expert roundtables

Emerging Therapies Add to Multiple Sclerosis Treatment Landscape

by Robert A. Bermel, MD, MBA; Malcolm H. Gottesman, MD; and Eric C. Klawiter, MD, MSc

Overview

Additional disease-modifying therapies (DMTs) allow for greater flexibility in considering agents that vary in mechanism of action and route of administration, meaning that there are now more options for more patients with multiple sclerosis (MS).

Q:

How would you describe the current MS treatment landscape? What do you see in store for the future?

Robert A. Bermel, MD, MBA

Director
Staff Neurologist
Mellen Center for Multiple Sclerosis
Cleveland Clinic
Cleveland, OH

The more recently introduced agents enable neurologists and their patients to consider therapeutic categories and mechanisms of action that they would not have considered a few years ago.”

Robert A. Bermel, MD, MBA

The MS therapies that have been developed and approved by the US Food and Drug Administration (FDA) in recent years provide additional options for patients who may have had specific restrictions, limitations, or issues with our existing therapies.

Anti-CD20 or B-cell–depleting therapies are highly effective and quite safe for those with MS. The first of these therapies was approved by the FDA for intravenous administration. The development of ofatumumab, another anti-CD20 agent that can be given by subcutaneous injection, is a welcome advance for certain patients (eg, those with very challenging intravenous access or those with difficulty traveling to an MS center or an infusion center). Along those same lines, patients who require a high-efficacy therapy but have trouble with parenterally administered medications may be candidates for oral medications such as cladribine.

Another therapeutic class that has improved in the last couple of years is the sphingosine-1-phosphate (S1P) receptor modulators, with newer agents such as ozanimod and siponimod emerging. The ability to begin treatment with an S1P receptor modulator without having a first-dose observation visit is a major advantage for many patients.

Thus, the more recently introduced agents enable neurologists and their patients to consider therapeutic categories and mechanisms of action that they would not have considered a few years ago. We are now able to deploy medications in certain patients with MS who otherwise would not have had high-efficacy options. Even if these are therapies that we would not use first line because of their safety profiles, such as in the case of cladribine, they are options for some individuals with MS. With this expanding armamentarium, I think that we are beginning to have effective options for many more patients with MS. There are also some exciting mechanisms under study, with the exploration of Bruton tyrosine kinase (BTK) inhibition, and also potentially more neuroprotective mechanisms; for example, ibudilast is a phosphodiesterase inhibitor that is interesting because it appears to affect markers of neurodegenerative processes rather than inflammatory processes.

Malcolm H. Gottesman, MD

Chief Emeritus, Division of Neurology
Winthrop Comprehensive MS Care Center, NYU Langone Hospital
Professor, Department of Neurology
NYU Long Island School of Medicine
Mineola, NY

“The anti-inflammatory landscape has been fairly well covered with our existing drugs, including the latest arrivals. What we need now is to develop new agents that promote remyelination and act against the degenerative aspects of the disease."

Malcolm H. Gottesman, MD

In general, newer high-efficacy DMTs are appropriate in patients who are newly diagnosed, are younger, and have active disease, and I do believe in a de-escalation paradigm. Natalizumab might be a good initial choice for high-efficacy therapy, but if the patient is JC virus—antibody positive, it is not recommended because of the risk of progressive multifocal leukoencephalopathy. The B-cell depleters are excellent drugs, although they do have contraindications such as hepatitis, tuberculosis, and chronic infection. Additionally, in consideration of the COVID-19 vaccines and/or vaccine boosters, immune reconstitution and getting an effective immune response are things to keep in mind, so the timing of therapy can be important.

The S1P inhibitors are very convenient DMTs, as they are oral and can be taken at home; as we all know, patient acceptability is no trivial matter. Newer agents in this class are being introduced with some rapidity. Patients should be serologically immune to the varicella-zoster virus. These are generally good agents, and I have been impressed with their efficacy.

In general, I think that the anti-inflammatory landscape has been fairly well covered with our existing drugs, including the latest arrivals. What we need now is to develop new agents that promote remyelination and act against the degenerative aspects of the disease. I would like to see the development of an entirely new class of drugs that would allow neuronal repair and remyelination.

Eric C. Klawiter, MD, MSc

Associate Neurologist
Massachusetts General Hospital
Associate Professor of Neurology
Harvard Medical School
Boston, MA

“The expanding number of DMTs has allowed us to have a lower threshold for switching therapies in patients with a suboptimal response to their current DMT.”

Eric C. Klawiter, MD, MSc

Many of the newly approved MS agents belong to previously approved therapeutic classes, but they were developed to have certain modifications, including changes in the mechanism of action or drug delivery, that make their addition notable. There is a need that is met by having more options, even within a class of treatments, as it may allow for the consideration of newer agents within a certain drug class that had been previously excluded or exhausted. For example, some patients have tried a number of different DMTs (eg, patients who may have switched therapies due breakthrough disease or side effects). As a result, they might be left to consider only medications that we would consider in the third or fourth line, but for a more recent arrival, that now becomes an option.

Additionally, the expanding number of DMTs has allowed us to have a lower threshold for switching therapies in patients with a suboptimal response to their current DMT. This has allowed for a general trend in having a lower tolerance for either inflammatory disease activity or disease progression in making therapeutic decisions.

Looking to the future, one potentially new DMT category that is being investigated in phase 3 clinical trials is the BTK inhibitors. At least 3 BTK inhibitors are currently in clinical development for MS, with favorable safety and efficacy demonstrated in phase 2 trials. The mechanism of action of these drugs may have some unique advantages, including the modulation of B cells and their antigen-presenting functions and improved central nervous system penetrance. These molecules represent a new group of treatments as an additional option for the treatment of relapsing, and potentially progressive, forms of MS.

References

Bhargava P, Kim S, Reyes AA, et al. Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition Brain. 2021 Mar 16;awab045. doi:10.1093/brain/awab045

Dolgin E. BTK blockers make headway in multiple sclerosis. Nat Biotechnol. 2021;39(1):3-5. doi:10.1038/s41587-020-00790-7

Kammona O, Kiparissides CK. Recent advances in antigen-specific immunotherapies for the treatment of multiple sclerosis. Brain Sci. 2020;10(6):333. doi:10.3390/brainsci10060333

Khoy K, Mariotte D, Defer G, Petit G, Toutirais O, Le Mauff B. Natalizumab in multiple sclerosis treatment: from biological effects to immune monitoring. Front Immunol. 2020;11:549842. doi:10.3389/fimmu.2020.549842

Naismith RT, Bermel RA, Coffey CS, et al; SPRINT-MS Investigators. Effects of ibudilast on MRI measures in the phase 2 SPRINT-MS study. Neurology. 2021;96(4):e491-e500. doi:10.1212/WNL.0000000000011314

Tong J, Zou Q, Chen Y, et al. Efficacy and acceptability of the S1P receptor in the treatment of multiple sclerosis: a meta-analysis [published correction appears in Neurol Sci. 2021;42(5):2155]. Neurol Sci. 2021;42(5):1687-1695. doi:10.1007/s10072-021-05049-w

Vargas DL, Tyor WR. Update on disease-modifying therapies for multiple sclerosis. J Investig Med. 2017;65(5):883-891. doi:10.1136/jim-2016-000339

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