The Great MS Debate: What does the evidence say about using a high-efficacy treatment approach sooner?

Welcome to the Great MS Debate.

DR. LUBLIN: Hello. This program will be a debate and reflective discussion with current treatment paradigms in multiple sclerosis, the potential role of the early high-efficacy therapy and outpatient preferences come into the play in the shared decision-making process.

DR LUBLIN: I'm Dr. Fred Lublin. I'm the Saunders Family Professor of Neurology and the director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at the Icahn School of Medicine at Mount Sinai in New York City.

DR. STANKIEWICZ: I'm James Stankiewicz. I'm the clinical director at the Partners MS Center in Boston. I'm an assistant professor of neurology at Harvard Medical School.

DR BAR-OR: Hello, my name is Amit Bar-Or. Hello, everybody. I'm a neurologist and neuroimmunologist from the University of Pennsylvania where I'm a professor of neurology and chief of the multiple sclerosis and related disorders division.

DR. VARTANIAN: Hi, I'm Tim Vartanian. I'm a professor at Weil Cornell Medical College, and I am a scientist that works on various aspects of disease initiation with MS.

DR. RILEY: And I'm Claire Riley. I'm the medical director of the MS Center at Columbia University in New York and assistant professor of neurology at Columbia.

DR LUBLIN: We can all agree that MS is certainly variable and can be progressive, whether trying to optimize outcomes in starting early or leaving future treatment options open, ultimately we're all trying to manage the uncertainty associated with the MS diagnosis.

But we also see how MS typically affects young adults in the prime of life who may have been looking forward to decades of employment or thinking about starting a family, or both. So there is urgency to offering them the optimal treatment which can mean the difference down the line between a patient being employed or unemployed, versus being ambulatory or perhaps disabled.

Subsequently, you want to better understand what evidence there is to support an early high-efficacy treatment approach and the barriers that effect initiating a high-efficacy treatment strategy.

DR LUBLIN: Let’s dig a little deeper. What are evidence-based benefits of using MS treatment strategies sooner? Could starting high-efficacy treatments early improve long term outcomes and disease progression? Amit?

DR. BAR-OR: I think that my personal view is that early initiation of high-efficacy therapy, if achieved safely, will translate into a better longer term outcomes. I think the challenge is that good data is not that easy to come by. We do know from, as was alluded to, a number of large MS trials, which compared high-efficacy treatments to lower efficacy or high efficacy to placebo, and then as part of their design, at some point after the active comparator period had switched people on to the high efficacy if they weren't on it to start with. And in those studies, it's pretty clear that these individuals do not catch up. The ground that they have lost, they don't catch up as compared to those who started the high efficacy early. However, these studies tend to be relatively short and don't firmly give us the evidence over the long term.

DR BAR-OR: Observational studies that have lasted longer may give us complementary insights. One example is another UK study that ran for approximately 16 years in some patients and what they did is they considered the time to sustained accumulation of disability or disability progression in a cohort of patients who started either with a high-efficacy therapy or with a lesser efficacy therapy, and they found that some five years out, it took about twice as long, or half the proportion of individuals to achieve this sustained disability progression in the higher efficacies as compared to the lower efficacy groups. So this study again is limited in the sense that it is a nonrandomized trial, but it does give some window of insight into longer term consequences of starting with high-efficacy therapy

DR. LUBLIN: So there are studies that the suggest high-efficacy treatments, may delay disability accumulation. So, Claire, how would you respond to this data?

DR. RILEY: Well, I think it's very interesting to look carefully at some of observational studies, because I mean you're just really limited by the design, you know, for example, the last study you mentioned, it ran for 16 years. You know, when you adjust for the baseline covariance, that difference between the time to sustained disability accumulation falls away. And so I think that some of the current efforts, and there are two large PCORI studies going on right now evaluating, in a randomized fashion, these two strategies. I think those are going to be really important to see, you know, if in at least in the medium term, is there a true difference in how people are doing neurologically in ways that matter to them, and then our best measurements and our best biomarkers, you know, do they support that as well.

And then the safety issues, you know, will be ongoing. And there

is something that's appealing to me about, and I absolutely agree with those of you who have mentioned, you know, early high-efficacy therapy, targeting that window of opportunity, but I wonder if we might think about, you know, a few years of a high-efficacy approach followed up by something that has a good, safe, long term profile.

DR. LUBLIN: So the fact that we need studies shows that we still have clinical equipoise on this question, and there is a difference on how prescribing is done at academic medical centers, like my colleagues here are involved in, and those out in the community.

And I think one of the lessons that the folks out in the community have learned, at least those that have been around for a while, are that there are patients that do well on all of our therapies. That's how they got approved, and so there is probably a role for all of them moving forward from one degree or another; although some of the early ones perhaps have been displaced, except in those individuals that are very concerned about safety.

DR LUBLIN: But we have this debate, you know, moving forward and until we get reasonable data, and I don't think we will ever get reasonable data from observational studies. I think they can only compliment randomized clinical trials, because there are so many biases and confounds to them. But let me ask the Dr. Vartanian to expand a bit further, then we will ask Jamie Stankiewicz to respond. Can you expand more on why it may or may not be possible or appropriate to start high-efficacy treatment approach early in a patient with the MS and why it may be appropriate to escalate therapy, and maybe not just for you, but for, you know, physicians in the community?

DR. VARTANIAN: Yes, thank you, Fred, and I agree with your, the points you just made.

And as you pointed out there is a, not a -- you know, there is a significant percentage of patients that seem to be doing well on modest efficacy, low risk medications. And -- and so, you know, part of the challenge is figuring out who those patients are, which we really have a hard time doing. I think the other part of the equation though is the adverse event and safety profile of these agents.

