Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder

Orrin Devinsky, LaToya King, Judith Bluvstein, Daniel Friedman, Orrin Devinsky, LaToya King, Judith Bluvstein, Daniel Friedman

Abstract

Objective: Ataluren is a compound that reads through premature stop codons and increases protein expression by increasing translation without modifying transcription or mRNA stability. We investigated the safety and efficacy of ataluren in children with nonsense variants causing Dravet Syndrome (DS) and CDKL5 Deficiency Syndrome (CDD).

Methods: This single-center double-blind, placebo-controlled crossover trial randomized subjects to receive ataluren or placebo for 12 weeks (period 1), a 4-week washout, then another 12-week treatment (period 2). The primary outcome was ataluren's safety profile. The secondary outcome measures were (1) changes in convulsive and/or drop seizure frequency and (2) changes in minor seizure types during ataluren treatment compared to placebo. Exploratory objectives assessed changes in cognitive, motor, and behavioral function as well as quality of life during ataluren therapy.

Results: We enrolled seven subjects with DS and eight subjects with CDD. Three treatment-related adverse events (AE) occurred during the blinded phases. Two subjects withdrew due to AE. Ataluren was not effective in reducing seizure frequency or improving cognitive, motor, or behavioral function or quality of life in subjects with either DS or CDD due to nonsense variants. Limitations included a small sample size and 12-week treatment phase, possibly too short to identify a disease-modifying effect.

Significance: There was no difference between ataluren and placebo; ataluren is not an effective therapy for seizures or other disorders in children with DS or CDD due to nonsense variants. There were no drug-related serious AE during the double-blind period, consistent with ataluren's favorable safety profile in larger studies. (Funded by Epilepsy Foundation, Dravet Syndrome Foundation, Finding A Cure for Seizures and Epilepsy and PTC Therapeutics, Inc.; ClinicalTrials.gov number, NCT02758626).

Conflict of interest statement

Orrin Devinsky has equity interests in Qstate Biosciences, Tevard Biosciences, Regel Therapeutics, and Script Biosciences, Privateer Holdings, Tilray, Receptor Life Sciences, Empatica, Engage, Egg Rock/Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises (CCE). Orrin Devinsky receives grant support from NINDS, NIMH, MURI, CDC, and NSF. He is an investigator for PTC Therapeutics, Inc., Stoke Therapeutics, Marinus, Ovid and GW Pharmaceuticals. Daniel Friedman receives salary support for consulting and clinical trial‐related activities performed on behalf of The Epilepsy Study Consortium, a nonprofit organization. Dr. Friedman receives no personal income for these activities. NYU receives a fixed amount from the Epilepsy Study Consortium toward Dr. Friedman’s salary. Within the past 2 years, The Epilepsy Study Consortium received payments for research services performed by Dr. Friedman from: Axcella, Biogen, Cerevel, Crossject, Engage Pharmaceuticals, Eisai, Pfizer, SK Life Science, Xenon, and Zynerba. He has also served as a paid consultant for Eisai and Neurelis Pharmaceuticals. He has received travel support from Medtronics, Eisai and the Epilepsy Foundation. He receives research support from the CDC, NINDS, Epilepsy Foundation, Empatica, Epitel, UCB, Inc and Neuropace unrelated to this study. He serves on the scientific advisory board for Receptor Life Sciences. He holds equity interests in Neuroview Technology and Receptor Life Sciences.

© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
Study trial design. EOS, end of study; F/U, follow‐up; IC, informed consent; Wk, week.

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