Multiple Sclerosis Discovery -- Episode 48 with Dr. Bruce Cree

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Forty-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features Dr. Bruce Cree on the EPIC, CLIMB, and SUMMIT clinical trials in MS. But first here are some new items in the MS Discovery Forum.   We're very happy to report that MSDF has received three generous grants that will allow us to continue our mission: to focus attention on what is known and not yet known about MS and related conditions in a way that builds bridges among different disciplines. Genzyme has given us two grants. One will allow us to continue producing this weekly podcast for another year, and the other will allow us to develop an additional 12 monthly data visualizations. And Biogen has given us a grant for general operating support. None of these grants will interfere with our editorial freedom, and you can continue to count on MSDF to be an independent source of unbiased MS news.   A conference in Cambridge, Massachusetts several weeks ago sponsored by Orion Bionetworks outlined the progress and challenges in turning computational modeling into actionable knowledge in MS and other brain disorders. Allison Provost, who is Orion’s scientific program manager, has written a blog post describing the parts of the conference of particular interest to MS researchers. You can find her post by going to msdiscovery.org and clicking first on News and Future Directions and then on Blogs.   According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected three of those papers as Editors’ Picks. Two of them are comprehensive review articles: one on biomarkers in MS and the other on MS immunogenetics. The third is an evidence-based consensus guideline on the use of MRI in MS diagnosis.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week we added 1 new trial, we updated information on 3 other trials, and we added 13 other pieces of information.  The drugs with important additions and changes are alemtuzumab, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab, and rituximab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   [transition music]   Now to the interview. Dr. Bruce Cree is a neurologist at the University of California, San Francisco. MSDF Executive Editor, Bob Finn, caught up with Dr. Cree in his office at UCSF’s Mission Bay Campus shortly after a departmental seminar entitled “An EPIC CLIMB to the SUMMIT.”    Interviewer – Bob Finn Dr. Cree, welcome.   Interviewee – Bruce Cree Thank you.   MSDF Now EPIC, CLIMB, and SUMMIT are acronyms for three MS clinical studies. So first, what's EPIC, what's CLIMB, what's SUMMIT?   Dr. Cree Great question. So the EPIC study is a long-term observational study now in its 11th year at UC San Francisco. It's a a cohort study of multiple sclerosis patients who have been followed annually for the last 11 years. And this cohort initially had about 517 participants, and now – in its 11th year – we have about 91% of those patients coming back for ongoing assessments. The assessments include annual MRI scans, as well as clinical assessments and the blood draws for biomarker studies.   The CLIMB study is a similar related study that was developed independently at the Brigham and Women’s Children's Hospital in Boston under the directorship there of Howard Weiner. And it is also a long-term followup study. And now, after about seven years, that study has some 217 patients who have been retained out of the original cohort.    SUMMIT is the idea of bringing together long-term, well-curated observational cohorts from multiple sites. And the first iteration of SUMMIT will involve investigators from Basal, Amsterdam, UCSF, and Harvard who will merge together their long-term observational cohorts into a larger study. And the hope here is that we will obtain greater statistical power and be able to answer some of the more pressing questions about MS therapeutics, outcome measures, and utility of both conventional and nonconventional MRI in assisting with the diagnosis and management of patients.   MSDF So in the EPIC study, I'm struck by the fact that you've been able to retain 91% of your patients after 11 years; whereas in the CLIMB study they've lost 90% of their patients in just 7 years. How do you account for that difference?   Dr. Cree The EPIC study has had a great amount of support for long-term followup and subject retention. And we've gone to great lengths to keep our participants interested in the study and wanting to come back. And we have a terrific group of study coordinators who work day and night to maintain contact with our patients, inform them about why it's important for them to participate in the study. And we've even done outreach where we've gone to people's homes to perform evaluations in their homes where they were too ill to come in, as happens with multiple sclerosis as people develop more advanced disability. So we have very good retention as a consequence of the hard efforts made on behalf of the overall study by the coordinators and other members of the team.    