2026 American Academy of Neurology Abstract Website

Objective:

Evaluate ACP-711 population pharmacokinetic (popPK) model and simulation and pharmacodynamic effects to identify target dose/exposure.

Background:

ACP-711, a GABA_AR α₃-selective positive allosteric modulator, is under development for essential tremor. This first-in-human single-and-multiple-ascending-dose trial evaluated ACP-711 pharmacokinetics, pharmacodynamics (receptor occupancy, neurophysiologic effects), and safety in healthy volunteers.

Design/Methods:

A popPK model with plasma concentrations (n=63 participants; 0.10-2.25 mg/kg oral BID) was developed and applied to a virtual NHANES population for simulation (n=1102, 50-150 mg, BID) to identify equivalent-exposure fixed doses. GABA_AR occupancy was evaluated by ¹¹C-flumazenil-PET at 1.16-2.25 mg/kg over 48 h. Neurophysiologic effects were assessed via EEG after 0-1.2 mg/kg; sleep was evaluated by polysomnography before/after 9 days. Target exposure and associated fixed doses were identified based on ACP-711 pharmacokinetics and pharmacodynamics.

Results:

ACP-711 pharmacokinetics were described by a 2-compartment model with first-order absorption and linear elimination. Body weight was a clinically significant factor for dose determination. No discontinuations, serious AEs, or dose-limiting AEs were observed.

In PET assessments (n=3), ACP-711 at 94-157 mg (1.16-2.25 mg/kg) indicated GABA_AR occupancy of 65.1%-86.0% (0.6-2.4 h postdose): estimated 50% occupancy at 301.1 ng/mL plasma concentration. EEGs showed dose-dependent decreases in delta-wave activity, an increase in alpha, and no change in beta or gamma activity vs placebo. ACP-711 did not alter sleep macro/microstructure after 9 days.

Simulations of 1.2- and 1.6-mg/kg-BID doses established target exposure ranges based on C_max,ss and AUC_0-12,ss medians ±20% (C_max,ss and AUC_0-12,ss, respectively; 1.2-mg/kg: 1194.0±238.8-ng/mL and 8072.0±1614.1-ng·h/mL; 1.6-mg/kg: 1592.0±318.4-ng/mL and 10,763.0±2152.6-ng·h/mL). Fixed doses of 100- or 150-mg-BID for <80 or ≥80 kg, respectively, resulted in exposures within target ranges.

Conclusions:

ACP-711 was safe/tolerable at concentrations reaching desired target occupancy. Results suggest specific EEG response and pharmacology distinct from benzodiazepines. Doses of 100- and 150-mg-BID for <80 and ≥80 kg, respectively, yielded target-exposure ranges and will guide dose selection in upcoming studies in essential tremor.