Abstracts

Rationale: TARPγ8, a transmembrane AMPA receptor regulatory protein (TARP), provides a novel target for seizure control due to its enriched expression in hippocampus, cortex, and amygdala without expression in hindbrain. RAP-219 is a TARPγ8 negative allosteric modulator that has been efficacious in preclinical seizure models. Here, we describe the pharmacokinetics (PK) and effect of a high-fat meal following a single dose of RAP-219 in healthy adult subjects.

Methods: Six healthy subjects (18-55y) were enrolled in a food effect (FE) cohort of the SAD study in an open-label, parallel design trial. The RAP-219 dose (single dose, 1mg) was determined based on the safety, tolerability, and PK determined during the SAD trials and did not exceed the highest dose evaluated. The demographics (age, mean ± 10 years; sex, equal number females; body weight, mean ± 10%; race, equal number non-White subjects) of the FE cohort were matched to the corresponding fasted cohort (single dose, 1mg).

Subjects were given a single 1mg dose of RAP-219 on Day 1, 30min after the start of a high-fat, high-calorie breakfast. Blood samples were collected pre-dose and over 12 timepoints post-dose (15min to 144h). Maximum plasma concentration (C_max), time to C_max (t_max), area under the serum concentration-time curve from time 0 to the last timepoint (AUC_0-144), and terminal half-life (t_1/2) were calculated.

The effect of a high-fat meal was assessed using ln-transformed C_max and AUC_0-144 in an ANOVA model (fixed effect) using 2 one-sided tests (α = 0.05). The model compared the fed cohort to the fasted cohort. Geometric mean ratios (90% CI) from ANOVA were reported; FE on RAP-219 PK parameters was determined by comparing the 90% CI to the predefined limits (80%-125%). T_max values under fasted and fed conditions were assessed using the Wilcoxon rank sum test (α = 0.05).

Adverse events (AEs; treatment-emergent [TEAEs] and serious [SAEs]) were recorded. TEAE severity was evaluated using the NCI-CTCAE v5.0 (Grade 1, mild, to 5, death related to AE).

Results: A single dose of RAP-219 following a high-fat, high-calorie meal led to a 42% increase in C_max and 25% increase in AUC_0-144, with a slight delay in the median t_max of 1h compared to the fasted condition (Fig 1, Table 1).

One subject experienced a TEAE (confusion, Grade 1) on Day 1. There were no other TEAEs reported in the trial. Additionally, there were no clinically significant changes in laboratory, ECG parameters, or vital signs.

Conclusions: Results from this initial evaluation of the effect of high-fat, high-calorie meal on RAP-219 PK suggest that there was a slight increase in C_max and AUC_0-144 as well as a slight delay in RAP-219 absorption under fed conditions compared to fasted. This study informs and supports ongoing clinical development. More robust FE studies are planned to fully characterize the effect of food on RAP-219 PK.

Funding: Funded by Rapport