Can you believe it's been 23-years since the first drug to treat relapsing MS was approved? That does not seem like too long ago, and may explain why treatments for progressive MS have been lagging. On November 29, 2016, Kate Milliken interviewed Dr. Fred Lublin, practicing physician at Corrine Goldsmith Dickinson Center for MS at Mt. Sinai in NYC, to discuss progressive MS and the future of treatment. Dr. Lublin has also served as the chair of the advisory committee on clinical trials of new MS drugs.
You can watch the One On One with Kate Milliken and Dr. Fred Lublin above, or read the transcript of their conversation below.
Kate: Hi everyone I’m Kate Milliken, the founder of MyCounterpane, and I have been living with MS since 2006. This is MyCounterpane One-on-One, and we’re coving the future of progressive MS. With me is Dr. Fred Lublin who works at the Corrine Goldsmith Dickinson Center for MS at Mt. Sinai in NYC. Dr. Lublin is a practicing physician. He has also worked at the National MS Society as the chair of the advisory committee on clinical trials of new MS drugs as well as a research programs advisory committee. Dr. Lublin has authored numerous scientific articles and served as a consultant to the National Institute of Health, the FDA, and numerous biotech companies, who work with MS drug development. I am thrilled to have Dr. Lublin with me. Dr. Lublin, I feel like there has been so much progress in the realm of relapsing MS, but not in progressive. Why do you think that is?
LUBLIN: Hi Kate, happy to be here. So, 23 years ago, we started the era of treatment of MS with the first approved drug in treating relapsing MS. Now 23 years later, we see the horizon for doing the same thing for progressive MS. So, our largest unmet need in 2016 is how to treat progressive MS. We have no approved therapies, we’ve had a number of unsuccessful attempts, and our general understanding of the mechanisms that underly progressive MS is not as fine-tuned as it is for relapsing remitting MS. That’s held us back in some ways, but the good news and the exciting news is that 2017 is going to be a banner year for our ability to approach, treat, and better understand progressive MS.
So, after a series of negative trials, and I should say that even when we do studies that don’t work, that are negative, we learn lots, and you have to do the trials, including the ones that don’t work and analyze them and it helps you move forward to get smarter and smarted with every study. So we now have two studies, one that’s about to be published, one that has not yet been published. Both have been presented, which opened the door for treating progressive MS. These include primary progressive MS, with one study with a modest but a definite result, and also for secondary-progressive MS, one study with a modest but definite result, and then there are some smaller studies with molecules such as Symbostatin (SP?) and Biotin that are interesting and need to be explored more.
Those studies are underway as well, but the two studies we have, one is with what’s called an S1-P1 modulator, that’s a subclass of drug that’s not yet available. The other is with a molecule called Ocreluzemab which targets B-cells. That one again is not yet available, but those studies will be coming out, and it’s a start.
Kate: What for you over the years of being in this space, what changed the viewpoint for researchers to actually start making progress?
LUBLIN: It wasn’t so much a change in viewpoint as it was trying different molecules, and even with the results we have now, the molecules we have are anti-inflammatory so we expect it to work very well, and in one case we even have the inflammation that works very well. In relapsing-remitting MS, the effect also carried over, but to a lesser degree than with progressive MS, but it’s the same strategy. So, the challenge for us now is to say “Who are the best individuals to apply that strategy to?”
We have some hints in terms of age and amount of disease activity that’s going on, but not enough yet to be definitive about who those populations are. Moving forward, we have to get a better grasp on what the best population with these agents are, and who needs a different strategy altogether, and there are some different strategies that are being tested at the moment or will certainly start testing phase.
Kate: So let’s talk bout these two studies that you feel are on the forefront in terms of where they are, their phase, their trials, and progress, and how soon they could get to a progressive patient.
LUBLIN: So first is the study with Ocreluzimab, which is a study called Oratorio. That’s been presented and produced a positive result compared to placebo. Modest, but positive.
Kate: What defines modest?
LUBLIN: 24%, so the group that was receiving Ocreluzemab had 24% less chance of progressing during the course of the study. It didn’t turn off all progression, but it was statistically significant, and it’s a start. That particular agent, that’s a phase 3, and so it’s now under consideration by the FDA for approval both for relapsing-remitting where they had two separate studies, and for primary-progressive MS. The FDA is supposed to give an answer by the end of this year as to what they think in both those indications, and as is typical of them, we don’t know what their deliberations are or what their decisions will be, but we’re anxiously waiting.
Kate: Phase 3 is great progress.
