Interview: Dr Tomas Kalincik – AAN Meeting 2016

AMERICAN ACADEMY OF NEUROLOGY (AAN) MEETING 2016

INTERVIEW WITH DR TOMAS KALINCIK – MELBOURNE BRAIN CENTRE, ROYAL MELBOURNE HOSPITAL

BD: Brett Drummond, MStranslate
TK: Dr Tomas Kalincik, Melbourne Brain Centre

BD:  Welcome everyone to our interview today.  We’re grateful to be joined by Dr Tomas Kalincik from the Melbourne Brain Centre at Royal Melbourne Hospital.  I’m sure most of you will recognise Tomas, having been a regular contributor to MStranslate before.  Tomas is currently attending the American Academy of Neurology conference in Vancouver, Canada, and he has been kind enough to give us his time (late at night Vancouver time) to talk about some of the work he is presenting there.  So Tomas, thanks for joining us, would you like to tell us a little about the work that you are talking about while you are there.

TK:  Thank you, Brett, and I’d like to thank MStranslate for this coverage, I think it’s very important for the community and for us as researchers and clinicians to stay in touch even when we travel overseas.  One of the reasons why I’ve travelled to Vancouver this year to join the AAN is to present two pieces of work that we’ve completed in Australia as part of the MSBase collaboration.  One piece was completed by a medical student, Nathaniel Lizak, under my supervision, who works jointly under The University of Melbourne and Monash.  He has looked very specifically at a very relevant and timely question of treatment of moderately advanced and advanced multiple sclerosis.   One of the reasons for asking this question is that many regulators and medical institutions would limit access to therapies once a patient has reached certain disability levels.  This decision would often stem from a result of a publication from about 6 years ago, which has shown that people who obtain a certain disability tend to progress further at the same pace regardless of whether they are treated or untreated, and regardless of how quickly they got to that certain disability level.  For example, someone would develop a significant weakness in their leg and after that it was believed before that for these people it would take the same time to reach the stage where they would require a walking aid.  Now using the MSBase data, we have questioned this concept and we have managed to prove otherwise, there are actually highly variable outcomes in terms of the time to the next disability milestone.  Very importantly, there are two variables that critically determine the time to that outcome.  One of them is the frequency of relapses that people experience before they’ve reached a particular milestone and the second, even more importantly, is the proportion of time that people spend on highly effective therapies (such as fingolimod, natalizumab and alemtuzumab).  This result comes at the right time because, at the moment, there is a heated discussion in the United States about treatment discontinuation.  The MS community in the United States, including clinicians and their patients, are energised and highly involved in the discussions.  I believe that our result can inform the community quite significantly at the present time.

The second result or piece of work that we are presenting here is the result of a study where we have developed a predictive model, a comprehensive model of various disease outcomes and various therapies.  It is an attempt to answer a question, a very common question in routine clinical practice which every clinician will be familiar with, which is the question where patients ask us “tell me, which drug is the best drug for me in this particular given situation, given my previous therapies, my previous amount of relapses, my previous disability” and so forth. There are many variables that we use to describe an individual situation of an individual patient with MS.  So far, we didn’t have very much of a centralised or standardised answer to that question, so mostly what we act on is the evidence that we read inside journals and our experience and a fair bit of extrapolation with the patient that sits in the clinical room with us.  What we have been trying to do is follow a statistical model that takes advantage of the wealth of the data in MSBase, which is data from 38,000 patients from 119 various MS centres and more than 200 clinicians and use the cumulative experience of neurologists and their patients to perform future clinical decisions.  We were able to arrive at a, I have to admit rather complex, algorithm, which, however, enables us to make individual predictions of disability, progression, relapse outcomes, the probability of reaching secondary progressive disease and so forth.  Most importantly, for all of this, each of the currently available disease modifying therapies separately.  So as a result of that, we are able to package that information into a predictive tool and deploy it in the new MSBase platform that has been developed, so that the clinician, when they see their patients in the clinic room, will be able to consult this platform and ask the question “If Mr A was to switch therapy, which therapy are they the most likely to experience no disease activity on?”.  So we are moving from, and this is a very important step from a clinical perspective because this hasn’t been done very much so far, we are moving from group prediction to individual prediction so we can give the most individualised therapy.

