Exploring Early Treatment Strategies for RRMS: An Interview with Neurologist Daniel Ontaneda

When it comes to initial treatment selection for relapsing-remitting multiple sclerosis (RRMS), there is one question that has yet to be answered: Is it better to start with potentially safer moderately effective disease-modifying treatments (DMTs) or to hit the disease immediately with a high-efficacy DMT that may be more effective but carries more risks?

In a recent opinion article published in the journal Lancet Neurology, Daniel Ontaneda, MD, a neurologist at the Cleveland Clinic, addressed the controversies surrounding early treatment selection for people with RRMS, stressing the variability of initial treatment selection and the weak existing data that guides those choices.

“I think the truth is we don’t have a lot of data to inform that [treatment] decision. Clinicians many times will make that decision based on their overall assessment of how active they think the MS is, also based on patient preferences for medication, how much risk the patient is going to take, and how much risk the physician is going to take as well by prescribing that medication,” Ontaneda said in an interview with Multiple Sclerosis News Today.

The traditional treatment approach for RRMS advocates the use of moderately effective DMTs (also called low-to-moderate therapies, or LMTs) — given as injections in the muscle (intramuscular) or under the skin (subcutaneous), or as oral medications — which generally have good safety profiles.

LMTs are given in escalating steps, where patients are switched to another DMT in the presence of breakthrough disease activity, i.e., relapses or new lesions shown by magnetic resonance imaging (MRI).

The alternative approach to LMTs involves first-line treatment with high-efficacy DMTs (HETs) — all monoclonal antibodies delivered by infusions into the vein (intravenous administration) — with potential exposure to greater risks.

There are four medications currently considered HETs: Tysabri (natalizumab, by Biogen), Lemtrada (alemtuzumab, by Sanofi-Genzyme), Ocrevus (ocrelizumab, by Genentech), and rituximab — an off-label therapy, marketed as Rituxan in the U.S. by Genentech and Biogen, and as MabThera by Roche in Europe.

But the question remains: Which initial treatment strategy is best for relapsing forms of MS?

Two ongoing trials — DELIVER-MS (NCT03535298) and TREAT-MS (NCT03500328) — are aimed at answering this question and providing evidence that will ultimately help doctors and patients in this decision-making process.

“What we’re trying to do here is get across that treating MS shouldn’t be left to chance, and if you develop MS, one hopefully would expect you to have similar treatment irrespective of what doctor you go to or what center you go to,” said Ontaneda, who is the lead investigator for the DELIVER-MS trial.

Variability of early treatment choices

Daniel Ontaneda, a neurologist with the Cleveland Clinic, is leading the DELIVER-MS trial. (Photo courtesy of Cleveland Clinic)

To decide which treatment to start with, doctors use “a combination of MRI, clinical characteristics, and how much risk the patient is willing to take, and we make a decision based on all those factors,” Ontaneda explained.

“So it’s not like an algorithmic approach where a patient with X, Y, Z characteristics definitely gets started on this or that. It’s very variable,” he added. “The truth is that there’s not a lot of guidance. … The American Academy of Neurology has provided some guidance on how to treat MS, but the recommendations are relatively vague.”

In addition, Ontaneda says, because MS is being diagnosed earlier and earlier, knowing how an MS patient will evolve and which medication is best is sometimes difficult. Several studies informing treatment selection were based on older diagnostic criteria; those predicting factors are useful, but perhaps only several years into the disease, whereas doctors are now assigning treatment as soon as the disease symptoms are identified.

Insurance companies add another layer of treatment variability.

“Many times payers will have step edits, a variable number of rules and algorithms for what patients can use what medications, and many times there’s barriers for the clinicians to say, ‘Oh, I want to use this medication’ and he prescribes it and then the insurance comes back and says, ‘Well, they have to have tried this medication in the past,'” he said.

HETs on the rise

Although a recent study from the Cleveland Clinic, presented at this year’s AAN meeting, showed that first-line use of HETs for RRMS still only represents one-third of initial treatments, their use is on the rise. 

Results showed that in the overall RRMS population, HETs were first used in 2006 by 27.3% of the patients, increasing to 43.8% in 2018 across 10 academic centers in the U.S. and Europe.

Even though safety concerns are still keeping some doctors from initially prescribing HETs, Ontaneda thinks the growing number of prescriptions over the past years has been driven by two main factors.

“One is that clinicians have a growing understanding that treating with high-efficacy therapies early might be a good idea, and there’s an increasing recognition of that. … The other driving factor is that the highly effective therapies perhaps have become a little bit safer or now we know how to risk-stratify patients,” he said.

Ontaneda cited Tysabri as an example of an HET that has been associated with a potentially fatal brain infection called progressive multifocal leukoencephalophathy (PML), which is caused by the JC virus.

