Why is it so important that Novartis investigated the use of Gilenya in kids with MS ?
“Kids are not young adults”. Perhaps you’ve heard this quote before in another context. It seems obvious to most of us from everyday experience. In medicine there are special hospitals and separate medical specialties just for kids. You would not send your child to a cardiologist, who by lack of the appropriate modifier is assumed to be an adult cardiologist; instead, we have pediatric cardiologists and other kid specialists in fields like gastroenterology, pulmonology and neurology to name just a few.
The field of Multiple Sclerosis (MS) specialists is no exception. In 2006 the Network of Pediatric MS Centers was established through a National MS Society initiative and has subsequently expanded with further support from the NIH and the Guthrie Jackson Foundation. The initial focus of the pediatric MS network was to facilitate the appropriate diagnosis and comprehensive care of people under the age of 18 with MS and related diseases. This focus was justified since fewer than 5 % of people with MS experience an onset of the disease before the age of 18, misdiagnosis was commonplace and the consequences of misdiagnosis with a treatable condition like MS were large. The Pediatric MS network established separate diagnostic criteria for kids with MS allowing for earlier diagnosis and treatment, and an enhanced understanding of the age dependent clinical features of MS. We learned that children with MS often experience a very aggressive onset, sometimes with altered mental state and seizures, followed by a high rate of relapses, but we also learned that children can recover more completely than adults in the early stages of the disease with a longer interval between symptom onset and the development of progressive disease. In fact, unlike adults, it is extremely uncommon for kids with MS to experience progressive disease from the onset of the disease.
The Pediatric MS Network also made it possible to organize clinical trials to determine the safety and effectiveness of disease modifying therapies (DMTs) in kids with MS. This was important since all clinical trials undertaken to obtain regulatory approval of MS DMTs in the US specifically excluded, and still exclude, children under the age of 18. Because of this age dependent exclusion the most effective DMTs, beginning with the approval of Tysabri in November 2004, were avoided in kids because of the lack of a specific FDA approval and the unknown risks in this vulnerable population. Without the evidence to support the safety of highly active disease modifying therapies, most kids with MS were relegated to treatment with potentially less effective and less tolerated injectable DMTs. There were, of course, exceptions mostly in academic centers, but injectable therapies remained the mainstay of management despite evidence of poor adherence to these DMTs, particularly in kids.
Novartis altered this landscape with the FDA approval of Gilenya on May 11, 2018 for children with MS 10 years of age and older. In many ways Gilenya is a natural treatment choice for kids with MS. First and foremost, it is a once a day pill with few immediate side effects to negatively impact adherence to the treatment schedule. Most of the concerns in adults treated with Gilenya, notably the cardiac risks and the reactivation of herpetic infections like shingles, are less of a concern in kids. Yet we also knew that Gilenya and other medications in this class of drugs could potentially have adverse effects in kids that could not be anticipated based on the experience in adults. Importantly, the study was designed to compare Gilenya to Avonex, one of the more popular DMTs used as initial treatment in kids with MS. We already knew based on many years of experience that Avonex and the other injectable DMTs were relatively safe and effective in kids with MS. What we really needed to know was whether Gilenya offered greater benefits than a popular injectable DMT with an acceptable risk profile and acceptance by kids.
It turns out that Gilenya is a lot more effective than Avonex in kids; 86 % of kids treated with Gilenya in the study were relapse free compared to only 46 % of kids treated with Avonex. Overall, there was an 82 % reduction in relapse rates. For kids, who tend to experience multiple relapses a year that take them away from school for prolonged periods of time, this is a very meaningful outcome. We also learned there is at least one unique risk when prescribing Gilenya in kids that can be potentially mitigated through preventative strategies. Six of the kids (5.6 %) treated with Gilenya experienced seizures compared to only 1 of the kids (0.9 %) treated with Avonex. This tells us that Gilenya may not be the best DMT in kids with a history of seizures or a susceptibility to seizures, particularly those not taking effective anti-seizure medications.
Now that Novartis has led the way with clinical trials of MS DMTs in kids with MS, other companies are following their lead with numerous clinical trials for kids with MS now in various stages of planning or recruitment. This will help us better understand the relative effectiveness and sequencing of MS DMTs in kids in the near future. But what about other vulnerable populations excluded from MS clinical trials, notably those over the age of 55? As many of you know, all MS clinical trials exclude people over the age of 55 from participation and the average participant in MS clinical trials is approximately 37 years old. This leaves MS specialists with virtually no information on the effectiveness and safety of DMTs in older, more vulnerable population. This is a huge problem since unlike pediatric MS, which is a rare condition, people between the ages of 55 and 64 now represent the peak prevalence age group for MS.
In the next blog we will begin to address the issue of MS management in older MS patients, starting with the need for specific clinical trials for people over the age of 55. Stay tuned.
Revere (Rip) Kinkel MD
Professor of Clinical Neurosciences
Director of the Multiple Sclerosis Program
Clinical Neurosciences Director
University of California San Diego
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