So, you know -- and that becomes part -- that's a complicated equation, because there is the patient decision-making, the patient, you know, how risk averse or how much of a risk taker the patient is, and then there are comorbidities. So if someone has, you know, already has liver disease, you're not going to put them on a drug that has a higher risk of hepatotoxicity, certain malignancies we see expanded with certain kinds of immunotherapies, in particular cutaneous malignancies. So that's always a consideration.

Patients with high JCV indexes, you know, probably one of our best biomarkers that helps us tailor, tailor our treatments; and risks of infections. So sometimes we see these adverse events appear after we've started a high-efficacy drug and they become almost intolerable, so we have to revert back for our modest efficacy drug. But I think, you know, I think as it's written here, infusion reactions, infections especially, serious infections, PML, secondary autoimmunity, malignancies, hepatotoxicity, as all are relevant factors that are going to shape a decision choice, and maybe influence a practitioner to start with a modest efficacy drug, which will still have a benefit. So it's still better than no drug at all. It may not be better than a high-efficacy drug, but better than no treatment at all.

DR. LUBLIN: Fair enough. So we are getting back to the risk of therapy and the uncertainties associated with the side effects, which a highly valid point.

DR. STANKIEWICZ: So I think these are the valid points. There is research suggesting that patients that have substantial disability still feel like they're doing well when they're surveyed. So I think patients oftentimes are willing to accept disability, and I guess in some ways that's a positive, that people can have a good outlook. But I think as neurologists, it's our job to prevent that from happening. And I think sometimes -- and I'm not saying this is always the case, but I think sometimes we think of patients and think they're doing well, but I think there is also this question sometimes like how hard are we actually looking, and are we really looking at cognition, are we looking at fatigue, are we looking at mild bladder dysfunction. And of course, I have patients that have been on lower efficacy disease modifying therapies that are running marathons, but these patients are still in their thirties and forties and will they be in tiptop shape as, in line with what they should be from normal aging at the age of 60 or 70 on this medicine, I don't know.

So I -- ultimately, we can advise it's the patient's choice and if the patient really is strongly wanting to be on a medication that has been around forever that we know is safe and they feel like it's -- they would rather do that because of some concerns around safety with some of the newer agents, that's their choice, as long as they are informed about it

DR. LUBLIN: Thank you for those, Jamie.

So, so far we have discussed evidence supporting the uses of different treatment approaches, escalation, high efficacy, while also thinking about some of the challenges associated with these approaches. As mentioned before, both approaches come from a desire to protect the patient, and even if this discussion, we don't have time to talk about all of the other factors that come into the treatment decision, like family planning and someone of them alluded to earlier, insurance issues and access to drugs and such.

So something to think about for a future discussion. While we come back to the idea of the balancing efficacy and safety, we also want to keep in mind the critical aspect of patient-specific factors.

DR. LUBLIN: So before we conclude, I have one final question for our panelists, which I think you kind of answered, but would an early high-efficacy treatment strategy optimize disease management for your MS patients?

DR. RILEY: Yeah, I think this remains to be seen. I believe that we do have equipoise around this issue. I certainly have seen it work very well, but I think our observations, as well as observational studies, are, you know, inherently pretty biased. So I look to, you know, the randomized studies to show us the way here.

DR. VARTANIAN: Yeah, I mean, Claire's points are well taken. I just think that it makes, it makes sense in terms of pathophysiology to try to intervene early, and with the most efficacious agent upfront to prevent establishment of immune mechanisms within the CNS, such as, you know, lymphoid neurogenesis in the meninges, and other areas where we think that once it's established then progression is almost inevitable.

DR. BAR-OR: So I certainly would think that early high efficacy is something that can work for many, if not most, but of course, as you pointed out, there will be those who will simply be uncomfortable. To me it's very important that the person subscribes and participants in fact in the decision-making approach. The other thing that we haven't talked much about is that high-efficacy therapy early on needn't necessarily can be high- efficacy therapy forever, and you had mentioned, Fred, the prospects of de-escalation, as was mentioned by Jamie and others, and I think that with the notion of biologies that Tim was alluding to and the ability to take away from the immune system and then allow cells to come back, the concept of reconstitution biology, we're going to be learning a lot more about the prospect at least in some patients of allowing their immune system to come back but not harbor MS to the same extent or at all, and maybe manage them either with no treatment and close monitoring, or with much gentler treatments, if you like; ones that are lower efficacy but not likely to represent the same long term commitment.

DR. STANKIEWICZ: I think Amit made the point that I was going make more eloquently than I was going to make it. So I think for brevity purposes, I will say, yes, I think high-efficacy therapy can optimize disease management in my MS patients.

DR. LUBLIN: Okay. So while we all want to be getting our patients optimal disease management from the beginning, we recognize limitations and current therapies, the need to make tradeoffs when selecting the right disease modifying therapy for patients, and the continuing use of first line DMTs with lower efficacy reinforces the need for an efficacious agent with a balance safety profile. At the same time we want to ensure that patients have a therapy that is flexible and convenient for them.

Our discussion today is reminder that while we have come a long way in managing MS, we should not be become stagnant in therapy, and that there is still unmet treatment needs, regardless of which side of the debate you find yourself on, especially in light of the current health challenges we face today.

We thank all clinicians for continuing to seek what is in the best interest of patients and for doing their part to advance the care of MS. And a special thanks to our audience tonight. Thanks to Dr. Stankiewicz, Dr. Bar-Or, Dr. Vartanian and Dr. Riley, and thank you to Novartis for sponsoring this debate.