NASHVILLE -- There were no available drugs for multiple sclerosis (MS) 25 years ago. Today, 18 disease-modifying therapies (DMT) have been approved to treat the disease.
The dramatic and rapid shift in the treatment landscape has brought with it questions and controversies about how the therapies can best be utilized to continue to improve MS outcomes and, possibly, stop the disease in its tracks.
Patricia Coyle, MD, of Stony Brook University Medical Center in New York, addressed several areas of ongoing controversy, including when certain patients should start therapy, in a presentation at the Consortium of Multiple Sclerosis Centers (CMSC) annual meeting.
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"We have entered the age of personalized medicine where we make individualized patient treatment decisions every day," Coyle said. "But we are not yet in the era of precision medicine, so there are some ongoing debates, including which disease-modifying treatment is best for the [individual]) patient. I think we will need precision medicine to tell us that."
MS is the only neurologic disorder with established DMT, including injectables (six glatiramer acetates; five interferon betas), orals (teriflunomide, dimethyl fumarate) and intravenous -- the monoclonals natalizumab (Tysabri), alemtuzumab (Lemtrada), ocrelizumab (Ocrevus) and the chemotherapy agent mitoxantrone.
All were approved for relapsing forms of MS and in 2017, ocrelizumab became the first agent also approved by the FDA for primary progressive MS (PPMS).
The American Academy of Neurology (AAN) recommend offering a DMT to all newly diagnosed patients with clinically isolated syndrome (CIS) and two or more brain MRI lesions (level B evidence), and patients with relapsing MS and recent relapses or evidence of MRI activity (level B).
Coyle said there is little debate about offering DMT to these patients.
"But much debate remains about whether to treat patients with radiologically isolated syndrome (RIS) and also relapsing forms of MS that have not been active for a long time," she said. "In addition, there is debate about which primary progressive MS patients to offer ocrelizumab to."
She added that there is also some debate about treating newly diagnosed patients in their late 40s, 50s, or older.
In general, she said, the earlier patients are treated the better because early injury caused by MS to the brain, spinal cord, and optic nerve is mostly silent.
"We know MS involves ongoing, permanent, accumulating damage to the central nervous system and we want to intervene as early as possible to minimize that," she said, adding that virtually all studies comparing outcomes among patients treated early to those receiving delayed treatment show the early-treatment group to be doing better.
But decisions about starting therapy are more complicated for patients who present with brain lesions with no symptoms, as a result of an MRI conducted for reasons unrelated to suspicion of MS, such as head trauma or headache.
First described in 2009, radiologically isolated syndrome (RIS) is very rare, with an incidence of around 0.1%, Coyle said.
About 35% of people with RIS progress to relapsing MS or PPMS within 2-5 years, and risk factors for progression include male sex, age <37, and spinal cord lesions.
People with one risk factor have a 10% progression chance, while those with all three have >80% chance, Coyle said.
RIS is not yet recognized as an MS phenotype, but two phase II randomized, double-blind, placebo controlled trials are underway accessing treatment versus no treatment in patients with the syndrome. The U.S. is comparing dimethyl fumarate to placebo in around 200 patients and the European is comparing teriflunomide with placebo.
"We will see if they can document a benefit of randomization to treatment in individuals who have not yet had any clinical expression of MS," she said.
With regard to PPMS, the AAN guidelines recommend offering ocrelizumab to patients "who are likely to benefit." But "they don't really state who is likely to benefit. They don't define that," Coyle said.
Phase III trials of the DMT excluded patients age >55, and those who with disease diagnosed >15 years prior to assessment. They also required abnormal cerebrospinal fluid, that patients be ambulatory, and that they had no prior relapses.
A post hoc analysis showed no difference in progression between ocrelizumab treatment and placebo among women, but a significant difference among men (30% progression in ocrelizumab group and 43% in placebo group).
Based on the studies, Coyle said it remains unclear if ocrelizumab should be offered to women, non-ambulatory patients, those age >55, those with disease duration of >15 years.
She noted that there is also increasing evidence that older age is a predictor of poorer response to treatment.
In a assessing worsening disability or progression in MS involving 28,000 patients on 13 DMTs, the researchers concluded that there was no benefit to treating the average patient age >53 with higher efficacy DMT.
A prediction model developed by the researchers also suggested that high efficacy drugs outperform low efficacy drugs only for patients < age 40.5.
"This finding is a nightmare in terms of what could happen with third party payers, and I don't believe it is correct," Coyle said. "I don't believe it is true that there is no benefit to treating disability or progression past age 53 and I don't think it is true that efficacy after age 40 or 41 doesn't matter. But it is a provocative finding because it tells us something important -- we want to treat at a younger age if we can."
Primary Source
Consortium of Multiple Sclerosis Centers
Coyle P "DMT Debates: Stopping, Switching, Re-starting" CMCS 2018.