BD:  Ok, that’s really interesting.  I think it’s really useful information for people because, as you say, one of the biggest difficulties is that uncertainty and going where do I go next, if this hasn’t worked, what is my next best choice?  And often, I guess previously, people have had to say ‘well we don’t really know’, but this gives a much more accurate way of being able to answer that question.

TK:  Yes, absolutely.  That’s the entire purpose of this exercise.  So this is definitely not the type of research that perhaps elucidates the pathology or the pathophysiology of the disease, we have to admit to that.  But I think it’s something that will offer valuable information to clinicians and because of that will be widely adopted by practicing clinicians.

BD:  Ok, so both of the studies that you just talked about have reasonably big impacts for people with MS.  Are either of those outcomes currently being utilised by clinicians?  Is this expected to be widely adopted by neurologists worldwide?

TK:  These are early days.  So where we are at at the moment with both studies is that we are in the process of scientific peer-review.  As the audience may be familiar with, each piece of new evidence that arrives from research such as MSBase or other sources, needs to first be validated and exposed to critique from our colleagues.  That’s what we are undergoing at the moment.  The work has been submitted to scientific journals and once it has been published and available in the public domain, we would be ready to roll it out and free to clinicians to utilise in their clinical practice.

BD: Ok, so those are the next steps?  Once it’s published and accessible to everyone, then it will begin to hopefully get adopted around the world?

TK:  Well, that’s what we hope for.  The reception has been very positive from various sources and various regions from around the globe, so we hope that, particularly given the reach of the MSBase that, these instruments and these pieces of evidence will not only find their uses in Australia, but also in a broader audience or around the globe.

BD:  Fantastic and great to see some Australian research, though I guess MSBase being global, but being driven by some Australian researchers, having such a big impact.  Earlier today, we posted across our social media platforms to ask people to submit any questions that they may have for you.  So we’ll just move onto them now.

The first one I guess was related to the first study that we were talking about and the question of defining advanced MS.  How you defined what was classified as advanced MS in the study, and whether this was people still with relapsing-remitting MS, or had moved to a progressive form of the disease?

TK:  What we defined as advanced MS was a mixture.  There will certainly be a large proportion of people with secondary progressive disease, but we should not limit ourselves only to this diagnosis because the data is that there are certain criteria and definitions around, which we didn’t necessarily implement in that research.  So these are people which have reached certain disability levels defined by a standardised measure, which is called EDSS.  We have looked at outcomes with certain EDSS steps as quantified by clinicians.  As opposed to that, the question of outcomes in secondary progressive disease is slightly different question because people can reach secondary progressive disease at relatively low EDSS steps, but also there will be people who reach secondary progressive at relatively high EDSS steps.  So we didn’t ask the question of secondary progressive disease here, but we are certainly planning to answer that question in the near future.

BD:  That probably leads into the next question, which was some experts are saying that there are progressive components present at the onset of MS, rather than necessarily a conversion process that we’ve always sort of assumed, would that have any impact on the findings that you are talking about?

TK:  That is a hypothesis that I’ve heard several times from Gavin Giovannoni and I have to say that I’m inclined to agree because it makes sense to me, it seems logical that people who have active, severe disease early after disease onset will be more likely to convert to secondary progressive MS later.  However, this is just my opinion, I can’t back this up with any evidence, for example, from the MSBase dataset, but it is an opportunity for future research.  It would be a logical assumption that treating aggressively early in the disease course may be beneficial from the perspective of preventing secondary progressive disease.  However, this is something that still waits from the clarification of evidence.

BD:  The next question was related to access to MSBase and really who has access to that data, and specifically do pharmaceutical companies have access to data from the MSBase database?

TK:  The way MSBase works is fairly democratic structure.  It is a collaboration of data owners, by data owners I mean various clinics around the globe, where the ownership of the data resides with the clinics.  We never at MSBase own any data, it’s all owned by our researchers and contributors.  So where any of the researchers who are part of the collaboration wants to utilise the entire dataset to a certain purpose or certain end, we obliged to apply for the data and any of the investigators can decide not to provide the data if they don’t agree with the particular use of the information that they own.  In terms of the accessibility by the industry, we have a very strict rule about not providing the information, the original data, with the industry.  We may receive requests from industry to collaborate on a specific project, but we never provide the access to the actual data.  At best, we can agree to conduct analysis together, in concert with our partners.

