Multiple Sclerosis Discovery -- Episode 57 with Dr. Timothy Vollmer

[intro music] Host – Dan Keller Hello, and welcome to Episode Fifty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast comes to you from last week’s big MS meeting in Barcelona, Spain, with an interview with Dr. Timothy Vollmer, who gives his take on the early results of a large Phase 3 study of ocrelizumab for primary progressive MS. The experimental drug blocks circulating B cells. We will have several extra meeting-related podcasts for you in the next two weeks. In the next one, Dr. Gavin Giovannoni talks about a new push to use long term brain health as a goal in MS treatment. And Dr. Vollmer will return in the coming weeks to discuss the Denver treatment experience with another B cell blocking drug, rituximab. But first, here are some new items in the MS Discovery Forum. Every week MSDF lists the latest scientific papers related to MS with links to the abstracts on PubMed. Of nearly 100 new studies published last week, we selected three as editor’s picks. Two of our editor’s picks come from a larger collection on MS in JAMA Neurology. One study reports on an equivalence clinical trial comparing a generic glatiramer acetate, Synthon, with Copaxone, the branded glatiramer acetate, for relapsing remitting MS. A global team of investigators found equivalent efficacy, safety, and tolerability in the randomized, controlled trial. The findings provide reassurance about well-made generics for patients and neurologists, say other researchers in an editorial. But the whole idea of generics is to make a dent in the skyrocketing costs of MS drugs, and the generic is priced at $63,000 a year instead of $65,000 and $74,000 for the two versions of the branded drug. Another paper in the same JAMA Neurology checked to see what the vitamin D levels of nearly 1500 people treated with interferon beta-1B might say about the course of their disease. Higher vitamin D levels were associated with fewer new active lesions in the mostly white, mostly female patients with relapsing remitting MS, but there was no correlation with clinical disability or brain atrophy. Our third editor’s pick is a paper investigating the cancer risk from cladribine compared to other MS disease modifying treatments. A large Phase 3 study showed the experimental drug to be highly effective in relapsing remitting MS, with nearly half of patients showing no evidence of disease activity after two years and two courses of the treatment. But it was refused a license by the European Medicines Agency in 2013. Now, based on their new meta-analysis of eleven studies, the authors say they cannot confirm nor deny a cancer risk, and that cladribine should be investigated further as an MS therapy. Our drug development pipeline contains 44 investigational and approved agents for MS. Last week, we added results from two new trials, we updated information from 16 other trials, and we added 20 other pieces of information. Trial updates include findings about ocrelizumab’s ability to reduce relapses and minocycline’s capacity to reduce the risk of conversion to MS after an initial demyelinating event. [transition music] And now to our interview with Dr. Timothy Vollmer, Professor of Neurology and Medical Director of the Rocky Mountain MS Center at the University of Colorado in Denver. When we met at the European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona, Dr. Vollmer laid out how results of the ORATORIO trial of ocrelizumab shed light on two hypotheses of what goes wrong in primary progressive MS, and which one is most likely. Interviewee – Timothy Vollmer There currently are two hypotheses for what drives primary progressive disease. One is that it’s like relapsing disease, and it’s driven by inflammation. And the other one is that it’s a noninflammatory disease that’s being driven by neurodegeneration and has a separate biology. Now that we have positive results from the ORATORIO study, which is a study of ocrelizumab which is an anti-CD20 monoclonal antibody that deletes B lymphocytes from circulation, given that this is the very first time we’ve ever succeeded, it’s telling us very important thing, and that is: inflammation does drive primary progressive MS. And the other important message from here is that this study studied a significantly younger patient population with primary progressive MS than all the other studies. The mean age was around 44. The reason that’s important is because, epidemiologically, we see a decrease in inflammatory activity as a function of age, and older patients often don’t express any evidence of that. And so far, in all the primary progressive studies, especially the OLYMPUS trial, those patient populations don’t respond to anything. So it’s telling us that we can treat primary progressive MS, but you’ve got to start early. Interviewer – Dan Keller That seems to be the message overall in MS, in general, though. Dr. Vollmer Yes it is. And the reason is, is because MS results in an accelerated brain volume loss, and brain volume loss is going to translate into disability, at some point, for almost everybody. Maintaining brain volume so that you can age normally late in life is a critical goal, not just in MS, but in other neurological diseases. MSDF Does that brain volume loss or other changes in the brain relate to really the onset of the progressive phase? Dr. Vollmer The answer is yes and no. From a statistical standpoint, it’s very hard to sort of identify a specific point in the process of brain volume loss that you can say, okay, they’re going to transition into progressive disease. That’s probably due to the fact that the mechanisms that underlie reserve capacity in brains may vary a little bit from patient to patient, and that they have different capacity to compensate