Novartis

May 9, 2019 News by Jose Marques Lopes, PhD

#AANAM – Scoring Tool Helps Identify Patients with RRMS or Transitioning to SPMS, Study Reports

A newly developed scoring tool enables better identification of patients with relapsing-remitting multiple sclerosis (RRMS) as well as those transitioning or already diagnosed with secondary progressive MS (SPMS). The research about that finding, “Validation of the Scoring Algorithm for a Novel Integrative Secondary Progressive Multiple Sclerosis (SPMS) Screening Tool,”…

April 8, 2019 News by Jose Marques Lopes, PhD

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…

April 3, 2019 News by Marisa Wexler, MS

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

When the U.S. Food and Drug Administration approved the disease-modifying therapy Mayzent for relapsing types of multiple sclerosis, it specified in its label that the treatment was for people with clinically isolated syndrome, relapsing-remitting MS, and — importantly — secondary progressive MS 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 , 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.

February 14, 2019 News by Santiago Gisler

Continuous Use of Gilenya for Up to 3 Years Can Lead to 50% Drop in Annual Relapse Rates, Real-world Study Says

Multiple sclerosis patients who began treatment with Gilenya and stayed with it continuously showed a more than 50 percent reduction in annual relapse rates, a real-world study following these people for up to three years found. Gilenya, marketed by Novartis, is an oral disease-modifying treatment for relapsing-remitting multiple sclerosis , approved in 2010. It acts by binding and modulating receptors — called sphingosine-1-phosphate receptor — on lymphocytes (adaptive immune cells). By binding to these receptors, Gilenya prevents lymphocytes from leaving the lymph nodes and reaching the brain and spinal cord, and so lower lymphocyte-induced inflammation and damage. Although several clinical trials have reported reduced annualized relapse rates (ARRs) upon treatment with Gilenya, few long-term real-life studies have examined the relapse rate reductions over a long term. A team, led by Novartis researchers and a scientist at Central Texas Neurology Consultants, collected MS patient data from the MarketScan database, a U.S. claims database including medical and pharmacy claims (bills submitted to health insurance providers), between 2009 and 2016. Among 9,312 MS patients in the database with at least one filled Gilenya prescription, 1,599 adults (mean age, 46) met the study's inclusion criteria, including having at least one inpatient or two outpatient claims, and a total of four years of continuous health plan enrollment. Among these 1,599 patients, all used Gilenya for one year (cohort 1), 1,158 (72.4%) took Gilenya continuously up to the start of year two (cohort 2), and 937 (58.6%) used the therapy up to the start of year three (cohort 3). Baseline analysis — measures taken at the study's start — showed that the most common MS-linked symptoms were disorders of the optic nerve and visual pathways (reported in 22-24%), followed by fatigue/malaise (20-21%). Hypertension (20-21%) and depression (15-16%) were the most common physical and mental comorbidities, respectively. The mean annualized relapse rates (AARs) at baseline in these three groups of patients — cohorts 1 to 3 — ranged between 0.48 and 0.51. A consistent reduction in ARRs was seen in all three groups: cohort 1 had a 0.25 ARR at the close of the first year, for a 51% reduction from the baseline rate; cohort 2 a 0.22 ARR at the start of year two, for a  54% lowering in relapse rates from baseline; and cohort 3 had 0.23 ARR at the third year, amounting to a 53% reduction. As expected, when researchers calculated ARRs among patients with continuous Gilenya use over these three years, they found a greater reduction in annual relapse rates. Mean ARRs in continuous-use patients were 0.19 (a 61% reduction) during the first year, 0.18 (a 62% reduction) during the second year, and 0.18 (a 61% reduction) at the start of the third year. “This retrospective claims database study found that patients with MS who received fingolimod [Gilenya] therapy experienced a durable and sustained reduction in relapse rates over a 3-year period,” the researchers wrote, with findings representing “a durable reduction in relapse rates by [more than] 50%.” Reasons that some patients discontinued treatment were not a focus of this study, they added.

January 29, 2019 News by Patricia Inacio, PhD

Gilenya Better at Lowering Relapse Rate than Tecfidera or Aubagio, Study Suggests

Gilenya is linked to significantly lower annualized relapse rates in relapsing-remitting multiple sclerosis (RRMS) patients compared to Tecfidera or Aubagio, a study suggests. All three therapies showed similar effects on disability outcomes. Oral immunotherapies — including Novartis’ Gilenya, Biogen’s Tecfidera, and Sanofi Genzyme’s Aubagio — are currently standard therapies for RRMS treatment. But while these therapies are highly effective at modulating MS activity, studies comparing their efficacy on relapse and disability are missing. This is an important point for MS patients, so that if a change in oral therapies is needed (due to lack of tolerance, for example), the decision on a more suitable therapy is based on scientific evidence. To address this matter, a group of researchers used the MsBase, an international observational MS cohort study, to identify RRMS patients who had been treated with Gilenya, Tecfidera, or Aubagio for at least three months. The team compared Tecfidera versus Aubagio, Gilenya versus Aubagio, and Gilenya versus Tecfidera, specifically for the therapy’s impact on relapse activity, six-month disability worsening or improvement, and persistence of treatment. Relapse was defined as the occurrence of new symptoms or exacerbation of existing ones for a period of over 24 hours, at least 30 days after a previous relapse. Disability was assessed using the Expanded Disability Status Scale (EDSS); the six-month disability worsening or improvement were defined as an increase or a decrease by one value in EDSS. The study included 614 patients treated with Aubagio, 782 with Tecfidera, and 2,332 with Gilenya. Patients were followed over a median of 2.5 years. Patients’ characteristics at baseline differed among the three groups. Aubagio-treated patients tended to be older, with longer periods of disease, fewer relapses, and lower EDSS scores compared to the other two groups. Patients treated with Gilenya had higher EDSS and more relapses during the prior year, compared to those treated with Tecfidera. The majority of the patients had been treated with other immunotherapies prior to being given one of these three oral treatments. Results showed that Gilenya-treated patients had significantly lower annualized relapse rates than those treated with Tecfidera (0.20 versus 0.26) or Aubagio (0.18 versus 0.24), while patients taking either Tecfidera or Aubagio had a similar rate. However, during the 2.5-year period analyzed, researchers found no differences in disability accumulation or disability improvement among the three therapies. Regarding treatment persistence, Tecfidera and Aubagio were more likely to be discontinued than Gilenya. Overall, the results suggest that treatment with Gilenya may have a greater impact on relapse frequency in RRMS patients compared to Tecfidera and Aubagio, although the "effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment," researchers said. “Choosing a therapy in individual patients remains a complex task that requires thorough and individualized evaluation of disease prognosis, and the corresponding risks and benefits of the increasing number of available therapies,” they concluded.

December 4, 2018 Columns by Ed Tobias

How Worried Should We Be About MS Medication Side Effects?

Over the past couple of weeks, two warnings have been issued about side effects of multiple sclerosis (MS) medications. First, the U.S. Food and Drug Administration warned about a slight risk of seriously worsening MS symptoms if someone who is using the disease-modifying therapy (DMT) Gilenya (fingolimod) stops using…

November 27, 2018 Columns by Ed Tobias

FDA Warns of Possible Dangers of Stopping Gilenya

If you are being treated with Gilenya, take note. The U.S. Food and Drug Administration is warning that if you stop using Gilenya (fingolimod), there’s a chance your MS could become worse. The FDA issued a safety alert saying that this only happens rarely, but when it does, the…

 

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