Thomas Leist, MD, PhD, Director of the Comprehensive Multiple Sclerosis Center and Professor of Neuroloy at Thomas Jefferson University Hospital, discusses the changing MS therapeutic landscape, the challenges of selecting an optimal treatment regimen, and his impressions on the future of treatment.
: With the addition of 2 recently FDA-approved agents so far in 2019, what are your impressions of the changing multiple sclerosis (MS) treatment landscape?
Leist: Siponimod, a recently approved second-generation S1P [sphingosine-1-phosphate] receptor agonist, has a shorter half-life and is more lipophilic than fingolimod, the first S1P receptor agonist that was approved. With an initial dose titration, a first dose observation that is mandatory with fingolimod is reserved for individuals with certain risk factors. Siponimod was specifically studied in secondary progressive patients. Despite this, the FDA has given it a broad indication that includes CIS [clinically isolated syndrome], RRMS [relapsing-remitting MS], and active secondary progressive MS. On the other hand, the FDA approval does not include secondary MS without disease activity, likely due to the fact that the clinical effect of siponimod appears to be more muted, based on the clinical results of the phase 3 trial in this population.
The second agent that was approved this year is oral cladribine. Unlike other MS disease-modifying therapies, [this] medication is given in short annual courses. Cladribine leads to selective depletion of peripheral lymphocytes, followed by gradual recovery of B and T cells. The aspiration of this treatment approach is that repopulation favors B and T cells that are naïve and not self-reactive.
About 1 year ago, I expected at least 1 of the oral medications to go generic, [but] this has not occurred. At the recent ECTRIMS [European Committee for Treatment and Research in Multiple Sclerosis] meeting, data from successful phase 3 trials of ofatumumab and ponesimod were presented, and ozanimod is currently under regulatory review, with possible market entry in late first quarter or early second quarter 2020.
: Can you discuss the increased emphasis on timely intervention and the implications for clinical trial design?
Leist: As noted, there are now agents with different modes of action available for the treatment of relapsing forms of MS, including patients with a first attack and with additional evidence of characteristic CNS [central nervous system] lesions. It is difficult to justify placebo cohorts in longer and later-stage MS trials, as patients assigned to the placebo cohort carry, in my opinion, a greater risk-burden than necessary to evaluate the efficacy of a new agent. The field is not necessarily interested in new agents that cannot surmount a minimal degree of efficacy. Once agents have been shown to be more efficacious than currently marketed products, the benefits of such enhanced efficacy need to be readily accessible to patients with the condition. Placebo cannot be justified in phase 3 and probably also phase 2 trials in relapsing forms of MS. It is also difficult to justify the step approach applied by many payers to require patients to fail certain treatments—that is, to incur the risk of enduring consequences of potentially avoidable inflammatory events in the CNS before they can access more effective therapies [in] a disease where the benefit of effective early treatment has been demonstrated across numerous studies.
: Given the number of therapies available for the treatment of MS, what are some of the challenges of selecting a regimen?
Leist: Although there is an increasing number of treatments, access to them may not be equal. Particularly in patients with less favorable characteristics at presentation, first-line access to highly effective therapies would afford patients a better chance for a successful long-term outcome. With an increasing number of medications, it is important to consider whether a patient had already been treated with a given mode of action. A patient who experienced breakthrough disease on one product is unlikely to respond to another product of the same mode of action.
: What are your impressions of the FDA’s recent inclusion of the first attack (CIS) as part of its classification of relapsing forms of MS, and how much do these classifications matter from a treatment perspective?
Leist: Trials completed in patients with a first demyelinating event and evidence of additional lesions in the CNS have uniformly proved that early treatment beats a wait-and-see approach. I don’t think that the FDA changed its approach to relapsing forms of MS, but calling out CIS more specifically formalizes the agency’s position that a first demyelinating event is the initial clinical manifestation of MS or, at minimum, a significantly increased risk of developing MS. I interpret it as the agency’s acknowledgement of the 2017 McDonald criteria. Patients with a first demyelinating event and no additional lesions on brain MRI [magnetic resonance imaging] have a 1-in-5 chance of developing MS. One characteristic lesion increases the risk to about 1 in 2, and when 2 or more lesions can be demonstrated, the risk is about 90%. Patients with a first event and demonstrating enhancing and nonenhancing lesions meet 2017 McDonald criteria, provided there is no alternate cause.
: Based on the current landscape of research and drug development, how do you expect the MS treatment spectrum to change over the next several years?
Leist: It is probably the majority view that MS is a syndrome and not a single disease. The current emphasis on relapsing-remitting, secondary progressive, and primary progressive MS is limited by the fact that these are phenomenological and not biological categorizations. It is very possible that there are unappreciated characteristics that would allow for the subcategorization of patients that could more favorably respond to a certain treatment mode of action. The evolution of treatment approaches of oncologic conditions serves as an example. Without the ability to personalize treatment approaches, patients will likely have to step through generic medications before they gain access to the higher-efficacy newer agents. This is concerning, as early effective management of MS affords patients better long-term outcomes. What is lost, in reality, cannot be regained.