BD:  So, the last question is a little bit in-depth, so I’ll ask it in a few little bits, but it relates to one of the statements made in the abstract about the first study that we were discussing, which says “increased utilisation of high-efficacy therapy ARR during advanced MS is associated with a lower likelihood of accumulating significant disability”.  So they were looking for some clarification on those statements and, the first way that they wanted that clarified was, what was the likelihood of accumulating significant disability and how was that defined?

TK:  The question can really be split into two parts, but what is the probability of accumulating significant disability and how do we define it?  We use EDSS, which is a quantitative scale that I mentioned earlier today, that is what neurologists tend to use to translate the outcomes of clinical observation into something that we are able to quantify.  We use this and we use something that we call EDSS steps, which range from 0 to 10, where 0 is no disability and 10 is death due to MS.  The disability scale that we used in this particular study moderately advanced or advanced disability, so we look at people who have reached EDSS step 3 – that means a significant disability acquired in one domain, so a significant weakness in one leg or a significant change in sensation in a part of their body and so forth, but without impaired ambulation.  That is the input, the output of the analysis is the probability of EDSS step 6, which is the likelihood of requiring a unilateral aid, such as a cane or a stick to walk 500 metres.  So, the latter is posited to be fairly stable, hard milestone and one that would be very obvious in clinical practice.  We have seen that in the observational data that for people who are either exposed to no therapy or at best to low efficacy therapy (such as the injectable therapies or some of the oral therapies), at 5 years from reaching EDSS step 3, about 80% of the patients would not have reached EDSS step 6, so the step when they would have required a walking aid.  Whereas for those patients who at the time had been exposed to a high efficacy therapy (fingolimod, natalizumab or alemtuzumab according to this study), at 5 years it would be about 90% who had not reached that step, so we are talking about a difference of 10% of patients who would not have reached the outcome disability step.  Even more importantly, we have looked at the transition from EDSS step 6 to 6.5.  This is the step from when people require a unilateral walking aid to the step, 6.5, which corresponds to the step when people require bilateral support, which is two canes or a walker.  Even though mathematically we are talking about 0.5 EDSS step, but clinically there is a very important transition for a patient because we are talking about someone who previously had one free hand to use when they walk around their house to now they need to hold onto two things while they walk and, if they want to do something, they have to sit down so they have free arms, so functionally it is an important outcome.  Again, we see a very similar trend, from the time when people have reached EDSS step 6 to EDSS step 6.5.  If we look at 5 years later after the initial EDSS step, it would be 40% of patients who would not have reached EDSS step 6.5 if they were treated by low efficacy therapy or they haven’t received any treatment.  Whereas for high efficacy therapy, 50% of patients would not have reached EDSS step 6.5.  Again, the difference is similar (10%) and this is important clinically, for example, here at the meeting in Canada I’ve spoken to many clinicians who look after patients here and they told me according to the local regulations, once people have reached EDSS step 6, they lose access to disease-modifying therapies.  So from this perspective, the result is very important for regulators because it shows them that by continuing highly effective therapy even after EDSS step 6, we can prevent further progression of disability.

BD:  Ok, I think that actually answers all of the specific questions that the person had.  I think what you touched on there is a really important point of, while they may be small grades in terms of EDSS, you have really isolated a very functionally important step that has a huge impact on the quality of life for people with MS.  So I think it’s highly important and the research outcomes of that are really significant.

Alright, I think we’ll leave it there, it’s very late at night in Vancouver where Tomas is and, as someone who has attended these conferences before, they can be very draining, so we’ll let Tomas get some rest.  Thank you very much for agreeing to chat to us about this – it’s much appreciated by, not only by us, but also by all of the MStranslate community and your continued involvement is really appreciated.

TK:  Thank you and thank you for the questions.

BD:  Enjoy the rest of the conference, we hope it is really beneficial and good luck with all of the future research and I’m sure we’ll talk soon.

TK:  Thank you, seeya.

BD:  Thanks, Tomas.