Carefully Consider Strategies When Switching Disease-Modifying Therapies for MS

With the rapid growth of disease-modifying therapies (DMTs) for multiple sclerosis (MS), the need to switch treatments is becoming more common. However, this presents challenges, particularly for some specific patient populations such as older patients or those considering pregnancy.

“We’re really fortunate in the MS community, because it really is the only chronic neurological disease where we really have had an explosion of disease-modifying treatments, and I know our colleagues in the movement disorders field and other neurodegenerative diseases look at us with envy,” presenter Jiwon Oh, MD, PhD, FRCPC, said, at the Consortium of Multiple Sclerosis Centers 2024 Annual Meeting.¹

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Clinicians have had a general shift toward earlier treatment and, for some clinicians, more aggressive DMTs early on, according to Oh, a neurologist and medical director of the Barlo MS Program at St. Michael’s Hospital. Additionally, prescribers have had less tolerance for clinically silent disease activity, choosing instead to treat patients regardless of patient-reported disease severity.

“In general, I think it’s safe to say that we’ve become quite aggressive in the MS field, and this is because the scientific evidence is accumulating,” Oh said. “But it’s also because we have so many treatments…it’s a little bit complicated, but also we have the luxury of selecting different treatments and then optimizing [them] when one doesn’t work out.”

Common reasons for switching DMTs include efficacy, safety, tolerability, preference or convenience, family planning, and aging. Although efficacy and safety are typically the most top-of-mind concerns for neurologists, she said considering the patient perspective is also crucial.

“I think as neurologists, we always focus on efficacy and safety because these are kind of like key components of a DMT that really influence decision making,” Oh said. “But in chronic care and in real life, tolerability is probably the determining factor of the effectiveness of the medication.”

With regard to efficacy, Oh said treatment escalation or change is warranted when there is significant relapsing disease activity, including MRI changes. There are numerous treatment guidelines and most recommend an annual MRI or more frequent during treatment initiation or switch. However, there are questions about optimal MRI frequency in patients with aggressive, active MS.

Similarly, most guidelines accept that 3 or more new lesions are enough to warrant switching treatments, although some clinicians may see 1 or 2 as enough to switch DMTs. Higher efficacy DMTs include sphingosine-1-phosphate (S1P) receptor agonists and cladribine tablets. Additionally, monoclonal antibodies such as natalizumab (Tysabri; Biogen), alemtuzumab (Lemtrada; Sanofi), and anti-CD20 agents are considered high efficacy. Moderate/low efficacy therapies include interferon-β agents, glatiramer acetate (GA), and dimethyl fumerate (DMF).

When deciding how to approach a DMT switch, another important consideration is the transition to secondary progressive MS (SPMS). Siponimod may offer one option, and a number of clinical trials with DMTs in remitting MS (RMS) have included a small proportion of patients with active SPMS, showing some benefit. However, more research is needed.

“I say this all hesitantly, just because I think we all know that in the clinic, it’s actually very difficult to pinpoint a time when you think someone has transitioned to SPMS,” Oh said. “There is a move in the field to reclassify the way that we describe MS disease subtypes, so this may be an obsolete point in the near future.”

Additionally, there are many lingering questions about how to handle DMT switches in patients with MS progression independent of relapse activity (PIRA). There are currently no treatments that dramatically alter the trajectory of non-relapsing disease biology, although anti-CD20 agents have seen some evidence of greater effect on PIRA versus an active comparator. However, this still represents a great unmet clinical need, Oh said.

Safety is another common reason for switching DMTs. Progressive multifocal leukoencephalopathy (PML) is a significant concern for patients with MS taking common DMTs. Although PML risk is rare, it is still notable and is sometimes seen with natalizumab, fingolimod (Gilenya; Novartis), and DMF.

Other adverse effects (AEs) to be aware of include liver enzyme elevation or drug-induced liver injury, infections, and, more rarely, immune thrombocytopenia, anti-glomerular basement membrane glomerulonephritis, and severe dermatological or allergic reactions. Oh emphasized that all DMTs have a wide range of potential AEs, highlighting the importance of frequent evaluation and careful management.

Researchers have also found that some agents are associated with higher risks of certain infections. For instance, early in the COVID-19 pandemic researchers found that anti-CD20 agents are associated with a greater risk of severe COVID-19.²

Although often considered secondary to efficacy and safety, tolerability is a major factor determining patients’ long-term compliance, and therefore represents a common reason for switching DMTs. Challenges such as injection site reactions, pain, or flu-like symptoms can all be cause for patients to consider a medication intolerable, in addition to headache, fatigue, mild upper respiratory tract infections, nausea, back pain, and more.

One study in Canada found that between 1996 and 2011, approximately 70% of patients with MS who were taking injectable DMTs discontinued within around 4 years due to tolerability concerns.³

“These are things that we do need to take into account because, ultimately, if it’s a tolerability [and] it makes a person…so miserable that they only take their medication some of the time, then that drug simply is not working,” Oh said. “And this is a very logical reason why you would consider switching to another agent that may not have the same tolerability issue.”

Patient preference and convenience is closely related to tolerability. Considerations for patient preference include dosing, compliance, and lab monitoring requirements. Additionally, Oh said some patients prefer a periodic infusion rather than a daily oral treatment, which can feel like a daily reminder of their disease.

DMT use in patients who are or are planning to become pregnant has a growing body of research, although Oh said more is needed. Some DMTs must be halted or require a washout period prior to conception, such as teriflunomide (Aubagio; Sanofi) and S1P receptor agonists. Others, such as GA, interferon-β agents, and natalizumab can be used during pregnancy and halted at 30 to 34 weeks’ gestation. Some DMTs can be used prior to conception if the timing is not urgent, such as immune reconstitution therapies, cladribine (Mavenclad; EMD Serono), and alemtuzumab (Lemtrada; Sanofi). Finally, anti-CD20 agents can be timed for safe conception.

Reference

1. Macaron G, Newsome SD, Oh J. The era of too many choices: starting and switching multiple sclerosis disease-modifying therapies. Presented at: Consortium of Multiple Sclerosis Centers 2024 Annual Meeting; May 29 to June 1, 2024; Nashville, TN.

2. Simpson-Yap S, De Brouwer E, Kalincik T, et al. Associations of disease-modifying therapies with COVID-19 severity in multiple sclerosis. Neurology. 2021;97(19):e1870-e1885. doi:10.1212/WNL.0000000000012753

3. Melesse DY, Marrie RA, Blanchard JF, Yu BN, Evans C. Persistence to disease-modifying therapies for multiple sclerosis in a Canadian cohort. Patient Prefer Adherence. 2017:11:1093-1101. doi:10.2147/PPA.S138263