CIS

FDA Approves Kesimpta, B-cell Targeting Therapy for Relapsing MS

The U.S. Food and Drug Administration (FDA) has approved Novartis‘ Kesimpta (ofatumumab) as a self-administered treatment for adults with relapsing forms of multiple sclerosis (MS), meaning those withĀ clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary progressive MS (SPMS). According to Novartis,…

Novel MRI Marker Better at Predicting MS Progression, Study Reports

A large retrospective study suggests that a magnetic resonance imaging (MRI) marker ā€” called ā€œbrain atrophied T2 lesion volumeā€Ā ā€” could help predict the timing of multiple sclerosis (MS) progression. According to the study, this marker was the only MRI parameter capable of predicting disease progression, compared with other…

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

When theĀ U.S. Food and Drug Administration approvedĀ the disease-modifying therapy Mayzent forĀ relapsing types of multiple sclerosis, itĀ specified in its label that the treatment was for people withĀ clinically isolated syndrome, relapsing-remitting MS, and ā€” importantly ā€”Ā secondary progressive MSĀ provided they have "active" disease. The approval is good news, an MS researcher and physician saidĀ toĀ Multiple Sclerosis News TodayĀ 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. ā€œIt's the first time that I've seen in the MSĀ field that regulatorsĀ made an approval designation ā€” activeĀ secondary progressive MS ā€” based on an underpowered subgroupĀ analysis,ā€ saidĀ Robert Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. Novartis'Ā medication, as a first oral therapy approved in the U.S. forĀ a form ofĀ SPMS,Ā is a big step forward in MS treatment, he said. But details of the FDA's decisionĀ caughtĀ him off guard. Fox served on the steering committee for the EXPAND Phase 3 clinical trial ,Ā on which the FDA decision was largely based.Ā His clinic was also one of the sites treating and evaluating patients in this pivotal study. Results of the EXPAND trial showed thatĀ Mayzent could reduce the risk of disability progression at three months (the trialā€™s primary endpoint, or goal) by 21% in treatedĀ SPMS patients, compared to those given aĀ 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,Ā alsoĀ decreased the annualized relapse rate by 55% and improved cognitive processing speed in all treated patients.Ā  ā€œWhat 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,ā€ Fox said. ā€œIt's a statistical concept ā€” obviously patients either progress or they don't progress ā€” but on an overall basis there was a 21% slowing in the rate of progression of clinical disability.ā€ The FDAā€™s decision is particularly important for SPMS patients. While Ocrevus (ocrelizumab) alsoĀ 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. ā€œReally, this is the only drug that's been found to be effective in secondary progressive MS," he said. ā€œTo that degree, it stands alone.ā€ That's why two points in the FDA's decisionĀ surprised him. The firstĀ is the label's specific mention of clinically isolated syndrome. CISĀ is defined asĀ theĀ first clinical presentationĀ of this diseaseĀ ā€” aĀ neurological episode that lasts at least 24 hours, and is characterized by inflammatory demyelination (the loss of myelin, the protective coat surrounding neurons). Ā  For clinicians like Fox, CIS is a first manifestation of MS ā€” a kind of "mono sclerosis."Ā Since thereā€™s only one documented attack, it canā€™t yet be considered multiple sclerosis, ā€œas the multiple hasn't happened,ā€ Fox said, but many "in the field consider CIS to be ā€¦ an early stage of MS." ā€œIf 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,ā€ he said. Regulatory bodies like the FDA,Ā however,Ā 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. Ā  ā€œIt's the first time I've seen them approve for CIS specifically when there wasn't a trial in CIS,ā€Ā Fox said. ā€œI agree with it ā€” I don't have a problem with it ā€” it just surprised me that the regulators were so progressive in their appreciation of MS.ā€ The second ā€” and far more unsettling ā€” surpriseĀ wasĀ the FDAā€™s decision toĀ only approve Mayzent for ā€œactiveā€ SPMS patients, instead of all SPMS patients. This decision didnā€™t come out of nowhere, he noted, but it remains puzzling in the context of the EXPAND trial.Ā  InĀ compiling trial results, investigators did a subgroup analysis ā€” as they often do, almost as an aside for research reasons ā€” and found more favorableĀ responses to Mayzent treatmentĀ in patients with active inflammation beforeĀ the trial's start, those it determined to be with "active" disease. Ā  ā€œThere 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,ā€ Fox said. This certainly does suggest that Mayzent can be more effective in people with active disease ā€” 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. Ā  ā€œWhat's important is that the trial was powered for the overall outcome. It was not powered for subgroup analysis,ā€ Fox said,Ā considering this a crucial point.Ā  In clinical studies, being ā€œpoweredā€ refers to theĀ enrollingĀ of whatever specific number of participants a study needs to ensureĀ itsĀ 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.Ā  In other words, Fox said, the only conclusions that can be drawn from the EXPAND study reliably ā€” with rigor ā€” are based on data drawn from all its SPMSĀ patients, not aĀ subgroup with active disease. This trial ā€œfollowed over 1,600 patients for the clinicalĀ disability. These are purposely powered so that you're not following twice as many people as you need toĀ ā€¦ you're powered for that primary outcome,ā€ he said. ā€œSo, how could they [the FDA] look at a subgroupĀ analysis and make an approval decision based on a subgroupĀ analysis that was underpowered?ā€ The neurologist gave as examplesĀ other subgroup differences found in trial analyses that didn't affect regulatory approval ā€” but to his mind, equally could have.Ā One was an analysis findingĀ female SPMS patients respondedĀ to the therapy better than males,Ā 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 labelĀ toĀ necessarily be an error. "My point is the absurdity of it," he said. "How could they make the regulatory approval based on a subgroupĀ analysis that wasn't powered for conclusions?" He was also particularly troubled becauseĀ the FDAĀ ā€œdidn't define what ā€˜activeā€™ means ā€”Ā is it just a relapse, or is it MRI disease activity?"Ā  For many clinicians, ā€œactiveā€ 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 ā€œobviously, 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.ā€ Mayzent, Fox agreed,Ā is likely to be expensive. The therapy is reported to carry a U.S. list price ofĀ $88,500 a year. ā€œI always have a concern about the cost of these drugs. They're all fearfully expensive,ā€ he said, noting he treats SPMS patients. His focus now is on working to ensure that possible regulatory and financial hurdles wonā€™t pose too much of an obstacle for patients, especially those with SPMS. ā€œI 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,ā€ Fox concluded.