Multiple Sclerosis Discovery -- Episode 15 with Professor Ludwig Kappos

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum - Ein Podcast von Multiple Sclerosis Discovery Forum

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Fifteen 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 Ludwig Kappos about a recent head-to-head clinical trial of the experimental drug, daclizumab, versus interferon. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   We recently released a news synthesis by science writer, Carol Morton, that goes along with this podcast. The article is all about daclizumab, its history, and the recent results of the phase 3 clinical trial. The results of the clinical trial show that the drug is better than interferon at reducing disease activity in patients with relapsing-remitting multiple sclerosis. Surprisingly, recent research suggests that daclizumab works by natural killer cells to target autologous T cells. It may also work in two more unusual ways—go to our website to read the whole story.   Antibodies to myelin oligodendrocyte glycoprotein—also known as MOG—may play a role in a subset of patients with neuromyelitis optica spectrum disorders according to several labs in Europe and Asia. At the ACTRIMS-ECTRIMS meeting in September, several of these labs presented data that showed patients who test positive for the MOG antibody had a very different clinical phenotype from the majority of NMOSD patients who have an antibody to a different protein, called aquaporin-4. The findings could mean that anti-MOG-positive patients represent a distinct disease subgroup.   Recently we’ve added quite a few items to our meetings and events page. From webinars to large annual meetings, there’s an event for everyone’s schedule in the remaining months of 2014 and well into the summer of 2015. Go to msdiscovery.org and click on the “professional resources” tab. From there, click on “meetings and events” to view all the items. And if you have a meeting you’d like us to list, please send the information to editor at msdiscovery.org. Hardly any meeting is too small. We’re even willing to list local departmental seminars.   [transition music]   Now to the interview. Professor Ludwig Kappos is the chair of neurology at the Neuroscience Network at the University of Basel in Switzerland. He met with me at the 2014 international ACTRIMS-ECTRIMS meeting in Boston to discuss the findings of the phase 3 DECIDE trial of daclizumab versus interferon. Daclizumab is a monoclonal antibody against the alpha subunit of the interleukin-2 receptor.    Interviewer – Dan Keller Welcome, Professor Kappos. Let's talk about the study you're presenting here at ACTRIMS on daclizumab. What was the aim of the study?   Interviewee – Ludwig Kappos The aim of the study was to position this compound in relation to an established treatment with interferon and to see if these positive effects that had been observed in studies where it was used as an add-on to interferon or as compared to placebo if these also stand in comparison with interferon.    MSDF How did you go about it: methods, interventions, patient population?   Dr. Kappos It was double-dummy controlled, parallel group study lasting a minimum of two years per patient in a population of active relapsing-remitting multiple sclerosis. And patients were randomized equally either to daclizumab once per month subcutaneous or to interferon beta-1a once a week intramuscularly and received dummy injections in order to keep the blind.    MSDF How did you decide on a once monthly dose for the daclizumab?   Dr. Kappos That was the result of previous studies where it had been shown that this once monthly dose is sufficient to achieve the effects that we expected to see.    MSDF Because it's a monoclonal it has a long pharmacokinetic profile. Is that right?   Dr. Kappos This is something that is shared also with other monoclonals. The advantage here is that you can apply it subcutaneously; they don't intravenous infusions like, for example, with natalizumab.   MSDF What did you find?   Dr. Kappos The primary outcome was reduction in relapse rate, and as compared to interferon beta-1a, it do add to a reduction that was close to 50%.    MSDF What about a proportion of patients experiencing relapse?   Dr. Kappos Again, there was a significant reduction, and the curves separated already after the first half year. So the effect was relatively early.    MSDF And what about some of the imaging? What did you find on MRI and how about patient disability?   Dr. Kappos Yeah again, as compared to interferon, it had a much more pronounced reduction of inflammatory activity, as depicted by T2 lesions or gadolinium-enhancing lesions in the scans during the study. And it also had an affect on T1 hypointense lesions that were reduced as compared to interferon. And interestingly enough, although it had a more pronounced antiinflammatory activity also in early and over the whole duration of the study, positive affect on brain volume loss.    MSDF It appears that in both groups about 30% of the people discontinued. Were there any differences in reasons or couldn't you discern that?   Dr. Kappos Overall there was a similar incidence of adverse events, but there were somewhat more serious adverse events and adverse events as a reason for discontinuation. This was mainly related to cutaneous side effects; so rashes itching that in some cases needed discontinuation, in others could be treated sufficiently with ongoing medication or resume medication with steroids.   