MSDF Now you've used several measures of disease progression in the EPIC study, as have others in other studies. There's the EDSS, there's the MSFC, and there are several other measures. But let's talk about the EDSS first. That's probably the most commonly used measures, and it's also the one that people seem to love to hate.    Dr. Cree Yes.   MSDF Can you tell me about the EDSS and what its advantages and disadvantages are?   Dr. Cree Yeah, so the Expanded Disability Status Scale of Kurtzke is an ingenious scale that was really intended to describe where patients are at during the course of their lifespan. And it's a 10-point scale with half-point increment changes after the score of 1. And this scale has been adopted for use as the disability outcome measure in all MS clinical trials. The scale has a fair amount of inter-rater variability, which makes it challenging to administer. Because anytime you have a scale where there's a fair amount of variability it gets harder to interpret change. We did look at the EDSS systematically and looked at change over the first few years in the study and used that as a predictor for long-term disability transitions. We also looked at harder endpoints in the EDSS such as the time it takes for patients to go from no systems, disease onset, to the time where they require a cane to ambulate.    You mentioned the MSFC, the Multiple Sclerosis Functional Composite. This is a set of scales that were developed for use in multiple sclerosis that included the Timed 25-Foot Walk, which is a measurement of how fast somebody can walk 25 feet. That is clinically relevant because the speed at which somebody walks correlates quite well with the distance they can walk. So the faster you can walk 25 feet the longer you can walk. The 9-Hole Peg Test is a test of upper arm coordination and function. And the Paced Auditory Serial Addition Test is a test of cognitive function that measures specifically the tension and processing speed.    So we looked at these things, and we set up thresholds based on other clinical work that were considered to be clinically meaningful changes. So with respect to the Timed 25-Foot Walk and 9-Hole Peg Test, we were looking for a 20% worsening in function over the course of the trial. And with respect to the Paced Auditory Serial Addition Test – or PASAT – we were looking at the reliable change index for that outcome. And so these have been validated outcomes that are related to actual disability.   So we looked at all of these measures. And what we found was that when we looked at our relapsing MS patients about half of the patients experienced worsening in terms of EDSS change over 10 years. For the patients who had progressive multiple sclerosis, about 70% of them worsened. And then for these more stringent measures with respect to the MSFC components, we found lower proportions of patients with relapsing MS in secondary progressive or primary progressive disease had worsening in those outcomes, as well. So those were our endpoints for the study; they're clinical endpoints.   MSDF One of the things I noticed in your talk was that there was a great deal of overlap between the EDSS and the overall MSFC score; whereas there wasn't much overlap between the individual components of the MSFC score. What is the significance of that?   Dr. Cree Well the EDSS is itself a composite measure, and people tend to forget that. Especially earlier on in the scores that go from 0 to about 4, there you have 6 functional scale scores that contribute to the overall EDSS. That includes assessment of vision, brain stem function, motor function, sensory function, cerebellar function, bowel and bladder function, and cerebral function. And those separate functional scale scores are scored independently and then are summarized into an EDSS score between 0 and 4. After that, the EDSS score becomes really much more of an assessment of how far patients can walk until they have hit the major disability milestones of an EDSS of 6, which is walking with a cane, 6.5 a walker, 7 a wheelchair, or 8 bed bound.    MSDF So why is there a lot of overlap between EDSS and MSFC but not so much overlap between the components of MSFC?   Dr. Cree So when you look at the MSFC, you have two measures to the MSFC that are looking at motor function: the 9-Hole Peg Test and the Timed 25-Foot Walk. They can also be measures of cerebellar function. Both of things are very well measured in the EDSS by the functional scale scores for pyramidal and cerebellar function. The PASAT is not as well measured in the EDSS, although we have a cerebral functional scale score it's not a very precise measure, and there's a weakness associated with EDSS. Whereas in the MSFC, it's a very precise measurement.    When we look at the individual MSFC scores themselves, you can have patients who worsen in terms of walking, patients who worsen in terms of arm function, and patients who worsen in terms of cognitive function. And there is some degree of overlap in those three domains but not complete. And that just underscores how MS will affect different individuals differently. Some people have more ambulatory impairment, other people have more upper limb function impairment, and still other people have more cognitive impairment.   