Multiple Sclerosis Discovery -- Episode 3 with Drs. Daren Austin and Susan Van Meter

[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.   [transition music]   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.   [transition music]   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.   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]