“Previously, we limited the use of this medication because we thought everyone was at risk of PML, but what we learned through research is that if a person doesn’t carry the virus and hasn’t been exposed to the virus in the past, the risk of PML is very, very low, so now what we do is we test people for JC virus. If they’re negative, then we can start them safely on natalizumab. So [that] now allows us to use these highly effective therapies in a safer way,” he said.

The safety profile of another HET, Ocrevus, approved as an MS therapy in 2017, “actually looks pretty good,” Ontaneda said, adding that it is natural that doctors will start using it more as a first-line therapy because there’s not that many risks associated with it.

Challenges in defining treatment failure

In the Lancet Neurology article, Ontaneda and his colleagues mention that with the availability of newer and more effective agents, the definition of treatment failure, and therefore, the threshold for escalation, has been lowered.

Most neurologists consider relapses as “a clear indication of treatment failure” and consequently a sign that treatment must be escalated. However, diagnosing relapses can be challenging, making it difficult to determine if a treatment is working or not.

“Once we start a patient on a given therapy, we expect them to be relapse-free and new MRI lesion-free. The truth is that sometimes adjudication of a relapse is a little bit hard, and that’s because there are several factors that can make an MS patient feel and also look worse on neurological examination that don’t represent relapses. This is something we call pseudo-exacerbations or pseudo-relapses,” Ontaneda said.

At times, certain illnesses may look like a relapse, including infections that cause fever and affect neurological function; sometimes even just heat can make MS patients feel worse and look worse, according to Ontaneda.

Conversely, patients could have relapses that don’t manifest as typical relapses. “If the patient is doing well clinically, physically feels well, but all of a sudden notices a drop in their cognitive performance, traditionally we wouldn’t call that a relapse, or by a clinical trial definition, that wouldn’t be called a relapse, but perhaps that is a relapse,” he said.

With the availability of a wider range of treatment choices, doctors are “very vigilant to any kind of breakthrough disease activity, and clinically, it’s just the tip of the iceberg,” he added. “We use mostly MRI for that, and so the amount of new lesions on MRI and enhancement on MRI are both indicators that the therapy perhaps is not working.”

Clinicians also need to be aware that some medications act quicker than others that may take more time before any meaningful effects on disease activity can be detected.

The future of early therapy

The DELIVER-MS and TREAT-MS trials are currently underway to assess the effectiveness of early treatment with HETs versus LMTs as a first-line approach for RRMS.

“As medications move in and out of the market, we wanted to provide an answer that will help patients make decisions more in a global sense, not should we pick medication A, B, C, or D, but what should be our overall treatment philosophy,” Ontaneda explained.

He is leading DELIVER-MS, a multicenter study taking place in the U.S. and the U.K. It is currently enrolling up to 800 RRMS patients, and is expected to end in September 2023.

“What we hope with the study is to do a long-term follow-up, and perhaps learn if we should be treating patients more intensively or not,” Ontaneda said. “Perhaps we are missing an opportunity to treat early and stamp out the disease.”

TREAT-MS intends to enroll 900 RRMS patients at 43 sites across the U.S. and is set to conclude in October 2022.

With both trials running in parallel, researchers will be able to pool the data and power the analysis of the results, as well as explore further comparisons among groups.

Because the primary focus is on efficacy, “we can subset the data back and say, ‘Well, why don’t we compare people who started out low efficacy versus a moderate versus a high efficacy,'” Ontaneda said, or determine “what factors specifically make patient A, B, or C respond to medication A, B, or C, and try to identify treatment response markers in individual patients. We’ll use the data from the trials to answer those questions; they’re very, very important.”

One such potential biomarker is neurofilament light chain (NfL). According to Ontaneda, it is “a very interesting biomarker because … it reveals widespread damage in the central nervous system, especially related to inflammation.”

Yet another potential treatment option for relapsing MS is autologous hematopoietic stem cell transplant (aHSCT), a therapeutic approach Ontaneda considers “a very, very interesting avenue to pursue.”

“The problem that’s been quoted with stem cell transplantation is that it’s a much more involved process, and it carries more risks,” he added. “I think significant advances have been made over the last 10–15 years in decreasing the mortality associated with these procedures … so it’s becoming a more feasible option.”

Nonetheless, Ontaneda believes that most clinicians still consider first-line therapy with stem cell transplant “slightly too risky.”

He points to a trial that will soon launch called BEAT-MS (NCT04047628), which will test the effectiveness of aHSCT versus HETs in patients with relapsing MS who have refractory, or treatment-resistant, disease.

Recruitment is not yet open, but is planned for two U.S. centers, the Cleveland Clinic Lerner College of Medicine in Ohio, and Fred Hutchinson Cancer Research Center in Washington.

“I think the key in that study is to look at what the safety outcomes look like. The question is when is the trade-off of safety OK,” Ontaneda said. “Hopefully, the trial will … provide some clear evidence in patients who have refractory disease.”