Abstracts

Rationale: ETX-020155 is novel chemical entity and a potent γ-aminobutyric acid A receptor (GABAAR) positive allosteric modulator (PAM) that binds to the neuroactive steroid site on synaptic and extra-synaptic GABAAR (median effective concentration [EC₅₀]: 150-330 nM). ETX-020155 showed antiepileptic activity in the maximal electroshock and pentylenetetrazol seizure models, antidepressant properties in the forced swim test, and antianxiety properties in the elevated plus maze test, indicating the potential to be an antiseizure medication (ASM) with mood-elevating effects. Toxicology studies revealed no genotoxic effects or organ toxicity. Central nervous system effects (hypoactivity, somnolence, sedation, ataxia), consistent with supra-pharmacologic activity from GABAAR activation, determined the no-observed-adverse-effect levels. This Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study was conducted to determine the safety, tolerability, and pharmacokinetics of ETX-020155 and the effect of food on the pharmacokinetics of ETX-020155.

Methods: In the SAD study, single doses of 5, 15, 30, 60, 90, or 135 mg of ETX-020155 (6/cohort) or placebo (2/cohort) were administered in the morning after a10-hour fast; the 30 mg cohort also received a 2nd dose (2 weeks later) under fed conditions. A 7th cohort (200 mg) was stopped after 1 of 2 sentinel subjects met a prespecified stopping rule (severe sedation, tremor, ataxia). In the MAD study, 2 cohorts received 60 mg of ETX-020155 (9/cohort) or placebo (3/cohort) once daily, in the morning or evening, for 7 days. Blood samples for pharmacokinetics were drawn up to 48 hours after morning dosing in the SAD study.

Results: A dose-proportional increase in area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax) was observed across the single-dose range of 5 to 200 mg, with small/moderate inter-subject variability (coefficient of variation ≤30%). Time of maximum concentration (Tmax) was 2 to 4 hours; half-life was 24 to 26 hours. No food effect was observed. Mild to moderate dizziness and somnolence were the most common adverse events (AEs). The maximum tolerated single dose was 135 mg.

No serious AEs, discontinuations due to AEs, or clinically significant abnormalities in vital signs, electrocardiograms, or clinical laboratory parameters occurred during once-daily administration of 60 mg ETX-020155 for 7 days. A total of 44 AEs were reported in 12 subjects during morning dosing of ETX-020155; somnolence (n=34) and fatigue (n=5) were the most common AEs. A total of 7 AEs were reported in 5 subjects during evening dosing of ETX-020155; somnolence (n=1) and dizziness (n=2) were the most common AEs. All AEs were mild (morning dosing) or mild to moderate (evening dosing) and transient.

Conclusions: ETX-020155 is a potent, selective GABAAR PAM that is well tolerated, has no food effect, and has the potential to be an ASM with antidepressant and antianxiety effects.

Funding: Please list any funding that was received in support of this abstract.: This study was funded by Eliem Therapeutics (UK) Ltd.