Cleveland Clinic Neurologist Applauds Mayzent’s FDA Approval, But Surprised by Those It May Not Treat

Cleveland Clinic Neurologist Applauds Mayzent’s FDA Approval, But Surprised by Those It May Not Treat

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.

14 comments

  1. Alison Khorasanee says:

    As USUAL, primary progressive MS is completely IGNORED.
    This is why I no longer donate to my State MS Research requests.
    When is ANYONE going to do ANYTHING for people with PPMS???
    I just get weaker, I can’t work, clean my house, take my dogs walking, play my musical instrument, do crafts, do the gardening or even do much local shopping? IS it any wonder suicide is so high among people with MS. Life expectancy is only reduced by a few years, but quality of life expectancy is abysmal. Just asking about we folk with PPMS.

    • Deb Whitmore says:

      My MS has been slowly made me feel the same as you, I can’t cover it up any more, I look ok, but my cognative part is really causeing a lot of not so good thoughts. It’s my illness an I’m tired of all the worthless Meds.

    • Mark Reaney says:

      Actually, Ocrevus has been designated as a treatment for PPMS and has been out for a couple years now. This is the first treatment for SPMS and if the article is correct, perhaps the findings of the study are suspect. Many with SPMSare taking Ocrevus or other treatments for RRMS, just as a shot in the dark, hoping something will help.

  2. RG says:

    While all the other DMT’s are running in the range of $60,000/year I don’t see how you expect them to voluntarily cover a drug at $88,000/year. That means that although there is a new drug to treat SPMS, most won’t really be able to take advantage of it!

    I realize a lot of R & D money went into developing Mayzent but for you to prove it works in the general population, get more units of it out there and be paid for it, change over physician’s views to prescribe it – you must put the cost in line with the other DMT’s!

    • Stephen says:

      RG you can bet that this drug will NOT come down 10 to 15 thousand dollars to be in line with others but you can be assured that all the rest will have no problem increasing their price to set a new entry standard for all existing and upcoming DMT! Take care.

  3. Therese De Serto says:

    Wouldn’t that population be considered primary progressive, since there are relapses with residual disability? My idea of active secondary progressive MS, is what I am living, no relapses but with continual disability progression.

  4. DJ Hartt says:

    This post is more Pharma propaganda with conflict of interests by Dr. Fox paid by Novartis.

    Simply put Mayzent/siponimod does not work in the majority of SPMS as pointed out by the FDA. It works 21% above placebo for reducing progression at a “whopping” 3 months. This 21% of SPMS is made up of all SPMS, including the small subgroup of active SPMS who skew the results in siponimod’s favour.

    One should take FDA’s statement (“in the subgroup of patients with non-active SPMS, the results were not statistically significant.”) very seriously before you pay for this ripoff clone of fingolimod/Gilenya, which is also owned by Novartis, who cancelled its trials in progressive MS second to its expiring patent.

    As far as R+D costs, this is non-sense as well. All these drugs are recycled pre-existing drugs maybe with a slight modification from other fields (rheumatology, dermatology, GI, oncology) astronomically marked up to profit off of MS patients while providing false hopes.

    I would pay anything for something that works but immunosuppressive B and T-cell medications simply do not work or works very little in progressive MS.

  5. Christina says:

    I too stopped donating to my local MS chapter. After all these years, they have only come out with one medication for progressive MS. Our quality of life is reduced significantly especially for progressive MS. In addition, my daughter is suffering bc I cannot do what I want. And, they think we have the funds to donate with our SSI check? Really, are you kidding? How about they find something else in addition to ocrevus for progressive MS and then we can talk.

  6. Kathy says:

    Hi I’ve had MS for 45 years. Secondary progressive for about 15 – 20. Therefore drugs, Avonex/betaseron that I only took for 2 years but discontinued due to onset of SPMS. I tried to get into the Siponimod trial but was turned down because they felt that I was progressing too slowly. During the last 10 years, I’ve progressed from walking with no aids to two crutches. Different perspectives, for some it is slow but – it is progressing.

  7. Dale Degraffenreid says:

    I agree with DJ Hartt. The more I read from the MS Society. it is apparent the big pharms and FDA are twins and they do not intend to find a cure when the medications are so expensive. It is a big come on at the public expense.

  8. Dave Uherek says:

    I would say that stem cell therapy might be an option today. However, this is done overseas (Russia or Mexico?) However only shown to be about 70% effective, it fairs better than just sitting around staring at the wall,succumbing to this slow death of a disease called MS. Any thoughts? Of course it is an out of pocket expense. It might be better, if the FDA was not so bloody slow! Please absolutely no suicide here. We have to be strong as possible and do what we can for GOD and our families. Do your best to hang in. GODSPEED. DCU

  9. Bernice says:

    I have had MS a long, long time, but I came from parents with many health woes and little medical help. I was finally diagnosed late, 2006 at 55. The doctor that diagnosed me left the clinic and there was little help around my home for me. I worked 27.5 years but the insurance was not great. I did get IVIG infusions and a beginning of Copaxone but I got really sick shortly after that and felt like I was dying. I was prescribed Avonex but had to have a hip restoring operation so went off that. Finally walking after 2 years of a wheelchair, I decided to stop Avonex, being needle weary. The Neuro I was seeing tried to coerce me to go on Tysabri, saying if I didn’t, he would undiagnose me. I left him thinking I could take better care of myself. Unfortunately my ability to walk, cope with pain, and see are flagging. I pray but would really like to get some medical help so I won’t lose my vision. I can’t afford to pay for medication myself, and I doubt the insurance co. will but I would really lie to try Siponimod if it doesn’t cause PML. I don’t know where to start though. I had to leave work in 2006 and you can’t get medicine asst. with Medicare. It is a real catch 22 situation. I get so down and depressed and of course you know what you think of then.

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