The “regulatory environment” favored Mayzent (siponimod) being approved as an oral treatment for people with relapsing multiple sclerosis (MS) — specifically, clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive MS (SPMS) — a top executive with Novartis said, although the pharmaceutical company had requested a label covering all with SPMS.
Dan Bar-Zohar, MD, global head of neuroscience development at Novartis, emphasized that he was not “disappointed” with the label chosen by the U.S. Food and Drug Administration (FDA) on March 26, because it will benefit a key group of MS patients — those “who are at early SPMS, those who are transitioning or just recently transitioned. And the vast, vast majority of them are active.”
“I wholeheartedly believe that it will change their lives,” Bar-Zohar said in an interview with Multiple Sclerosis News Today.
The study included 1,651 SPMS patients (mean age of 48), all with evidence of disability progression in the prior two years. Compared with people in pivotal RRMS studies of MS treatments, EXPAND patients were “by far older and by far more disabled,” making Mayzent’s effectiveness stand out. Up to 80% of RRMS patients are estimated to progress to SPMS. (Those in this trial had Expanded Disability Status Scale, or EDSS, scores — which quantify disability — of 3 to 6.5 on a scale that starts at zero and peaks at 10.)
“This makes the population unique — other drugs have either not tried to go to that population, or tried and failed,” Bar-Zohar said.
Mayzent’s success likely reflects its dual way of working: that of sequestering circulating lymphocytes — which can promote brain inflammation — within lymph nodes and away from the central nervous system, and that of “avidly” entering the brain to modulate (stop from “acting” in inflammatory and myelin-damaging ways) two sphingosine-1-phosphate receptors — S1P1 and S1P5.
Breaking the ‘circle of denial’
Overall, EXPAND trial results showed Mayzent treatment lessened the risk of disability progression at three months in SPMS patients — its primary endpoint, or goal — by 21% compared with placebo, and significantly improved their cognitive processing speed at 24 months.
“Cognitive processing speed is extremely important in SPMS, and we showed magnificent data again for the first time,” Bar-Zohar said.
But in a subgroup analysis, SPMS patients with active disease — those with a relapse in the two years prior to screening, or with an inflammation-related lesion seen on a magnetic resonance imaging (MRI) scan — showed greater reductions in disability progression at three months — 33% and 36% respectively — “something very substantial,” Bar-Zohar said.
At six months, the risk of disability progression was 26% lower overall with Mayzent than with a placebo. The therapy also decreased the annualized relapse rate — the number of confirmed relapses per year — by 55%. Such reductions, also seen in active brain lesions, were already evident in the Phase 2 BOLD trial (NCT00879658) in RRMS patients, supporting Mayzent’s approval for people transitioning from RRMS to SPMS.
In contrast to active disease, three-month benefits in non-active SPMS patients — 13% in people with prior relapses, and 18% in those with a MRI lesion — were not statistically significant.
Still, the FDA’s decision to cover only active-disease SPMS patients surprised Robert Fox, MD, a neurologist at the Cleveland Clinic who served on EXPAND’s steering committee.
Fox, too, didn’t oppose the agency’s specifications. But in a recent interview, he spoke at length about how the subgroup analysis was underpowered, meaning the study was not designed and did not have enough patients to test such differences. Fox was also troubled by the FDA’s lack of a definition for “active” disease, asking, “Is it just a relapse, or is it MRI disease activity?” He voiced concern about how this lack might affect insurance coverage.
Bar-Zohar agreed such analyses were underpowered, but didn’t think that an overriding concern. Rather, as he emphasized, “when we zoom out, I do think and we wholeheartedly believe, that the patients who will benefit really the most … are those who are at early SPMS, those who are transitioning or just recently transitioned. And the vast, vast majority of them are active.”
Besides, “a patient who was not active in the last two years can become active tomorrow morning; it’s not that clear-cut.”
Neurologists well understand the two ways of determining active SPMS, Bar-Zohar added. In fact, a revised classification of MS has defined active disease since 2013 as “either clinical activity in the form of a relapse, or imaging activity in the form of a clinically silent relapse” seen on an MRI. Its first use was in the European label given Lemtrada (alemtuzumab, by Sanofi-Genzyme) in late September of that year.
“What’s mostly important here,” he said, is that “everything in terms of the subgroup analysis … goes in the right direction, everything favors siponimod [Mayzent]” to give crucial support to “the internal consistency of the data when we run such a huge study.”
Overall, Bar-Zohar thought Mayzent’s success parallels a considerable change in pinpointing SPMS onset. Previously, RRMS patients would be diagnosed when their EDSS score climbed to about 6, he said, a point where there’s little disease activity. Now, researchers and doctors “know” that between 70% and 80% of RRMS patients have signs of secondary progression at a much lower disability level, an EDSS of 2 to 3, he said.
“These are the patients that are almost exclusively active, and these are the patients in which the efficacy of Mayzent has been shown.”
This also represents a major shift in how such patients are treated, Bar-Zohar said. People in transition are either “treated with drugs that actually have not been tested in secondary progressive MS … [a] brutal truth,” or not re-diagnosed and treated at all. They were “in a sort of circle of denial between themselves and their treating physician, because nobody wants to be declared as having something that has few [treatment] options.”
Another tough truth is that “we cannot revive neurons,” Bar-Zohar said. “We must diagnose, identify the patient as early as possible, and treat with the appropriate therapy.”
Still, Bar-Zohar said, Novartis is pursuing a broader label in Europe “because the study in general met its primary endpoint in a very convincing manner.”
Novartis is also addressing concerns regarding insurance coverage. “We will spend the next few months, maybe more than a few months, in education,” Bar-Zohar said, “making sure that we are on the same page on what activity means, but also in terms of education of the payers, and to show them the data.”
Benefits versus cost
Mayzent comes with a list price of $88,500 yearly, well above the $12,000 annual cost limit that the Boston-based Institute for Clinical and Economic Review (ICER) determined appropriate to hit a cost-effectiveness threshold of $150,000 per added year of health, a measurement called QALY (for quality-adjusted life years). At $150,000 QALY, this works out to $995 a month, or just under $12,000 a year, ICER reported in March.
That annual figure is 87% lower for Mayzent than the price Novartis chose, Bloomberg reports.
Kathy Costello, associate vice president of healthcare access at the National Multiple Sclerosis Society, called this list price “still too high” and said Novartis “missed an opportunity to continue the downward trend started by the last new entry to the market.”
Ocrevus, by Genentech (part of the Roche Group) and FDA-approved to treat both relapsing MS forms and primary progressive MS, has held to its $65,000 yearly price since its 2017 entry. But Ocrevus is an intravenous infusion, and not an oral therapy, which might make it less attractive.
In relation to other oral therapies for relapsing MS, Bar-Zohar said, Mayzent was “priced … at the relatively lower end … or maybe even the relatively very low.”
These include Gilenya (fingolimod), also by Novartis, which Bloomberg notes carries a 7.4% higher annual price than Mayzent — and expects to face generic competition within five years.
“I wholeheartedly believe that we priced it responsibly and based upon the value in SPMS patients,” Bar-Zohar said, adding that the company is in close contact with ICER, but is concerned that the watchdog group’s focus is on best-supportive care, which is “a bit problematic” in active SPMS because most patients are being treated with relapsing MS medications.
Added Fox, “I don’t know what the insurance companies are going to do with this, but I’m hoping that it is available for my patients, and I say that as their clinician.” Whether $88,500 “is too much or appropriate, I really don’t know.”