Effect of Fingolimod in Pediatric MS: Further Insights from Paradigms

Abstract

BACKGROUND In PARADIGMS, a double-blind phase 3 trial in 215 pediatric MS patients (age 10 to <18 years), fingolimod administered for up to 2 years significantly reduced the annualized relapse rate (ARR) and the rate of new/newly enlarged T2 (n/neT2) lesions compared with interferon (IFN) β-1a. Here, we present further differences between the two treatment groups across various subpopulations, e.g. treatment-naive, younger/prepubertal patients, and results from a post-hoc analysis of disability progression. METHODS Predefined sensitivity/supportive analyses of the endpoints were performed after 1) excluding patients in the IFN β-1a arm who were positive for IFN neutralizing antibody (NAbs) at study end, and 2) evaluating patients who were treatment-naive. ARRs in patients at 10, 11, and 12 years were estimated based on predefined modeling extrapolations. Changes in expanded disability status scale (EDSS), and in 3-month (3M) and 6-month (6M) confirmed disability progression (CDP) were evaluated post-hoc. FINDINGS Excluding NAbs-positive patients (n=9) did not meaningfully change the primary and key secondary results (81·5% ARR reduction and 47·6% reduction in n/neT2 lesions, versus 81·9% and 52·6% in the overall population, respectively). The effect of fingolimod treatment in the treatment-naive subpopulation were 85·8% ARR reduction and 53·4% n/neT2 lesion reduction versus IFN β-1a (both p<0·001). ARR reductions in younger patients (≤12 years) estimated from the modeling extrapolation were 91·9%- 94·6% versus 83·8% for the overall population. The proportion of fingolimod-treated patients who had worsening in EDSS score at study end was half that of IFN β-1a-treated patients (10·5% versus 20·6%, p=0·043). There was a risk reduction in 3M-CDP of 77·2% (p=0·007) and 6M-CDP of 80·2% (p=0·040). INTERPRETATION Fingolimod in pediatric MS was associated with consistent control of disease activity across younger and treatment-naive patients. Fingolimod-treated patients versus IFN β-1a treated patients had less disability progression over treatment duration of up to 2 years. Funding: Novartis Pharma AG, Basel, Switzerland Declaration of Interest: KD received personal compensation for speaker activities from Novartis. PH received compensation for serving on a scientific advisory board from Novartis, and for speaking from Bayer Health care. BB has served as a remunerated central MRI reviewer for the present trial (Novartis). EW volunteers on an advisory board for a Novartis trial. She is a site PI for clinical trials with Roche and Novartis. JG in the last three years has received honoraria for lectures and consultancy fees from Bayer, Teva and Novartis. LK has received personal compensation for activities as a speaker, consultant and/or participant on an advisory board from Biogen Idec, Novartis, Teva Neurosciences and Multicell in addition, LK has royalty or license fees from ER Squibb & Sons, Avenir, Johnson & Johnson and Osmotica, and has received research support from Novartis, Biogen Idec, Celgene Corporation and Genentech. TC has received personal compensation for advisory boards/consulting for F. Hoffman-La Roche, Biogen and Novartis; TC has also received financial support for research activities from Biogen, Merck Serono, Verily and Novartis. TS, GLP and MM are employees of Novartis. Ethical Approval: The trial was conducted in accordance with the provisions of the International Conference on Harmonization Guidelines for Good Clinical Practice and the principles of The Declaration of Helsinki.12 The study protocol was approved by an institutional review board or ethics committee at each study site.