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Abstract Details

A Phase 1 Study to Assess the Safety, Tolerability and Pharmacokinetics of Two Formulations of a Novel Nav1.6 Sodium Channnel Blocker (XEN901) in Healthy Adult Subjects.
Epilepsy/Clinical Neurophysiology (EEG)
P10 - Poster Session 10 (5:30 PM-6:30 PM)
12-003

This study evaluated the safety, tolerability and pharmacokinetics (PK) of single and multiple ascending oral doses of XEN901 in healthy adults.
XEN901 is a potent, highly selective NaV1.6 inhibitor in clinical development for treatment of adult focal seizures and SCN8A-DEE.

This was a single center, randomized, double-blind, placebo-controlled, PK and safety study in 95 healthy adults. Subjects received single oral doses of XEN901 (5-80 mg), multiple doses of XEN901 (15, 23, or 45 mg BID, 50 or 75 mg QD) for 7 days, or placebo. Both API-in-capsule and tablet formulations were evaluated. A preliminary food effect assessment was conducted. Transcranial magnetic stimulation (TMS) techniques were used to assess potential central nervous system (CNS) actions. Safety assessments included AE monitoring, clinical and laboratory evaluations and ECGs.
XEN901 was well tolerated at single dose (80 mg) plasma levels up to 2300 ± 219 ng/mL and multiple dose (45 mg BID) plasma levels up to 2040 ± 551 ng/mL. There were no serious or severe treatment-emergent adverse events (TEAEs), all related TEAEs were mild or moderate and resolved. Relevant TEAEs considered related to XEN901 treatment (single/multiple dosing) included nausea (4 subjects), dizziness (3 subjects) and muscle twitching (2 subjects). Exposure increased in a near dose-proportional manner with single ascending doses of XEN901. Exposure was slightly higher in a fed state than a fasted state. Mean terminal elimination half-life ranged from 7.9 to 8.9 hours and steady state was reached in 2-3 days with a mean accumulation index of ≤1.6. In 8 subjects with plasma levels >1000 ng/mL during TMS assessments, XEN901 showed CNS activity as indicated by increases in resting and active motor thresholds.
These results suggest that XEN901, a first-in-class NaV1.6 inhibitor is safe and well tolerated with suitable PK and preliminary evidence of CNS activity. 
Authors/Disclosures
Gregory N. Beatch, PhD
PRESENTER 		Dr. Beatch has received personal compensation for serving as an employee of Xenon Pharmaceuticals Inc. Dr. Beatch has stock in Xenon Pharmaceuticals Inc. Dr. Beatch has received intellectual property interests from a discovery or technology relating to health care.
No disclosure on file
No disclosure on file
No disclosure on file
Ernesto Aycardi, MD (Kyowa Kirin) Dr. Aycardi has received personal compensation for serving as an employee of XENON. Dr. Aycardi has received stock or an ownership interest from XENON.