LUBLIN: It is. And again we learned how to do the studies there, because there have been other Phase 3 studies of anti-inflammatories in Primary Progressive MS that haven’t worked at all. Now we have to say “What’s different? Why does this anti-inflammatory with agents that work well with relapsing remitting MS, why are they different with Primary progressive MS?” And that, we just need to keep studying. The other study is with a molecule called an S1-P1. It’s the next generation of Gilenia. It’s a little more selective, and they did their study in secondary progressive MS, where also we haven’t had any successful trials, and again the best result is about 21% different between the treatment group and the placebo, but it’s a start.
Kate: In the world of progressive MS versus relapsing remitting years back, there was an assumption that progressive MS was just a more severe form of relapsing remitting, and now that’s changed. Is that true?
LUBLIN: I think what you're saying is correct. Not all MS becomes progressive. Before we had treatments for relapsing remitting disease, there was a high likelihood that individuals would transition into a progressive phase. Our sense is in the treatment era, fewer people are going into a progressive phase, but there still are some who do. What we don’t understand yet is what changes. There is an important distinction here: people can get worse in MS by two different mechanisms, One is they have an attack, and they don’t completely recover, so they’re left with some residual of some sort, and then in a little longer they have another attack, and more residual.
This can build up to a point where they can actually have significant impairment. That’s not progressive disease. Progressive disease is independent of what’s happening with the attacks, individuals gradually worsen over time. Some individuals never have an attack, but just the onset and gradual worsening over time. Now it’s not constant. You can have periods where you plateau, but it’s this idea of this gradual worsening, rather then what’s leftover from the accuse attacks. That distinguishes progressive disease from other types of worsening MS.
Kate: In the world of being a researcher, talk about the mindset of other researchers that you interact with when you talk about progressive MS.
LUBLIN: We’re now looking to see how we can better characterize progressive disease. We have made recommendations that the field has generally accepted as how we’re going to sub-categorize a disease. So for example, we’ll take a progressive patient, we’ll say over this period of time, are they progressing or are the stable, and also over this period of time, are they active or not active. Those kind of distinctions may help us to better pick the individuals to treat with this therapy or that therapy.
Kate: So what about your work specifically, Dr. Lublin?
LUBLIN: Well, we’re looking at several things. We’re looking at some additional ways to treat progressive disease, and also we’re trying to look at better ways of imaging it. I have colleagues here working with what’s called a ultra high field MRI, it’s called a 7-Tesla, which takes beautiful pictures of the brain, and we’re looking at that to see if we can make distinctions between relapsing remitting and progressive disease using the MRI, and how different therapies effect those outcomes. I’m also trying to determine how to better define progressive disease, how early can we say that someone’s actually progressing, can we find a marker that says this is now the onset of progressive disease. Right now, just based on clinical experience, it takes a long time until you are pretty confident that someone is transitioned into this progressive phase.
Kate: In kind of a bigger, more philosophical response here, how do you feel like the general mindset of making progress within progressive has changed?
LUBLIN: Well, we’ve gone from having nothing, to not only having these two successful phase 3, but more molecules coming in and better design strategies going on. There is one study going on in Great Britain with this new type of design where you can test multiple agents and then you stop along the way and knock off the ones that don’t look promising as a way of rapidly screening different agents. We also have a better understanding of some of the molecular mechanisms involved so we can employ new strategies, and we’re learning more in the laboratories every day.
Kate: One of the things I also like is spearheaded by the MS Society, there is the International Progressive MS Alliance. Is there anything you want to talk about that?
LUBLIN: This is a wonderful endeavor where the majority of the major international MS societies and the MS international foundation came together, pooled funds and resources to specifically target progressive MS because it was time. So the alliance has generated lots of interest from researchers around the world, some of the best in the world have some proposals, and they’ve had the difficult task of picking just a few because they didn’t have as much money as they would like to fund all of them, to start moving the field forward in terms of biomarkers and MRI’s and things of that sort. So it’s a very exciting endeavor, not only because this group is doing it, but because the MS research community has responded so nicely to it.
Kate: Last question for you, in light of the patients and the people who are living with progressive MS now, what would you recommend to them, or is there anything that you could speak to about things that they could do for their own health in the present versus the future?
LUBLIN: So, for the present, until we have an approved therapy, we sort of treat progressive MS on an Ad Hoc basis, but there are things individuals can do. One of the important initiatives we’re undertaking now is looking at the role of wellness in a very positive sense. Actually looking at the things that will make a difference. For example, smoking. We know that smoking is specifically bad for MS, not just for your health, but specifically bad for MS. We’re also looking at diet. There is a lot of diet information on the internet. None of it is scientifically sound, none of it is proven, much of it is contradictory. We’re looking at how we can better study diet because it’s not an easy thing to do, because there may be roles there, we know that there are interactions between the immune system and the bacteria in the gut. We’re looking at that. Weight, obesity may be a factor. Vitamin D has to be studied. Exercise, activity, there’s lot’s going on that people can do, and that’s in addition to what we hope will be these therapeutic breakthroughs.