Mayzent ‘Will Change Lives’ of MS Patients Transitioning to SPMS, Novartis Says

Mayzent ‘Will Change Lives’ of MS Patients Transitioning to SPMS, Novartis Says

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 FDA’s decision was largely based on results of the international Phase 3 EXPAND clinical trial (NCT01665144), “the largest-ever conducted study in a very typical SPMS population,” Bar-Zohar said.

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 — S1Pand 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.”

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has studied Biochemistry also at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario, in London, Ontario. His work ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has studied Biochemistry also at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario, in London, Ontario. His work ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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  1. Larry williams says:

    MS drug prices continue to be too expensive for most patients, especially when over 65 and on Medicare which does not cover these costs, way to expensive

  2. DJ Hartt says:

    Thanks for this biased commercial this time by Novartis and its associated neurologists with massive COI. They have not come up with a meaningful treatment for the majority of SPMS, who do not have relapses. Prevention of relapses does not equal prevention of progression of MS.

    Simply put the massively overpriced Mayzent/siponimod does not appear to work in the majority of SPMS at stopping progression as pointed out by the FDA. It works 21% above placebo for reducing progression at a “whopping” 3 months and 26% at 6 months. This 21% of SPMS is made up of all SPMS, including the selection bias subgroup of active SPMS who skew the results in siponimod’s favour (active SPMS group 33% reduction of progression above placebo). Does anyone think it is an accident that they chose “relapsing or active” SPMS for their trial to have a positive outcome?

    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.

    If someone has “active” SPMS or late RRMS, then why not take any more effective MS drug like alemtuzumab, ocrezulimab, cladribine or even fingolimod, which works in the same manner as siponimod?

    • Sandra C. Williams says:

      With regard to comments about drug companies, please consider that businesses are in the business of making money and are accountable to stockholders. R & D (research and development) costs for drug companies are extremely high, and must be recovered in order to continue research and production.
      Government grants for scientific research in settings such as university hospitals began drying up years ago. If not for free enterprise or philanthropy, how far we would be toward new treatment options, and, perhaps one day, a cure?
      Personally, I am thankful that research continues, and breakthroughs are made, providing hope for many.
      Thank you for considering another perspective.

    • Jukka OLLGREN says:

      The power issue is very clear: everybody knows that it is much more easier to treat active SPMS than overall SPMS, so this subgroup, what ever is the exact definition, is powered nearly automatically because the effects are greater and relatively more events. It is quite natural that in some groups the treatments effects differ from each other compared with “placebo”. Probably the active disease effects are quite robust even if the exact definition the active group changes somewhat. In the data observed power is in monotonic relatioship with p-value. Power has nothing to do with the concept of bias.
      In the non-active subgroup the point estimates are so low that NNT=”numbers needed to treat” for the most outcomes are clearly over 10 then, maybe over 20 or more. The active subgroup analysis here has nothing to do with p-value phishing.

  3. Sandra C. Williams says:

    $88,000 annually, and Medicare patients (65 and older) will not be covered by insurance. Really? What an absurd and obscene situation!
    After nearly HALF a CENTURY of working, building businesses and making regular contributions to government systems to fund my retirement benefits, now that I need them I’m to be told they won’t pay??!? — Translation: Too old to be of value?
    How many members of congress (with their own ‘special insurance and benefits’) are over 65 now, or approaching that age?
    An elite group of elected individuals who live under a different set of standards should not be allowed to decide the value of citizens lives.

    • KIM FLORES says:

      I COMPLETELY AGREE WITH SANDRA C WILLIAMS!! I am currently still working to pay for my nearly $9000 per year insurance payment that does not cover my Ocrevus.

  4. Tim Niccum says:

    Their is money available from the drug companies. All you have to do is talk too the right person. I have had MS for over ten years and have Never paid out of pocket for any drug that I have taken.

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