MSDF This was not just local infusion reactions but more generalized skin reaction?   Dr. Kappos They were independent of the injection site; so they did not occur at the site of injection but in other parts of the body.   MSDF Is there an explanation in terms of IL-2 for that, or was it just sort of idiopathic?   Dr. Kappos Of course, you would expect that this regulation of the immune system has this effect perhaps in the interaction of innate and adaptive immune system, but it's not yet clear what it means. The fact is that we didn't see other autoimmune diseases of relevance, only of increased incidence, and therefore it must be something unique to the skin. And fortunately, it's usually quite well manageable.    MSDF Is there a role for biomarkers? Can you discern anything here where it would indicate that you should use one drug versus another? Does daclizumab have anything unique about it that you can follow?    Dr. Kappos In the previous studies, we had had the observation that a certain subpopulation of immune cells – the so called CD56bright natural killer cells – are increased after initiation of treatment in those patients who seem to respond better to the drug. In this study, this response was seen in nearly all patients, and therefore it doesn't seem to differentiate good responders from perhaps not optimal responders. We have not finished the evaluation, and there were a series of biomarkers that had been evaluated during this trial. So I hope that we still will be able to find something.   MSDF In the oncology arena, sometimes adverse effects actually correlate with good efficacy. Did you see anything like that here?   Dr. Kappos No, there was no increased efficacy in those with cutaneous reactions, and otherwise the drug did not create problems. So you would not expect on a regular basis to experience adverse events. It's a different case than, for example, as compared to interferons where you have a very high frequency of flu-like symptoms. This is not the case here. So usually you would not realize, except for the injection that happens, that you take the drug.    MSDF Would there be any use to having a combination arm in a trial like this – interferon plus daclizumab?   Dr. Kappos The first studies had been as an add-on to interferon and have shown an effect as compared to interferon without this add-on, without daclizumab. At the moment, yes, it would be something that could be followed, but I don't really see what the ideal combination would be and then not really the necessity for this drug in contrast to other drugs that have similar or lower grades of efficacy.   MSDF I know it wasn't included in this trial, but can you compare the efficacy of daclizumab with anything currently available that people use?   Dr. Kappos I think it's very difficult to tell because it's always a problem to compare across studies because of different methodology; even the selection criteria formally are very similar may result in different populations of patients. So I would say from the grade of efficacy that was achieved it is certainly at least at the level of fingolimod or dimethyl fumarate. How it relates to natalizumab; if it could be used in patients who stopped natalizumab? These are questions that will have to be explored in the future.   MSDF Will you follow these patients further to see if there are any late effects either positive or negative?   Dr. Kappos Yes, most of them are in the extension studies and had the option to continue with open-label daclizumab. I think it's approximately 80% or more of the patients who decided to continue in this followup, and we will have a long-term followup for another four or five years.   MSDF From all of what you've said, what you make of this in terms of clinical significance, in terms of the future of this compound?   Dr. Kappos Well I think that it deserves to be approved and also to be one of the available options that we will have in the treatment of relapsing multiple sclerosis. If it has also an effect on progressive disease is something that my personally would be interested to know more about.   MSDF  Is there anything important to add that we haven't discussed?   Dr. Kappos The data now are consistent with a good data that were derived from the placebo controlled SELECT trial. And we have to take into account that they are against one established drug with approved efficacy. So it's more than that, and that's, of course, encouraging.    MSDF I suppose anything that gets you away from the side effects of interferon are a good thing.   Dr. Kappos Yes, anyway, of course, most other drugs that get you away from the side effects of interferons. But it seems, except for these cutaneous, manageable side effects, it seems also to be well tolerated. So a drug that could be used with a low threshold.    MSDF Is there tachyphylaxis? Does that side effect go away, or you just have to keep treating it the cutaneous?   Dr. Kappos It was different. It seems to be the case that if we had treated initially with steroids and then do not wait too long then it recovers, and then you can also resume treatment, or you can continue treatment. But there are the cases where we didn't continue treatment and then it result, but we didn't start again.   MSDF Very good. I appreciate it, thank you.   Dr. Kappos Thank you.   [transition music]   MSDF Thank you for listening to Episode Fifteen 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]          

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