for this injury. The other complication is that MS, as a multifocal disease, is not necessarily distributed evenly throughout the nervous system, though. In some patients, they have a relatively small amount of disease, but it’s in the neck, and they’re still highly disabled. And because of that very complicated pattern for it, it is hard just to use one global measure to predict how patients are going to be from a disability standpoint. MSDF Do the results of the ORATORIO study give us more confidence in pursuing the B cell as an important effector in MS? Dr. Vollmer Absolutely. The converging data, now, both in progressive forms and in relapsing forms, says the B cell is playing a critical role. There are CD20-positive T cells, and so there’s still some discussion whether the drug may be having an effect on those, but in the most recent reports, it does decrease those with first administration, but then they recover very quickly. And at subsequent administrations of the anti-CD20, they’re not deleted. So that pattern suggests to me it’s not an effect on T cells, it’s an effect on B cells which remain suppressed for months after a single injection. MSDF CD20 is on B cells but, as I understand, not on plasmablasts or plasma cells. So what is the relative contribution of B cell biology versus just antibody? Dr. Vollmer A major difference is that plasmablasts and plasma cells are not very good antigen presenting cells. Whereas, B cells, if they can engage the antigen that their B cell receptor is targeted for, become extremely effective antigen presenting cells: the most effective antigen presenting cells in the body. And they can be about ten thousand times more effective that dendritic cells or macrophages. So that’s why I think that, given the fact that the most effective therapies we’ve currently studied right now are all B cell based therapies, I think it’s telling us is that the B cell is playing that critical role, and most likely, that is in both cytokine release and in antigen presentation in the brain. MSDF From the ORATORIO study, what more do you want to see? The data is just coming out, and they’re going to do a bunch of analyses. What sort of things should they be looking at? Dr. Vollmer Well, they have a number of other clinical measures, and I believe they also have some patient reported outcomes, so I’d be very interested to see if the patients actually perceive a benefit as measured by those PROs. They have the timed twenty-five foot walk out, which they reached and was statistically significant. They had sustained disability progression at both three and six months which was statistically significant. And they reported brain volume loss was decreased in the ocrelizumab treated patients and was statistically significant. We would like to know more about the inflammatory markers in the patients and the correlation between having baseline evidence of disease activity, such as a gadolinium enhancing lesion, and the probability of response to therapy. MSDF What about the time course of response to the therapy? It seems like it’s more rapid than you would expect if an insult sometime in the past led to what you see today. But the ocrelizumab results seem to be on a faster track than that. Dr. Vollmer Well, the reason I believe that is, is because, as I said before, they really pushed down the median age in their population to much younger patients. And again, in long term studies that have looked at gadolinium enhancing disease activity, we do see it in primary progressive disease. So it’s not true, in my view, that primary progressive MS patients have a different MRI pattern. In studies that actually controlled for observer bias, where the neurologist didn’t have a chance to look with an MRI scan, but made the decision whether it was progressive or not progressive disease based on clinical history, which is the only way that we really can do it, then the previously reported biases of having nonspecific noninflammatory MRIs disappears. And that paper was published about six years ago. So, I think that we have a lot of built in biases, as a field, when you think about MS, and, unfortunately, those biases are often not supported by objective data. And yet, they do make their way into the literature, mainly because they don’t control for age. And when comparing progressive patients, relapsing patients, or primary progressive patients to relapsing patients the fundamental difference is progressive patients tend to be 10 to 15 years older on average than the relapsing patients they’re comparing them to. And it’s that age difference that explains most of the differences that people talk about. It’s not the fact they have a different form of the disease. MSDF Anything else to add on this that we’ve missed? Dr. Vollmer As I said, we need to get subset analysis out of the ORATORIO study to see just which age group and demographic the patients really got the most benefit. My suspicion is we’re going to again find it’s the younger patients that show the biggest effect, again emphasizing that starting early in the disease with therapy is a key issue. And, again, I think it’s going to argue that you need to use highly effective therapies as early as possible, in order to get the best effect. MSDF Very good, thank you. Dr. Vollmer Thank you. [transition music] MSDF Thank you for listening to Episode Fifty-Seven 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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdicovery.org is part of the nonprofit Accelerated Cure Project for multiple sclerosis. Robert McBurney is our President and CEO, and Holly 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 a comments, criticisms, and suggestions to [email protected]. For Multiple Sclerosis Discovery, I’m Dan Keller. [outro music]