ARTICLE IN BRIEF
Researchers reported that fingolimod lowered the annualized relapse rate by 82 percent compared to interferon-beta 1a in children, ages 10 to 17, with multiple sclerosis. But the children on fingolimod also experienced more adverse events.
Fingolimod was more effective than interferon beta-1a in reducing relapses and lesion accumulations on magnetic resonance imaging in children with relapsing multiple sclerosis (MS), according to a large international, multicenter, randomized controlled trial.
Results of the PARADIGMS study, which also found an increased rate of serious adverse events in the fingolimod group, were published September 13 in The New England Journal of Medicine.
“The efficacy was quite dramatic,” said the study's lead author, Tanuja Chitnis, MD, FAAN, professor of neurology at Harvard Medical School and director of Partners Pediatric Multiple Sclerosis Center at Massachusetts General Hospital.
“Given that MS relapses cause significant disability both in the short-term and the long-term, I think this is a major advance for the treatment of pediatric MS,” Dr. Chitnis told Neurology Today.
Among findings of the two-year study period, fingolimod lowered the annualized relapse rate by 82 percent compared to interferon-beta 1a. Eighty-six percent of the children taking oral fingolimod were relapse-free compared to 39 percent of those who had intramuscular interferon-beta 1a injections.
Based on the study's findings, in May the US Food and Drug Administration approved fingolimod for children with MS. The decision marked the first time that a medication received approval in the United States for pediatric MS.
MS typically strikes in young adulthood, but an estimated 3 to 5 percent of cases have an onset in childhood or adolescence, generally with a relapsing–remitting pattern, the study authors noted. During the initial six years of the disease, relapse rates are more than double as high among pediatric patients as among adult patients, they wrote.
Until this phase 3 trial, treatment of patients younger than 18 years of age with MS had not been sufficiently evaluated in randomized trials.
“There were no real data in the past on the effectiveness of this drug in children because all the trials were done in adults,” Emmanuelle L. Waubant, MD, PhD, a co-author of the study and professor of clinical neurology and pediatrics at the University of California, San Francisco (UCSF), told Neurology Today.
As a result, neurologists were limited by the lack of available information they could provide to parents and guardians. “Now, I can share with them what we know,” said Dr. Waubant, who directs the Regional Pediatric MS Center at UCSF.
In advising families on the risks versus the benefits, Dr. Chitnis said she would acknowledge the higher incidence of seizures in the fingolimod group compared to the interferon beta-1a group in the study.
In general, “seizures do occur in children at a slightly higher rate than adults,” Dr. Chitnis said. “The developing brain is slightly more susceptible to seizures, and we need to understand if there is an interaction of fingolimod and seizure risk.”
Common infections, including influenza and upper respiratory tract infection, also were more frequent in the fingolimod arm of the study.
STUDY DETAILS, FINDINGS
From July 2013 through August 2016, investigators screened 348 patients at 87 centers in 26 countries. Of these patients, 215 participants were enrolled at 80 centers in 25 countries.
Investigators randomly assigned patients 10 to 17 years of age with relapsing MS in a 1:1 ratio to receive either oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to two years.
The primary endpoint was the annualized relapse rate. The major secondary endpoint of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; p<0.001).
The mean relapse rate was 2.4 during the preceding two years for both study cohorts. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; p<0.001).
Excluding MS relapses, adverse events occurred in 88.8 percent of patients who were randomly assigned to fingolimod and 95.3 percent of those who received interferon beta-1a.
Serious adverse events, which affected 18 patients (16.8 percent) in the fingolimod group, included infection (in four patients) and leukopenia (in two patients). Six patients on fingolimod experienced seizures.
In the interferon beta-1a group, serious adverse events occurred in seven patients (6.5 percent) and included infection (in two patients) and supraventricular tachycardia (in one patient).
The authors indicated that longer studies are needed to assess the durability and safety of fingolimod in pediatric MS.
