Bridging the Gap, De-Escalation of MS Disease Modifying Therapies

Carolyn H Goldschmidt, DO

Clinicians are constantly trying to find the most effective strategy for sequencing disease-modifying therapies (DMT) for patients with multiple sclerosis (MS). Although there is a variety of practices using DMTs, there is a lack of universal guidelines for providers on how to use them effectively.¹ One approach that has been favored is escalation, focusing on minimizing long-term risk. There has also been a growing emphasis on early, highly effective treatments as well. Previous research has investigated the discontinuation of DMTs, but there is little evidence regarding the safety of doing so.

In a recent study of 135 patients with MS, investigators analyzed the safety of de-escalation of DMT from high or moderate efficacy to low-efficacy treatment on annualized relapse rates (ARR), MRI activity, disability measures, and patient-reported outcomes. Lead author Carolyn H. Goldschmidt, DO, a neurologist at NorthShore University Health System in Chicago, presented the findings at the 2023 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 31 to June 3, in Aurora, Colorado.¹ In the study, the most common DMT 1s were dimethyl fumarate (70.4%) and fingolimod (23.7%), whereas the most common DMT 2s were glatiramer acetate (42.2%) and interferons (21.5%). Notably, the most common reasons for patients switching were because of adverse effects, safety concerns, and tolerability.

During the meeting, Goldschmidt sat down in an interview with NeurologyLive^® to provide an overview of the findings that were presented and their implications. She also talked more about the transitioning between different types of DMTs and what should be further investigated in this area. In addition, Goldschmidt spoke about the most important aspect of care for patients on DMTS, as well as promising emerging concepts in the coming years.

NeurologyLive®: Could you provide an overview of the study?

Carolyn H. Goldschmidt, DO: We did a retrospective study on patients with MS from the Cleveland Clinic system who switched from a high or moderate efficacy DMT, which included any of the monoclonal antibodies or oral medications except teriflunomide (Aubagio; Sanofi). Then, we compared those to the time when patients de-escalated to a lower efficacy DMT, which included any of the platform injectable therapies and teriflunomide. We looked at annualized relapse rates, MRI activity, disability scores, and patient-reported outcomes as well.

We used a noninferiority statistical method to try to prove that de-escalating from DMT 1, a high efficacy DMT, to DMT 2, a lower efficacy DMT, was noninferior. We found that most of our results were not significant, but tended to show that annualized relapse rates and disability was not inferior when patients switched from a high efficacy to low efficacy DMT2. There was one significant finding in terms of moderate or severe T2 lesion burden, which was significantly noninferior during that switch. Overall, we think that it is a safe possibility for a number of patients. We need more trials, ideally a randomized controlled trial, to identify what patient population would be most appropriate for and what DMT people should be escalated to.

What are the implications of these findings?

Well, now the field is really changing into starting this early, highly intensive therapy, early in the disease course. The first DMT will use monoclonal antibodies, and things that are pretty potent DMT. So the question is, if somebody's been on that for 10-15 years, what do you do after that? This is study is trying to answer that question. There are studies looking at the discontinuation of DMT, like the DISCOMS study [NCT03073603] that recently came out. So that answers part of this question, is it safe to stop the DMT? When is it safe to stop the DMT? But there's a gap in the middle, what do we do in-between the early, highly effective treatment and discontinuation of DMT? I think that's where de-escalation fits in.

Among the different types of DMTs, how do you go about transitioning between those types of treatments for patients?

That's what we were looking at, going from the highly effective to the more low or moderate efficacy with DMTs. Again, the question is always about the risk benefit, as patients are younger and healthier earlier in the disease course. The risk benefit ratio of a monoclonal antibody is definitely on the side of the highly effective DMT, but as patients get older, they have immune senescence as the disease naturally becomes less active. We're trying to answer, what is the safest choice?

In terms of these treatments, what else is there that we should investigate?

Well, again, it would be nice to have a randomized control trial. This was just a retrospective chart review, so definitely. During my presentation, I brought up the possibility of having a dose de-escalation or titration [study]. So instead of changing DMT, could the dose of the monoclonal antibody or either the actual dose or the dosing schedule, be titrated? Could that be a version of de-escalation? I think would be an interesting question to look at as well.

What do you think is the most important aspect of care for these patients?

Every year, it's always reconsidering the risk benefit of, “is this the best medication for you in terms of your disease activity and your risk profile?” It's really about readdressing that with the patient every year to determine what the best sequence of DMT is for them. We're coming out with so many new DMTs and the CMSC Annual Meeting is all about the Bruton tyrosine kinase (BTK) inhibitors. So where are these new DMT going to fit into the sequencing? Even with like stem cell transplants that are being used now too, how is that going to fit in? What do we do with those patients 10 years later? I think these are all interesting questions to ask.

Is there anything that you're like excited about, besides the growing amount of therapies coming up?

I'm really excited about the BTKs and seeing the results of the phase 3 trial, especially in progressive MS. I think that's really the big thing because that's the area we are really lacking a lot of treatment options. There's been a lot of disappointment in previous trials so fingers crossed that there's some good evidence for the progressive disease.

Is there anything else you think should be brought more awareness about in the field?

I like the point of personalized medicine, really identifying the most appropriate patient populations for each of these choices: for starting early highly effective therapy, for de-escalating, for discontinuing the progressive patients. A lot of our baseline characteristics and studies have looked the same for many years but that's not necessarily representative of the MS population. I think really trying to 'hone in' on what patient population will respond best to these different choices is important. We're getting better at it, but there's still a lot of room to grow in terms of the diversity in our clinical trials and who we include to look at.

Click here for more coverage of CMSC 2023.

Transcript edited for clarity.

Editor's Note: Carolyn H. Goldschmidt disclosed relations with EMD Serono, Genentech, and Novartis (advisory board).

REFERENCES
1. Goldschmidt CH, Glassman J, Ly B,Harvey T,Hua LE. A Retrospective Study on the Effects of De-Escalation of Disease-Modifying Therapy in Patients With Multiple Sclerosis. Presented at: 2023 CMSC Annual Meeting; May 31 to June 3; Aurora, CO. DMT01.