Abstracts

Rationale: XEN901 is a potent and highly selective NaV1.6 inhibitor currently in clinical development for the treatment of adult focal seizures and SCN8A (gain of function) early infantile epileptic encephalopathy (EIEE13). The objective of this first in human study is to evaluate the safety, tolerability and pharmacokinetics (PK) of single and multiple ascending oral doses of XEN901 in healthy subjects. XEN901 is expected to have an enhanced safety profile through potent block of NaV1.6, with >100 fold selectivity over NaV1.1 (CNS inhibitory) and NaV1.5 (cardiac) sodium channels. Methods: In this randomized, double blind, placebo controlled study, 40 healthy subjects (4 subjects [3 active and 1 placebo] per each of the first two cohorts; 8 subjects [6 active and 2 placebo] per each of cohorts three through six) were planned to receive ascending oral doses once daily, and 24 healthy subjects (8 subjects [6 active and 2 placebo] per each of the three cohorts) were planned to receive multiple ascending oral doses two times daily (BID) for seven days. XEN901 was formulated as an immediate release capsule. Serial plasma PK samples were collected at selected time points for single dose (pre dose and up to 48 hours post dose) and multiple dose cohorts (pre dose and up to 48 hours post last dose). Safety evaluations throughout the study included adverse event (AE) monitoring, clinical laboratory tests, vital signs, electrocardiograms (ECGs), physical examinations, Columbia Suicide Severity Rating Scale (C SSRS) and a brief cognitive assessment. The study features an adaptive design. Results: To date, 32 subjects have completed dosing across five single ascending dose cohorts (5, 10, 15, 30 and 45 mg). One additional cohort of 9 subjects received a single 5 mg dose of XEN901 under fed and fasted states in a crossover design. XEN901’s PK profile displayed a reasonable dose-proportional exposure, low inter-individual variability and a modest food effect. The terminal elimination t_½ was 8-11 hours. Single doses of XEN901 were well-tolerated at plasma levels up to and including 1600 ng/mL, with no clinically significant ECG or laboratory findings. Blinded safety data have indicated that all reported AEs to date were mild or moderate and unrelated to the investigational product, with the exception of one mild related AE of transient restlessness which resolved spontaneously. There have been no SAEs. The multiple dosing portion of the study is ongoing and complete results will be presented at the meeting. Conclusions: These preliminary results suggest that single doses of a novel, first-in-class Nav1.6 inhibitor XEN901, up to and including 45 mg, are safe and well tolerated. XEN901 has PK and safety profiles that support continued clinical development. More detailed results, including those for multiple dosing, will be presented at the meeting. Funding: None