MSDF You made an interesting analogy to rheumatology in the treatment MS: the question of whether you should treat to no evidence of disease activity. I wonder if you can talk about that analogy and the NEDA, or no evidence of disease activity, goal.   Dr. Cree Sure. So in rheumatology in the 1990s, the discussion at that time had to do with how to treat rheumatoid arthritis. And this concept was advanced, which was a treat-to-target approach. The idea of using increasingly effective therapies to silence and suppress any evidence of active rheumatoid arthritis. And this strategy turned out to be extremely effective in treatment of rheumatoid arthritis. And instead of waiting for people to develop more disability, initiation of early highly effective treatments and really suppressing all joint inflammation became the current standard of therapy. And this has resulted in significant improvements in long-term disability in patients who are living with rheumatoid arthritis.    So taking that example and extending it to the field of multiple sclerosis, the idea here is that you have evidence of active multiple sclerosis on MRI scans such as gad-enhancing lesions and new T2 lesions; and evidence of relapses, which are clinical manifestation of acute inflammation; and disability progression, which is looking at the EDSS score and saying okay well if we have a combined measure that looks all of these things, and we try to suppress disease activity perhaps we're going to wind up with better outcomes. And so, this metric of no evident disease activity is defined as no evidence of relapses, no evidence of disability progression by the EDSS, and no evidence of MRI disease activity.    And it was originally developed in the context of clinical trials; specifically the pivotal trial of the natalizumab versus placebo study. And a certain proportion of patients in that study met this criteria of no evidence of disease activity. Subsequently, with more recent trials, other compounds have also been looked at and compared to their placebo or active comparator controls. And in each of these studies, you can see differences between treatments with respect to the proportion of patients with no evident disease activity.    The field of MS today is considering use of no evident disease activity as a therapeutic strategy or goal so that one would escalate therapy to the point where you see no evident disease activity. And the hypothesis here is that if you are able to effectively reach no evident disease activity that that is similar to putting patients in remission or preventing further disability from occurring. So we were very interested to find out whether there was long-term prognostic value of this marker, no evident disease activity.    And so, within the EPIC study, we looked at no evident disease activity over the first two years of the trial, and there was a proportion of our patients from this study who met those criteria: who had no change in terms of disability, no change in terms of clinical relapses, and no evidence of active multiple sclerosis by MRI scan. And we thought that that group would have a better outcome overall than the rest of the cohort. To our surprise, we found that there was no predictive value of no evident disease activity on any of the clinical markers that we looked at for 10 years.    So these patients had exactly the same risk for disability progression as patients who had evidence of active multiple sclerosis. And this was very perplexing; we just didn't really understand why that would be the case until we really started to look at the impact of treatment and use of escalation therapy in our cohort. And I think that when you look at the influence of therapeutic intervention in multiple sclerosis the effect size of therapeutic intervention is so great that other markers of biological disease activity such as new lesions wind up being minimized by the therapeutic impact. And as a consequence, things that might have been predicted based on natural history studies – such as brain volume loss, new lesions – become less apparent as having clinical meaning over a 10-year period of time because of the dominant influence of therapeutic intervention.    With respect to the no evidence disease activity, one of the questions that I think needs to be answered is do we really have the best markers for this? And if we are going to use a treat-to-target approach, are the things that are currently being looked at in no evident disease activity the right things to look at? And there is now interest in looking at other markers, as well, looking in incorporating, for example, brain volume into the no evident disease activity. And it will remain to be determined whether other ways of looking at no evident disease activity wind up performing better as a long-term predictor.   MSDF So when you're confronted with an individual patient – a new patient early in their course of disease – every neurologist is confronted the question of whether you start them with an interferon and escalate as they progress, or whether you start them with a highly active therapy. How do you make that decision, and how does the evidence from EPIC inform that decision?   