First-in-Human Trial Begins for an Antisense Oligonucleotide in KCNT1-Related Epilepsy

Servier has begun dosing children with KCNT1-related developmental and epileptic encephalopathy (KCNT1-DEE) in a first-in-human trial of S230815, an antisense oligonucleotide (ASO) designed to degrade the messenger RNA produced by mutated copies of the KCNT1 gene. Investigators presented the trial's design, known as KANDLE, at the 2026 Child Neurology Society (CNS) Annual Meeting in Montreal, Quebec, Canada.¹

KANDLE is a phase 1b/2, open-label, multicenter, sequential dose-escalation study enrolling children ages 2 to 12 years with a genetically confirmed pathogenic or likely pathogenic KCNT1 variant and a phenotype consistent with epilepsy of infancy with migrating focal seizures or another early-onset epileptic encephalopathy. Participants receive intrathecal S230815 across 4 sequential ascending-dose cohorts in the trial's first part; those who complete it may roll over into a long-term extension period.

The primary endpoint is safety and tolerability, based on the incidence and severity of adverse events. Secondary endpoints cover pharmacokinetics and pharmacodynamics, including change from baseline in seizure frequency assessed through daily logs and 24-hour video EEG. Exploratory endpoints include neurodevelopmental outcomes, caregiver burden, quality of life, immunogenicity, fluid biomarkers, and the feasibility of a wearable seizure-detection device.

“This asset was developed by Servier scientists and highlights our commitment and capability to translate scientific discoveries into clinical innovations that may deliver meaningful benefits to patients,” Nitza Thomasson, global head of research and development in neurology at Servier, said in a statement after the first US patient was enrolled in June 2026. Additional sites are open across the US, Europe, and Japan.²

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KCNT1-DEE is caused by gain-of-function variants in a gene encoding a potassium channel that regulates neuronal excitability, producing one of the more severe early-childhood epilepsy syndromes, with high rates of drug resistance, developmental impairment, and mortality. “In many children with a KCNT1 variant, seizures can begin as early as the first days or months of life, and some never get to go home,” said Justin West, co-founder and president of the KCNT1 Epilepsy Foundation, in Servier's announcement of the trial.^1,2

The only treatment aimed specifically at the KCNT1 mechanism to date has been quinidine, which blocks the overactive channel in laboratory models but has shown inconsistent clinical benefit and carries a risk of QT prolongation; KANDLE excludes children who have taken quinidine within 30 days of screening. S230815 instead aims to reduce production of the abnormal channel at its genetic source, administered directly into the cerebrospinal fluid to reach the central nervous system.^1,3

As the study's authors note, KANDLE is the first clinical trial to evaluate a KCNT1-targeting ASO in children with KCNT1-DEE. Its design is intended to maximize safety monitoring and mechanistic insight in this ultrarare population; the authors describe findings from the trial as intended to support the further development of S230815 as a potential disease-modifying therapy for KCNT1-DEE, rather than as evidence of clinical benefit at this stage.¹

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REFERENCES
1. Estevez-Fraga C, Auvin S, Nabbout R, et al. A first-in-human study of the antisense oligonucleotide S230815 in paediatric participants with KCNT1-related developmental and epileptic encephalopathy. Abstract 45. Presented at: 2026 Child Neurology Society Annual Meeting; October 14-17, 2026; Montreal, Quebec, Canada.
2. Servier announces first patient enrolled in Phase Ib/II study for the treatment of a rare pediatric epilepsy syndrome in the U.S. News release. Servier. Published June 25, 2026. Accessed October 15, 2026. https://servier.mediaroom.com/2026-06-25-Servier-Announces-First-Patient-Enrolled-in-Phase-Ib-II-Study-for-the-Treatment-of-a-Rare-Pediatric-Epilepsy-Syndrome-in-the-U-S
3. Xu D, Chen S, Yang J, Wang X, Fang Z, Li M. Precision therapy with quinidine of KCNT1-related epileptic disorders: a systematic review. Br J Clin Pharmacol. 2022;88(12):5096-5112. doi:10.1111/bcp.15479