Novartis Pharma, which sponsored the trial and supplied the drugs, developed the study design in collaboration with an advisory group, members of the International Pediatric Multiple Sclerosis Study Group, the European Medicines Agency, and the FDA.
One of the challenges in studying rare disorders, such as pediatric multiple sclerosis, lies in recruiting enough participants to demonstrate the efficacy and safety of any therapy, said Eluen Ann Yeh, MD, FRCPC, director of the pediatric MS and neuroinflammatory program at the Hospital for Sick Children in Toronto.
Involvement of a substantial number of sites in this trial reflects the relative rarity of MS in children, she said, but it also highlights the researchers' commitment to identifying better treatments.
“The study itself was well-designed, and the results are impressive,” said Dr. Yeh, associate professor of pediatrics (neurology) at the University of Toronto and associate scientist at the SickKids Research Institute.
However, Dr. Yeh emphasized the need to be cautious in prescribing fingolimod due to the potential for serious adverse events, particularly seizures. “I'm not sure I understand the mechanism of why it occurred,” she said, speculating whether the adverse events could be related to infection, cortical lesions, or an underlying seizure disorder. One patient in the trial was classified as having epilepsy.
As for children under 10 years of age, who were not included in the trial, “the jury is out,” Dr. Yeh said. “The effects on the immune system are unknown.”
MS is so unusual in young children that neurologists may wonder whether it is “exactly the same disease or not” as in adolescents and adults, said Jack Antel, MD, FRCPC, FAAN, professor in the department of neurology and neurosurgery at McGill University in Montreal, and coordinator of the multiple sclerosis and neuroimmunology program at the Montreal Neurological Institute.
Dr. Antel, who wrote an editorial published in the same issue as the study, told Neurology Today that at a minimum, “we have good documentation that, in the teenage population, fingolimod looks at least as effective in the young adult population.” However, he cautioned that fingolimod did not entirely halt disease activity among trial participants.
“A child with multiple sclerosis may look well, but there may be learning problems,” Dr. Antel said, while adding that MS is not a benign disease in the pediatric age group because demyelination affects brain development. He said he would have concerns about prescribing fingolimod to a child 8 years old or younger, citing a lack of data to draw conclusions about the drug's safety and efficacy in that age group.
The frequent appearance of pre-existing asymptomatic lesions on MRI around a patient's first clinical event makes it difficult to determine the exact timing of MS onset in both children and adults, Dr. Antel noted in the editorial. “Retrospective studies indicate that smoldering symptoms may have been present for years before the diagnosis is certain,” he wrote, suggesting that multiple sclerosis may be more common in the pediatric age group than previously realized.
Children with MS have a higher risk of brain atrophy and cognitive deficits. They relapse more often than adults but recover more quickly, only to experience numbness and weakness, said Mary R. Rensel, MD, staff neurologist and director of wellness and pediatric MS at the Cleveland Clinic's Mellen Center for Multiple Sclerosis.
Families appreciate the time and energy expended “to look more consistently and persistently” for up to two years at fingolimod's effects on pediatric patients in a clinical trial, Dr. Rensel said.
In considering the potential for adverse events, Dr. Rensel would exercise caution about prescribing fingolimod in youth with frequent infections, a very low heart rate, or high blood pressure. Furthermore, patients on certain antidepressants could be at higher risk for arrhythmias, so adding a second medication with that possible side effect would be ill-advised. “If they've had a history of cardiac disease, we would have to take pause,” she said.
Dr. Rensel also recommends factoring in the long-term damage that pediatric MS can inflict. It is more prudent to intervene sooner rather than later after onset, she explained, to reduce the possibility of brain scarring that worsens with decades of poorly controlled MS.
“With every relapse, it puts a person at risk of symptoms that stay with them, and eventually, that accumulates into disability,” Dr. Rensel said, citing foot drop as an example. “You want to decrease the chance of these kids having any kind of disability.” The trial, she added, “changed the outcome for these kids in a short amount of time.”