PARADIGMS trial shows fingolimod reduced rate of brain atrophy by up to 40%

Treating multiple sclerosis in pediatric patients is clinically challenging, which makes studies in this population particularly useful. This report, first published March 9, provides useful information about the efficacy and safety of one therapeutic in this select group, which is why BreakingMED is republishing the report as part of its year-end clinical review series.

MRI data from the PARADIGMS randomized phase III pediatric multiple sclerosis (MS) trial comparing fingolimod (Gilenya) and interferon (IFN) β-1a showed that the fingolimod group had reduced brain MRI disease activity and a slower annualized rate of brain atrophy.

On serial 6-month MRIs for 2 years, fingolimod reduced the annualized rate of formation of new/newly enlarging T2 lesions by 52.6%, and end of study mean MRI volumes showed less atrophy for the fingolimod group, with an annualized rate of brain atrophy of −0.48% for fingolimod and −0.80% for IFN β-1a.

Previously published PARADIGMS efficacy and safety data showed that compared to INF β-1a, fingolimod reduced the relapse rate by 82%, in pediatric MS, with concern for more serious adverse events in the fingolimod group.

“We conclude that treatment with fingolimod showed better efficacy compared with IFN β-1a in reducing MRI activity, relapses and brain volume loss, supporting the overall beneficial effect of fingolimod in pediatric patients with MS,” wrote Douglas Arnold, MD, of McGill University in Montreal, Canada and co-authors, in the Journal of Neurology, Neurosurgery, and Psychiatry. “Fingolimod provides an effective treatment option for children and adolescents with MS.”

“It was not known if brain atrophy could be slowed in children with MS, until now,” observed Arman Eshaghi, MD, of the University College London in England, in an accompanying editorial.

“Importantly, this paper shows that fingolimod reduced the rate of brain atrophy in children with MS up to 40% compared with the interferon beta-1a treatment (absolute difference of 0.32% per year),” Eshaghi continued. “Therefore, similar to adults, children with MS benefit from fingolimod treatment due to a direct anti-inflammatory effect, with a possible secondary effect on brain atrophy.”

Multiple MS treatments for adults have been approved by the FDA, but evidence supporting use in children has been sparse. In May 2018, the FDA approved fingolimod for patients age 10 or older for relapsing MS.

PARADIGMS was a double-blind, active-controlled, parallel-group multicenter study of MS patients ages 10 to 18 randomized to daily weight-dosed oral fingolimod (n=107) or weekly 30 μg IFN β-1a given intramuscularly (n=108). Participants were enrolled from July 2013 and August 2017 and had evidence for recent disease activity — one relapse within one year or two relapses within 2 years, or had evidence of one or more Gd+ lesions on screening or other MRI within 6 months. Researchers included participants with Expanded Disability Status Scale scores of 0–5.5 (0 no disability; 5.5 implies disability severe enough to preclude full daily activities, but able to walk without aid or rest for 100 meters). Followup was 2 years with imaging every 6 months.

The study population’s average age was 15 and 62% were female. More participants in the fingolimod group completed on-study treatment at 18 and 24 months (69% versus 51% at 18 months; 28% versus 18% at 24 months).

In addition to reducing the annualized rate of formation of new/newly enlarging T2 lesions, compared with IFN β-1a, fingolimod reduced:

  • Number of gadolinium enhancing (Gd+) T1 lesions per scan by 66.0%.
  • Annualized rate of new T1 hypointense lesions by 62.8%.
  • Combined unique active lesions per scan by 60.7% (all P < 0.001).

“Our findings from the first randomized controlled clinical trial in pediatric patients with MS confirms that inflammatory disease activity in children with MS is substantially higher than in adult patients with MS,” the authors noted.

In addition to reducing the annualized rate of brain atrophy compared to IFN β-1a, the fingolimod group showed advantage in lesion volumes:

  • T2 lesion volumes increased by 18.4% in the fingolimod group versus 32.4% for IFN β-1a.
  • Gd+ T1 lesion volumes decreased by 72.3% for fingolimod but increased by 4.9% for IFN β-1a.

“The behavior of T1 hypointense lesion volume deserves special consideration,” Arnold and colleagues noted. That the percent increase in lesion volumes (and possibly lesion number) for T1 hypointense lesions was substantially greater than for T2 lesions, “may indicate that degenerative processes associated with progressive disease are already present in pediatric onset MS,” they wrote. “This finding also suggests that even very young patients with MS fail to fully remyelinate within lesions, further emphasizing the need for therapies that reduce new T2 lesion formation.”

Subgroup and sensitivity analysis continued to show reduction in the annualized rate of formation of new/enlarging T2 lesions with fingolimod compared with IFN β-1a in analysis by sex; age > 12; weight >40 kg; and in both those treated previously with disease-modifying therapy and those who had not been.

Limitations of the study included a progressive drop-out of patients completing on-study treatment by 18 and 24 months.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This work was supported by Novartis Pharma AG.

Arnold receives grant support and consultant fees from Novartis, which manufactures the drug tested in this study. He has an equity interest in NeuroRx Research, which performed the MRI analyses for the study.

Eshaghi received funding for travel from the U.S. National Multiple Sclerosis Society, speaker’s honorarium (paid to his institution) from Biogen and At The Limits educational program.

Cat ID: 130

Topic ID: 82,130,730,130,36,138,192,925