PARADIGMS: Fingolimod Effective, Well Tolerated in Children

Pauline Anderson

September 14, 2018

Children and adolescents with multiple sclerosis (MS) who are treated with fingolimod have a much lower relapse rate than those receiving interferon β-1a, although they may experience more seizures or other adverse events, phase 3 results of the PARADIGMS trial show.

"The study shows that fingolimod is highly effective in pediatric MS, with 86% of patients being relapse-free for the study duration," lead author Tanuja Chitnis, MD, professor of neurology, Harvard Medical School, and director, Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital, Boston, told Medscape Medical News.

Dr Tanuja Chitnis

The results also indicate that overall the drug is "well tolerated," although prescribing physicians should note the "imbalance" in risk for seizures and increased rate of infections in children taking fingolimod, said Chitnis.

Based on the trial findings, the US Food and Drug Administration (FDA) approved fingolimod for pediatric MS earlier this year. It's the first drug approved for this indication. Interferon has been considered the standard of care for pediatric patients with MS.

The results were published September 13 in The New England Journal of Medicine. They were presented previously at the 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting and reported by Medscape Medical News at that time.

Contributing Factors

Fingolimod is an oral sphingosine-1 phosphate receptor modulator. Essentially, it works by preventing the migration of immune system cells, such as T cells, from the lymph nodes to the brain and spinal cord, thereby reducing attacks on the myelin.

MS is considered an autoimmune demyelinating disorder for which there are genetic as well as environmental risk factors. Obesity, low vitamin D levels, tobacco smoke, and Epstein-Barr virus exposure have been identified as possible contributing factors, the authors note. MS typically appears in early adulthood, but about 3% to 5% of cases have an onset in childhood or adolescence, usually with a relapsing-remitting pattern.

"Pediatric MS is probably an early form of MS in general," said Chitnis. "We know that many adult patients will have evidence of prior lesions before their first clinical symptoms."

Pediatric patients with MS have a very inflammatory form of disease, noted Chitnis. "We and others have shown that they have a higher relapse rate — two to three times as many relapses in kids compared to adult patients."

Relapses in youngsters may be more severe than those in adults, although most recover from their initial and subsequent attacks, the authors write.

The multicenter, double-blind, active-comparator PARADIGMS trial included 215 patients with relapsing MS age 10 to 17 years (median age, 16 years), who had an Expanded Disability Status Scale (EDSS) score of 0.0 to 5.5. The mean time from onset of MS symptoms to entry into the trial was longer in the interferon group than in the fingolimod group (2.4 years vs 1.9 years; P = .03).

Patients were randomly assigned to receive oral fingolimod (0.5 mg once daily, or 0.25 mg once daily for patients with a body weight  ≤ 40 kg) or intramuscular interferon β-1a (30 μg once weekly). They were treated for a median of 1.61 years.

Of those assigned, 93.5% in the fingolimod group completed the trial, as did 81.5% of those in the interferon group.

The primary endpoint was the annualized relapse rate, defined as the average number of confirmed relapses per year. A relapse was confirmed by an independent physician unaware of group assignments.

The decision was based on a 0.5-point or greater increase in the EDSS score, a 1-point increase in two functional system (FS) scores, or a 2-point increase in one FS score (excluding the bowel and bladder FS and the cerebral FS), compared with the most recent evaluation of the EDSS score that did not occur during a relapse.

The study found that the adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon (rate ratio, 0.18; 95% confidence interval [CI], 0.11 - 0.30; P < .001; relative difference, 82%; absolute difference, 0.55 relapses; 95% CI, 0.36 - 0.74; P < .001).

"The most important finding of the study was that there was an 82% reduction in annualized relapse rate in the fingolimod group" compared with the interferon group, commented Chitnis.

New Lesions

A key secondary endpoint was the annualized rate of new or newly enlarged lesions on T2-weighted MRI compared with baseline. Results showed this rate was 4.39 with fingolimod and 9.27 with interferon (rate ratio, 0.47; 95% CI, 0.36 - 0.62; P < .001; relative difference, 53%; absolute difference, 4.88 lesions; 95% CI, 2.91 - 6.84; P < .001).

Another secondary endpoint was the percentage of patients free of relapse, which was 85.7% in the fingolimod group and 38.8% in the interferon group (between-group difference, 46.9 percentage points; unadjusted 95% CI, 33.7 - 60.1).  

There was "a limited number" of younger kids in the study, but Chitnis noted that the fingolimod seemed to work just as well in 10- and 11-year-olds as in older children. "There were not enough to do a robust subanalysis to say that it worked better; it worked similarly," she said.

But in general, the drug appears to work better in children than in adults. Chitnis noted that in other studies with a similar design, adults had about a 55% reduction in annualized relapse rate.

"The earlier you treat any disease, especially a neurologic disease, the better the response," Chitnis said.

Also, fingolimod reduces relapses, and because children have more relapses than adults, it makes sense that the drug would reduce more of them in these younger patients.

