Fingolimod in children with Rett syndrome: the FINGORETT study

Yvonne Naegelin, Jens Kuhle, Sabine Schädelin, Alexandre N Datta, Stefano Magon, Michael Amann, Christian Barro, Gian Paolo Ramelli, Kate Heesom, Yves-Alain Barde, Peter Weber, Ludwig Kappos, Yvonne Naegelin, Jens Kuhle, Sabine Schädelin, Alexandre N Datta, Stefano Magon, Michael Amann, Christian Barro, Gian Paolo Ramelli, Kate Heesom, Yves-Alain Barde, Peter Weber, Ludwig Kappos

Abstract

Background: Rett syndrome (RS) is a severe neurodevelopmental disorder for which there is no approved therapy. This study aimed to assess safety and efficacy of oral fingolimod in children with RS using a pre-post and case-control design.

Methods: At the University of Basel Children's Hospital, Basel, Switzerland, children with RS were included if they were older than 6 years and met the established diagnostic criteria of RS, including a positive MeCP2 mutation. Participants were observed 6 months before and after treatment and received 12 months of fingolimod treatment. Serum samples of 50 children without RS served as reference for brain-derived neurotrophic factor (BDNF) measurements. Primary outcome measures were safety and efficacy, the latter measured by change in levels of BDNF in serum/CSF (cerebrospinal fluid) and change in deep gray matter volumes measured by magnetic resonance imaging (MRI). Secondary outcome measure was efficacy measured by change in clinical scores [Vineland Adaptive Behaviour Scale (VABS), Rett Severity Scale (RSSS) and Hand Apraxia Scale (HAS)].

Results: Six children with RS (all girls, mean and SD age 11.3 ± 3.1 years) were included. Serum samples of 50 children without RS (25 females, mean and SD age 13.5 ± 3.9 years) served as reference for BDNF measurements. No serious adverse events occurred. Primary and secondary outcome measures were not met. CSF BDNF levels were associated with all clinical scores: RSSS (estimate - 0.04, mult.effect 0.96, CI [0.94; 0.98], p = 0.03), HAS (estimate - 0.09, mult.effect 0.91, CI [0.89; 0.94], p < 0.01) and VABS (communication: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/daily living: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/social skills: estimate 0.07, mult.effect 1.08, CI [1.05; 1.11], p < 0.01/motoric skills: estimate 0.04, mult.effect 1.04, CI [1.03; 1.06], p = 0.02).

Conclusions: In children with RS, treatment with fingolimod was safe. The study did not provide supportive evidence for an effect of fingolimod on clinical, laboratory, and imaging measures. CSF BDNF levels were associated with clinical scores, indicating a need to further evaluate its potential as a biomarker for RS. This finding should be further validated in independent patient groups.

Trial registration: Clinical Trials.gov NCT02061137, registered on August 27th 2013, https://ichgcp.net/clinical-trials-registry/NCT02061137 .

Keywords: BDNF; Fingolimod; Rett syndrome.

Conflict of interest statement

Yvonne Naegelin’s employer, the University Hospital Basel, received payments for lecturing from Celgene GmbH and Teva Pharma AG that were exclusively used for research support, not related to this study. Jens Kuhle received speaker fees, research support, travel support, and/or served on advisory boards by ECTRIMS, Swiss MS Society, Swiss National Research Foundation, (320030_189140/1), University of Basel, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi. Alexandre N. Datta has served on scientific advisory boards for UCB, Eisai, and Nutricia. He has consultancy activities for Roche, Idorsia, Neurocrine, and Epilog. He has received funding for travel from UCB, Sanofi, Eisai, and Nutricia. Stefano Magon is an employee of F. Hoffmann-La Roche Ltd. Roche was not involved in the study. Ludwig Kappos’s institution (University Hospital Basel) received in the last 3 years and used exclusively for research support at the Department: steering committee, advisory board, consultancy fees and support of educational activities from: Actelion, Allergan, Almirall, Baxalta, Bayer, Biogen, Celgene/Receptos, CSL-Behring, Desitin, Excemed, Eisai,Genzyme, Japan Tobacco, Merck, Minoryx, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi Aventis, Santhera, Teva, and license fees for Neurostatus-UHB products; the Research of the MS Center in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, Innosuisse, the European Union, and Roche Research Foundations. Sabine Schädelin, Michael Amann, Christian Barro, Gian Paolo Ramelli, Kate Heesom, Yves Alain Barde, and Peter Weber have nothing to disclose.

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