose range, a cumulative dose range, of 3 mg to 180 mg, with the primary endpoint being evaluation of MRI lesions at 12 weeks. Placebo patients were then given a 3 mg active dose. All patients were then followed for a further 12 weeks, and we now have the 24-week data. And, again, treatment then ceased and patients were followed-up to see repletion of B-cells.
And what we found in the study was, yes, that ofatumumab is is extremely potent at depleting B-cells. That single 3 mg dose was capable of knocking out about 75% of circulating B-cells, and the 60 mg dose given every 4 weeks depleted almost all patients right down to the undetectable levels, which is had been seen in the past. What we were able to do then is to look at the dose response to dosing of ofatumumab at the 12-week endpoint, and what we found is that at the cumulative dose of 180 mg, we see over 90% suppression of lesions. But we found that there was no incremental benefit in going above doses of about 60 mg, and in fact the dose that generated the half maximum effect from an analysis of the data was predicted to be less than 3 mg; a single 3 mg dose generated half of the maximum benefit.
Having shown that we have got clinical suppression of MRI lesions, we then decided to relay the pharmacology of ofatumumab, which is suppression of B-cells, to the clinical benefit, which is suppression of MRI lesions. And that was the purpose of this abstract, that the analysis that we presented showed quite clearly that there was a very strong relationship between how much you suppress B-cells and how much you suppress MRI lesions. But the surprising thing from this data is that you don’t have to fully deplete all patients to below the limit of quantification to derive benefit. We showed using a variety of analyses that patients that have circulating B-cells of less than 32 to 64 cells per microliter on average over the course of the dosing interval would still derive maximal benefit, i.e., suppression of lesions, to 90%. And that’s intriguing. And the reason it’s intriguing is that the doses that we gave are only acting on peripheral B-cells. There’s been speculation as to where the drug needs to get to give clinical benefit, and that the doses that we give – up to 60 mg doses – the drug can’t penetrate the blood-brain barrier. And, therefore, we know that by modulating peripheral circulating B-cells, we are deriving the maximal benefit in suppression of MRI lesions.
MSDF
Is the drug acting on mature B-cells, or in B-cell development which may then migrate into the CNS during development?
Dr. Austin
So ofatumumab only binds to the cells that express CD20, so there is some consideration as to where those cells exist. Now it is entirely possible that immature cells maybe sort of enter the periphery not expressing CD20, move to across the blood-brain barrier where they subsequently develop. That is a possibility. And if that is the case, our drug is not capable of reaching those B-cells. Only cells that express CD20 are depleted, so plasmablasts, for example, are not depleted because they do not express CD20. It is just that that population of of of B-cells that are expressing CD20. There’s a lot of hypotheses about how B-cells are working, how they may be producing pathogenic antibodies that may be detrimental. In MS it could be anti-myelin antibodies, for example. But we don’t absolutely know that that is the sole pathogenic mechanism in MS, as in other diseases. It may well be that B-cells are modulating other, say, T-cell activity, which we do not yet know. What we do know from our trial is that modulation of peripheral B-cells gives you benefit, and that’s the principal finding, and that the doses that we modulate at are much, much lower than the oncology doses that have previously been given.
MSDF
So you don’t yet know whether you have a direct antibody effect on B-cells, or whether it’s acting possibly through antibody-dependent cellular cytotoxicity.
Dr. Austin
We do know that the mechanism of B-cell depletion is through both ADCC and complement-dependent cytotoxicity. That is the primary pharmacology of ofatumumab on cells that express CD20. We do not and cannot say for certain what those B-cells were doing prior to being depleted and how they were driving the pathogenic process, but we have shown that by depleting them to levels of less than 32 cells per microliter, you see suppression of disease activity. One of the important things to say is that the regimens at the every 12-week dosing that we’d selected, there is some evidence that B-cells do start to grow back in at least half of patients, so dosing every 12 weeks pre-dose, there are some circulating B-cells. If we look at immature B-cells, there are lots of immature B-cells but they haven’t yet moved to the to express CD20. So what we see is that the regimens we’ve designed, there is some evidence of of repletion, i.e., that patients are seeing clinical benefit despite having circulating B-cells.
MSDF
How does this fit in with the pathogenetic mechanisms of T-cells? Are there interactions in the pathologic process besides the regulatory effect of T-cells themselves?
Dr. Austin
The truth is I don’t think we can say. All we can say is that modulation of B-cells circulating in the periphery gives clinical suppression of of MRI lesions, and by implication we believe at the clinical efficacy in multiple sclerosis, and possibly other diseases, although such low doses have not have yet to be tested in other diseases.
MSDF
In terms of B-cell repletion, have you also followed new lesions after B-cells come back?
Dr. Austin
We have the 24-week data and we have preliminary data out to 48 weeks, and that data won’t be reported yet because we’re still in the process of ana analyzing it. But in the trial we designed, we had individual follow-up to watch patients B-cell replete back up to the lower limit of normal or their baseline, and we are measuring their follow on MRI lesions.
MSDF
Working along with Dr. Austin on this project is Dr. Susan Van Meter, the clinical physician involved in the project. Let me ask you, what sort of adverse effects did you see during the trial?
Dr. Van Meter
The most common adverse effect that we saw was injection site reactions, and that can include things such as redness at the injection site, nausea, flu-like symptoms. That occurred in most of the patients receiving ofatumumab. It also, very interestingly, occurred in about 15% of patients who received placebo.
MSDF
In terms of the more serious and chronic effects, did you see any opportunistic infections or especially progressive multifocal leukoencephalopathy?
Dr. Van Meter
So you would certainly worry about infections, especially serious infections. We did not see any cases of PML or other opportunistic infections, and, in fact, no serious infections. As typical for patients with MS, patients did have a variety of infections – urinary tract infections, respiratory infections – but this was seen in all patients including placebo patients, and there was really no evidence of an increased rate of infection in patients receiving ofatumumab.
MSDF
What do you see as the potential clinical significance of these findings?
Dr. Van Meter
Well, I think it offers another therapy option for patients with MS. Obviously, we have to do further development and show that the benefits that we saw on MRI translate into clinical benefit on relapse rates and disability progression. But we’re offering a subcutaneous dose as opposed to an intravenous dose of medication, and potentially offering a medication that doesn’t completely wipe out one part of your immune system.
MSDF
Is there a reason for selecting ofatumumab over rituximab?
Dr. Van Meter
Well, I think that would be a clinician choice, to be honest. Rituximab has certainly been studied for multiple sclerosis even though it’s not indicated for multiple sclerosis. There’s another B-cell therapy that will be on the market when we launch, ocrelizumab, and I think it will come down to physician and patient choice.
MSDF
Is there anything we’ve missed or that’s important to add?
Dr. Van Meter
Well, I think at Glaxo we are very excited about this data; this is new science. Obviously, we need to understand more about it, replicate it. But for the first time, we’ve shown that you don’t need to completely destroy all the B-cells to have effect in multiple sclerosis.
MSDF
Very good, I appreciate it. Thank you.
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Thank you for listening to Episode Three 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 nonprofit 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.
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