Article In Brief
ICER found that siponimod reduced the risk of MS progression and decreased inflammatory disease activity. But the evidence to date does not support the high price of the drug.
Add siponimod (Mayzent) to the long list of multiple sclerosis therapies that are overpriced relative to the benefits they provide. That's the finding of the Institute for Clinical and Economic Review (ICER), an independent organization that assesses the cost-effectiveness of emerging treatments. The nonprofit, which bills itself as a drug-pricing watchdog, evaluates the efficacy, safety, and cost of drugs to determine whether the benefit is worth the money from a societal perspective.
Siponimod, a once-daily tablet, was approved by the US Food & Drug Administration (FDA) in March to treat clinically isolated syndrome, relapsing remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS). It was studied in comparison to “best supportive care” but not compared with other MS treatments.
“The general finding in that report was that overall this class of drugs are overpriced for the benefit they provide,” said Daniel Hartung, PharmD, MPH, an associate professor at the Oregon State University and Oregon Health & Science University College of Pharmacy, who tracks the prices of therapies for MS and other conditions. “Their finding here is consistent with that.”
ICER's review found that the drug reduced the risk of progression, as measured by the Expanded Disability Status Scale, and decreased inflammatory disease activity. However, significant benefits on other mobility measures were not observed; thus, the degree to which it delays progressions is not clear. The drug was studied—but not approved—for non-active SPMS.
In a news release accompanying its approval this spring, the FDA said active SPMS is one of the relapsing forms of MS and clarified for the first time that “drugs approved for the treatment of relapsing forms of MS can be used to treat active SPMS,” although they have not been studied for that purpose.
“Evidence and clinical testimony suggested that siponimod does not have a unique role in therapy for any phenotype of MS, including active SPMS,” ICER said.
To be considered cost-effective by ICER's standard, siponimod would need to cost no more than $12,199 a year to treat people with SPMS overall and no more than $31,996 to treat those with active SPMS. The drug is priced at $88,561, earning it a thumbs-down for cost-effectiveness.
Evidence to date does not appear to justify siponimod's price, said Brian C. Callaghan, MD, MS, FAAN, an assistant professor of neurology at the University of Michigan in Ann Arbor.
“Maybe all the medicines that we use for (RRMS) might also be effective in this (active SPMS) population,” Dr. Callaghan said. “I think that, once again, what is a very small incremental advance in the field is coming with a very big price tag.”
Siponimod Review in Context
ICER's evaluation of siponimod is an expansion of a 2017 report, in which the organization assessed 15 treatments, ranging from the beta interferons—the first disease-modifying therapies for MS—to ocrelizumab (Ocrevus), which was awaiting approval at the time the review was published. ICER found that each of the drugs showed a “high certainty” of clinical benefit.
Alemtuzumab, natalizumab, and ocrelizumab were deemed to be most effective in reducing the number of relapses. Fingolimod, daclizumab, rituximab, and dimethyl fumarate were grouped as second most-effective options; interferon beta-1a, interferon beta-1b, glatiramer acetates, and teriflunomide were considered least effective.
All the drugs reduce disability progression—except for rituximab, for which data were not available—but ICER reported “greater uncertainty” on exactly how well they performed. Alemtuzumab and ocrelizumab were deemed most effective at reducing progression, followed by natalizumab and daclizumab. Another group—dimethyl fumarate, peginterferon B-1a, interferon B-1b and fingolimod—were the next most effective. Teriflunomide, glatiramer acetate and the remaining interferons were the least effective but still better than nothing.
Considering their high costs, however, the MS treatments did not show well in ICER's cost-effectiveness analyses. Only alemtuzumab was considered cost-effective by ICER's standards, although safety issues—its boxed warning includes sometimes-fatal autoimmune conditions, malignancies, and other problems—make it appropriate for only a subset of patients.
ICER's assessment was not surprising in light of the long-running and as-yet-unexplained rise in the cost of MS therapies. The interferon and glatiramer acetate-based therapies have not improved in efficacy over the years but their prices increased by 16 to 18 percent a year between 2002 and 2010 and only slightly less than that in the ensuing years, according to a study by Dr. Hartung published in Neurotherapeutics in 2017.
Dr. Hartung found that eight of 15 MS treatments available that year were priced above $80,000; four were priced between $72,000 and $78,000; and three were priced in the $63,000 to $69,000 range.
Prices have continued to rise and, in this milieu, Novartis drew attention in the financial press for launching siponimod at the (relatively-speaking) low price of $88,500. A March 27 Bloomberg article with the headline “Novartis Makes New MS Drug Cheaper Than Its Older Option” compared siponimod with the current price for fingolimod: “That's about 7.4 percent less than Novartis's Gilenya [fingolimod], the nearly decade-old pill that Mayzent is meant to replace at least in part.”
Indeed, siponimod's price shows that factors that might be expected to influence price—efficacy, route of administration, and class of medication—do not apply to MS treatments. Traditionally, patients and payers justified high prices for biologics on the idea that they worked better and were harder to manufacture than pills.
“I think we need to remind ourselves that, if we're going to have biologics be more expensive than pills, then pills that act in a similar way should not cost as much as biologics,” Dr. Callaghan said. “The pharmaceutical companies win when they come out with a biologic but they also win when they come out with a pill that's competing with biologics.”
Where Siponimod Fits
When ICER's assessment of siponimod was presented at a meeting of its Midwest Comparative Effectiveness Public Advisory Council in May, Jeremy Fredell, PharmD, director of Trend Solutions at Express Scripts, one of the leading pharmacy benefit manager, said he expects all payers to cover siponimod.
However, he expects that the FDA's recent statement that drugs approved for RRMS can be used for active SPMS—and its approval of siponimod to treat relapsing forms of the disease—may change coverage policies.
“Since the FDA kind of brings them all together in one group, it may open up opportunities for us to look at them from a step-therapy perspective,” he said.
Annette M. Langer-Gould, MD, PhD, regional lead for Clinical and Translational Neuroscience at the Southern California Permanente Medical Group/Kaiser Permanente, participated in the meeting as an invited clinical expert. She called siponimod a “fingolimod me-too” drug —both are sphingosine-1-phosphate receptor modulators—developed because Novartis' main patent on fingolimod is due to expire in August.
In discussions with her Kaiser colleagues, she has identified no patient scenario in which siponimod is the preferred treatment.
“I don't see us using it at all at Kaiser because no one can seem to think of a reason they would use it over fingolimod,” she said. “And that drug in and of itself has become much less popular, both here and in Europe, over the last five years.”
The other invited clinical expert, Bruce A. Cohen, MD, chief of neurology at Northwestern University Feinberg School of Medicine, was not happy to hear that step therapy would be used for SPMS patients, who suffer greater disability from relapse than those with relapsing-remitting disease.
“I can tell you that my experience with (step therapy) in a relapsing population is that it's often capricious,” he said. “And that would be a critical issue because if you're treating a population that has secondary progressive disease and you're not using a highly effective therapy in that population, then you're undertreating.”
Dr. Callaghan has served as a consultant for Dynamed for evidence-based reviews. Dr. Cohen receives consulting income from Biogen, Celgene, EMD Serono and receives research funding through Northwestern University from Hoffman LaRoche/Genentech, and Med Day. He owns stock in Abbott Laboratories, AbbVie, and CVS Health. Dr. Langer-Gould has no relevant conflicts of interest.