Reducing relapses likely improves quality of life, "which is huge" for young people, said Chitnis. "Relapses involve going into the hospital, steroid courses, more symptoms, and change in lifestyle."

Relapses "add up over time" and can lead to disability, including cognitive disability, she added.

The overall incidence of adverse events was 88.8% in the fingolimod group and 95.3% in the interferon group. Chitnis noted that many of these events involved flus and colds.

As for serious adverse events, 16.8% in the fingolimod group and 6.5% in the interferon group experienced at least one such event.

About 2.8% in the interferon group experienced leukopenia compared with14% in the fingolimod group. This higher rate was presumably related to lymphocyte sequestration, which is attributable to the mode of action of fingolimod, said the authors.

Convulsions occurred in 5.6% of those receiving fingolimod and 0.9% of those taking interferon. Seizures may be a more important side effect in children than in adults receiving fingolimod, the authors note. This "imbalance" in seizures "is something for prescribing physicians to note and to advise their families and patients about," said Chitnis.

Overall, 3.7% of the fingolimod group had infections (including appendicitis, cellulitis, gastrointestinal infection, oral abscess, viral infection, and viral pharyngitis), as did 1.9% of the interferon group (paronychia and viral gastritis). A reduction in peripheral lymphocyte counts may increase the risk for infection, noted the authors.

There were no reports of skin carcinomas, an increased risk for which has been associated with fingolimod among adults, but longer monitoring may be necessary to assess dermatologic risks, they said.

A 5-year, open-label extension trial is ongoing, said Chitnis. "Patients are being monitored both clinically and with MRI, and we're also using patient-reported outcomes and cognitive testing and safety measures."

Fingolimod was approved for adults in 2011. "We now have 7-year plus data, long-term data, and so we understand the safety profile" in this population, said Chitnis. "That will be important to replicate in children."

Not the "Best We Can Do"

Jack Antel, MD, professor, neurology, McGill University, and coordinator, MS Program, Montreal Neurological Institute, Quebec, Canada, who contributed an accompanying editorial, pointed out that in the current trial, fingolimod was superior to interferon but did not completely suppress disease activity. The MS community is "pushing" the concept of "no evidence of disease activity" (NEDA) which, if attained, might further reduce neurologic deficit, Antel said.

The article does not include imaging data that might point to an effect of the drug on the rate of myelination, he added. "If there is even some ongoing inflammation in the brain, is that contributing to ongoing injury?"

On the other hand, halting all inflammation may not be a good approach, he said. "Is there toxicity of the drug if you push too hard?"

The study shows that fingolimod is superior to interferon, "and that's very worthwhile," said Antel. "But I don't think we should accept that that's the best we can do."

He noted that most of those enrolled in the study were older teens who were approaching adulthood, and that the medical community may already have been treating such patients with fingolimod off-label.

"It raises the issue of whether it's worth doing this trial if you're going to pack it with 16- and 17-year-olds."

Antel also questioned whether the sponsor did this trial "because they've been mandated to do it and they're meeting the letter of the law by doing it in 16- and 17-year-olds."

But he acknowledged that it's difficult to recruit younger patients with MS and that the disorder is "extremely rare" in children before puberty.

He also stressed the "challenge" of knowing "when the disease actually starts." For example, when MRI shows multiple lesions in a 20-year-old, "we know they didn't all come at the same time, so did some of them come when that patient was 14 or 15?"

Antel noted that pediatric MS "is not a benign disease" because demyelination affects brain development and cognition. Youngsters with MS may not do well at school, experience cognitive issues, and even have changes in brain volume, he said.

Finally, he also questioned whether interferon, the comparator in this trial, continues to be the standard of care for pediatric MS. In his opinion, clinicians may be as likely to use something like glatiramer acetate (Copaxone, Teva Pharmaceuticals) a drug that is not only effective but safe.

Also commenting for Medscape Medical News, Lily Jung Henson, MD, chief of neurology, Piedmont Healthcare, Atlanta, Georgia, said the study is "really exciting" because it suggests that treating kids with fingolimod will make a significant difference in their accumulation of injury to the central nervous system.

"This hopefully means that they are less likely to develop disability over the course of their life span compared to an adult who develops MS."

Although fingolimod does carry a greater likelihood of serious adverse events, "you have to weigh that against a better chance at a normal life with less disability," said Henson.

She pointed out that compliance with a pill vs an injection in a youngster "is that much more likely. This means that we're giving these kids a better chance at an improved outcome over the course of their lives."

The study was supported by Novartis Pharma. Novartis supplied the trial drug ( Gilenya) , analyzed data, and reviewed results as did the advisory group. Chitnis was compensated for her role in developing the study design and being a member of the study steering committee. She is on the steering committee for other clinical trials for pediatric MS. Antel does not have current conflicts, but in the past, McGill has received funds from Novartis and from the Canadian Institute of Health Research for fingolimod- and MS-related research. Jung has disclosed no relevant financial relationships.

N Engl J Med. Published September 13, 2018. Article, Editorial

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