Community Q&A: Ellen Mowry, MD, on the TREAT-MS Trial

Ellen M. Mowry, MD

At the 2021 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, October 25-28, one of the presidential lectures focused on the ongoing discussion about the initial treatment approach that should be taken for patients with multiple sclerosis (MS), specifically whether or not high-efficacy disease-modifying therapies (DMTs) should be used from the start of care.

Ellen M. Mowry, MD, director, Multiple Sclerosis Experimental Therapeutics Program, and professor of neurology, Johns Hopkins Medicine, offered a look into the potential reasons why this approach, often referred to as the induction approach, may not necessarily provide patients with better long-term outcomes compared with moderate- or low-efficacy DMTs.

Mowry concluded her lecture by urging physicians to get involved in a pair of trials aimed at improving the available data on induction vs escalation in the real world, TREAT-MS and DELIVER-MS. The TREAT-MS trial is a pragmatic trial aiming to assess 900 patients with MS who were diagnosed under the 2017 McDonald criteria over the course of 60 months, with a primary outcome of disability progression measured by EDSS plus, a compound outcome which includes the 9-Hole Peg Test and Timed 25-Foot Walk Scores alongside the standard EDSS measures. DELIVER-MS is a parallel trial being conducted in both the US and the UK. The secondary measures will include patient-reported disability, impact of disease, health-related quality of life, relapse recovery, imaging outcomes, clinical performance metrics, social status, and safety.

After her lecture, Mowry opened the floor to a question-and-answer session and offered additional context to the CMSC attendees. NeurologyLive compiled these responses in order to highlight the clinical community’s questions.

Do you believe there is a subset of patients that we need to start on high-efficacy therapies from the start, and if so, what clinical and or paraclinical factors should be considered in that decision-making process?

Ellen M. Mowry, MD: That's a great question, whether certain subgroups of individuals may need to use higher-efficacy therapies from the start. I think that we are going to find that this is likely the case. That tends to be our experience to some extent, that certain people kind of run right out of the gate with pretty active MS. Again, as I mentioned, a lot of the observational studies to date try to drill down on exactly who those people are most likely limited because they don't really include all of the factors in a bin. It's not like we're measuring all 20 or 40 of them. And in fact, in TREAT-MS, we actually have a list of those things that we capture for each individual. In the trial that we're doing, the reason that we decided to stratify the randomization based on high-risk versus low-risk indicators was really to get better clarity on that, but the reason that we're measuring all those factors in parallel is that, hopefully, we’re making for a better prognostic model that might tell us a little bit more about whether there are specific people who most benefit from the early, high-efficacy therapy treatment strategy. I think that we will find that to be the case. There are patients that all of us know this about right out of the gate. But I think the specifics of who those patients are still need some clarity.

Are you collecting data on COVID-19 in the treatment of MS?

I'm assuming we're talking about the clinical trials and TREAT-MS, but yes, we are collecting information about COVID-19 infection, suspected and confirmed COVID-19 infection, as well as looking at hospitalizations for COVID-19 and deaths from COVID-19. We’ll also be trying to understand how the pandemic impacts the care of people enrolled in this study, both with respect to ancillary services and any delays in treatment, et cetera.

It’s interesting to see that in TREAT-MS, after a breakthrough event, there’s an unforced decision about whether to escalate versus continue on therapy—might this introduce the same biases that you see in observational studies?

This is a pragmatic trial. It's sponsored by the Patient-Centered Outcomes Research Institute, and we really wanted to align major changes in a person's disease-modifying therapy with decisions that people encounter in the real world. So, if a person with MS has 2 new lesions on their brain MRI scan and I force a change, that may not take into account the fact that the clinician and the patient know that they weren't taking their medicine for the last month. There are the things that I think are important in the clinician-patient relationship that require some flexibility, and pragmatic trials are designed to really parallel the real world rather than being too prescriptive about treatment changes.

In reality, though, the trial algorithm does strongly encourage people to consider a treatment switch if anything more than a very minimal amount of breakthrough disease has occurred. And, in fact, the scripting that we provide says that you need to tell people that—at least based on data like the Modified Rio score and other things like that—not switching could be associated with an increased risk of disability for that patient. It really is fairly suggestive that a switch should occur but allows for the fact that the patient and the clinician may know something that's relevant to their treatment choice that I don't, or Scott Newsome, MD, doesn’t, as the principal investigator of the overall study.

A recent paper showed that the first medication for MS can affect the second medication, in terms of the immune system, which can persist for weeks and months. How might that affect the choice of the second medication, and would you escalate in light of these profound effects?

I find transitioning from one therapy to another to be some of the scariest moments in my relationship with patients in my real-world clinics. I can fully appreciate that that's the case. I think that we tried to carefully document the timing of stopping and starting medication in the clinical trial. I'm not sure if we'll have enough data in this 900-patient study to really drill down on those overlaps, but we'll do the best we can.

What emerging biomarkers are you most excited about that can help decipher which treatment strategy is best for the patient?

Excellent question. I didn't mention that we do have a biobanking sub-study for TREAT-MS, which has been harmonized with DELIVER-MS as well. So, we have a large component of our patients are getting blood at baseline and at the time of the 6-month appointment, and then anytime that they have breakthrough disease where there's a treatment switch. I think serum neurofilament light is an exciting biomarker to think about using for treatment monitoring. Our colleague Peter Calabresi, MD, actually has funding that includes studying neurofilament light in the TREAT-MS population to evaluate how it performs as a biomarker of treatment success. I think it'd be particularly interesting if you could predate the prediction of unsuccessful treatment compared to our standard MRI protocol, which in our study, as well as DELIVER-MS, follows the CMS guidelines for monitoring over time.

Transcript edited for clarity.

REFERENCE
Mowry EM. Presidential Lecture: Escalation Therapy vs. Early Aggressive Treatment. Presented at CMSC 2021; October 25-28, 2021. LEC2.