Dr. Cree That's a great question, and I think this is probably one of the most provocative aspects of this long-term study. In EPIC, we used the escalation strategy where we began with so called platform therapies; drugs that are used as disease-modifying therapies that have been around for a long time, specifically the interferons and glatiramer acetate. And in the event that patients experienced relapses or had other markers of worsening such as brain volume loss, many of those patients were escalated onto what we would consider to be high-potency therapies. Drugs like natalizumab or medications that are off-label but still used in treatment of multiple sclerosis like rituximab or cyclophosphamide.    So we used this escalation strategy in this cohort. And what we found was the following. Treatment escalation was not associated with improved outcomes. In fact, treatment escalation was associated with worse outcomes in some patients. Now, why would that be the case? Well there's probably a confounder there of the indication to treat so that the patients who were getting escalation therapy are doing worse, and so they get the escalation therapy. So what we don't know from this study is if those patient hadn't gotten escalation therapy how would they have fared? We can't answer that question. That would require a randomized controlled trial.    But what this study does provide is this provocative idea that perhaps escalation therapy was really too little too late. That we were identifying a group of people who were at high risk of disability progression, but we weren't really setting things back to restore them onto a normal pathway and certainly not to prevent long-term disability. And this raises the idea that perhaps we should be utilizing these higher-potency therapies earlier. Now, that type of approach – the maximal efficacy approach – doesn't have data yet to support its use, but there are a few provocative studies that suggest that high-potency therapy might be associated with better outcomes. And we have the recent results of the cladribine study in clinically isolated syndrome where we had the best data yet for use of a broad-spectrum immune suppressant in terms of venting, time to the next clinical or radiographic event in patients who have presented with a first demyelinating event. And that study out performed all prior trials in clinically isolated syndrome so raises the question should be using an aggressive therapy right from the get-go?   And then, we have the alemtuzumab pivotal trial where alemtuzumab was compared head-to-head versus interferon beta-1a twice weekly in newly diagnosed patients. And in that study, alemtuzumab also out performed interferon beta-1a on many of the short-term markers of inflammatory disease activity. And we recently saw long-term data with alemtuzumab indicating that those patient do really quite well over a four-year period of time. So actually midterm data.    So we have a few lines of evidence to suggest that perhaps we should be using these high-potency therapies earlier. What we don't know is the relative risk-to-benefit profile. Certainly these higher-potency therapies carry greater risk to the individual subjects who are treated with these medications. And what we ultimately have to determine is whether those risks at a population level are worth the potential benefits of using a greater potency therapy early on in the course of MS.    It's my opinion that it's unlikely that the pharmaceutical industry is going to answer this question for us definitively. This type of approach to compare escalation therapy to high-potency therapy or maximal efficacy therapy from the get-go will require quite a bit of time of followup – at least five years if not longer – and will require large studies. So it seems to me unlikely to be endorsed by the pharmaceutical industry. It also seems unlikely that it's going to be sponsored by national organizations such as the National Institute for Neurological Disease and Stroke because of the extremely high costs associated with this type of clinical trial.    So that raises the question how are we going to answer this pressing unmet and unanswered question? And I think observational studies such as EPIC will be able to do this when merged together with other long-term followup cohorts. Today we have treatments that we didn't have 10 years ago, for example, fingolimod, dimethyl fumarate, alemtuzumab. These medications are currently being used in clinical practice. And I think we should be responsible for aggregating data on the patient experience with these medications, putting it into a systematized process for analysis, and aggregating this type of data across multiple centers. And that really is the goal of SUMMIT, which is going to involve pooling together our patient experience with our existing cohort, as well as new cohorts from UCSF, from Harvard, from Basal, from Amsterdam, and hopefully from many other MS centers as well. And then, with that pooled data, we'll hopefully be able to answer this question in a meaningful way.    MSDF Well, Dr. Cree, thank you very much.    Dr. Cree My pleasure.    [transition music]   MSDF Thank you for listening to Episode Forty-eight 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]