When the U.S. Food and Drug Administration (FDA) approved the disease-modifying therapy Mayzent (siponimod) for relapsing types of multiple sclerosis (MS), it specified in its label that the treatment was for people with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and — importantly — secondary progressive MS (SPMS) provided they have “active” disease.
The approval is good news, an MS researcher and physician said to Multiple Sclerosis News Today in an interview, but “surprising” in that the FDA’s decision was largely based on a trial that didn’t involve CIS patients and wasn’t focused on responses among particular types of SPMS.
“It’s the first time that I’ve seen in the MS field that regulators made an approval designation — active secondary progressive MS — based on an underpowered subgroup analysis,” said Robert Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic.
Novartis‘ medication, as a first oral therapy approved in the U.S. for a form of SPMS, is a big step forward in MS treatment, he said. But details of the FDA’s decision caught him off guard.
Fox served on the steering committee for the EXPAND Phase 3 clinical trial (NCT01665144), on which the FDA decision was largely based. His clinic was also one of the sites treating and evaluating patients in this pivotal study.
Results of the EXPAND trial showed that Mayzent could reduce the risk of disability progression at three months (the trial’s primary endpoint, or goal) by 21% in treated SPMS patients, compared to those given a placebo. Among those with active SPMS (meaning with relapses), a 33% reduction was observed.
The treatment, an S1P modulator that works in part to keep lymphocytes from entering the brain to trigger inflammation, also decreased the annualized relapse rate by 55% and improved cognitive processing speed in all treated patients.
“What was found, and I think quite clearly found in a large-size study, was that siponimod in patients with secondary progressive MS clearly slowed the progression of clinical disability over the course of the trial,” Fox said. “It’s a statistical concept — obviously patients either progress or they don’t progress — but on an overall basis there was a 21% slowing in the rate of progression of clinical disability.”
The FDA’s decision is particularly important for SPMS patients. While Ocrevus (ocrelizumab) also treats all relapsing MS forms and people with primary progressive disease (PPMS), it’s an intravenous therapy given every six months. Mavenclad (cladribine), approved for relapsing patients in the U.S. just days after Mayzent, is another oral and active disease therapy.
To Fox, Mayzent seemed to reach beyond only those secondary progressive patients with clinically active disease. “Really, this is the only drug that’s been found to be effective in secondary progressive MS,” he said. “To that degree, it stands alone.”
That’s why two points in the FDA’s decision surprised him.
The first is the label’s specific mention of clinically isolated syndrome. CIS is defined as the first clinical presentation of this disease — a neurological episode that lasts at least 24 hours, and is characterized by inflammatory demyelination (the loss of myelin, the protective coat surrounding neurons).
For clinicians like Fox, CIS is a first manifestation of MS — a kind of “mono sclerosis.” Since there’s only one documented attack, it can’t yet be considered multiple sclerosis, “as the multiple hasn’t happened,” Fox said, but many “in the field consider CIS to be … an early stage of MS.”
“If the patient has a whole bunch of lesions on their brain [as seen on an MRI scan] and they had a single clinical event, ah, probably, they have MS,” he said.
Regulatory bodies like the FDA, however, have historically considered CIS to be its own separate entity. That makes this decision doubly surprising, according to Fox, since the EXPAND trial only enrolled patients with SPMS, not CIS.
“It’s the first time I’ve seen them approve for CIS specifically when there wasn’t a trial in CIS,” Fox said. “I agree with it — I don’t have a problem with it — it just surprised me that the regulators were so progressive in their appreciation of MS.”
The second — and far more unsettling — surprise was the FDA’s decision to only approve Mayzent for “active” SPMS patients, instead of all SPMS patients.
This decision didn’t come out of nowhere, he noted, but it remains puzzling in the context of the EXPAND trial.
In compiling trial results, investigators did a subgroup analysis — as they often do, almost as an aside for research reasons — and found more favorable responses to Mayzent treatment in patients with active inflammation before the trial’s start, those it determined to be with “active” disease.
“There was a third of patients who had a relapse in the two years prior to enrollment, and those patients actually had a 30% slowing in disability progression, compared to the 21% overall,” Fox said.
This certainly does suggest that Mayzent can be more effective in people with active disease — but there’s a catch. The trial itself was not designed to make such a distinction. It enrolled SPMS patients regardless of activity, and its priority goal was changes in disease progression across all who were treated with Mayzent or given a placebo.
“What’s important is that the trial was powered for the overall outcome. It was not powered for subgroup analysis,” Fox said, considering this a crucial point.
In clinical studies, being “powered” refers to the enrolling of whatever specific number of participants a study needs to ensure its results will reach statistical significance. More people are redundant and, as such, an unnecessary cost; fewer could mean that trial’s conclusions cannot be supported by rigorous scientific measures.
In other words, Fox said, the only conclusions that can be drawn from the EXPAND study reliably — with rigor — are based on data drawn from all its SPMS patients, not a subgroup with active disease.
This trial “followed over 1,600 patients for the clinical disability. These are purposely powered so that you’re not following twice as many people as you need to … you’re powered for that primary outcome,” he said. “So, how could they [the FDA] look at a subgroup analysis and make an approval decision based on a subgroup analysis that was underpowered?”
The neurologist gave as examples other subgroup differences found in trial analyses that didn’t affect regulatory approval — but to his mind, equally could have. One was an analysis finding female SPMS patients responded to the therapy better than males, showing lesser disease progression. “So why didn’t they just approve it for the females and not the males?” Fox asked.
But, when asked, Fox did not think the label to necessarily be an error. “My point is the absurdity of it,” he said. “How could they make the regulatory approval based on a subgroup analysis that wasn’t powered for conclusions?”
He was also particularly troubled because the FDA “didn’t define what ‘active’ means — is it just a relapse, or is it MRI disease activity?”
For many clinicians, “active” SPMS refers to ongoing inflammation that can be observed on MRI (magnetic resonance imaging) scans. In EXPAND, however, the active subgroup was defined as patients with clinical relapses within two years of being enrolled in the trial. Fox worries about this apparent lack of a regulatory definition of “active” SPMS, since “obviously, the insurance companies are going to seize upon that, and they’re going to look for every way they can to avoid covering it for patients.”
Mayzent, Fox agreed, is likely to be expensive. The therapy is reported to carry a U.S. list price of $88,500 a year.
“I always have a concern about the cost of these drugs. They’re all fearfully expensive,” he said, noting he treats SPMS patients.
His focus now is on working to ensure that possible regulatory and financial hurdles won’t pose too much of an obstacle for patients, especially those with SPMS. “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,” Fox concluded.