Single‐ and Multiple‐Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies

Abstract

ASP8062 is an orally active γ‐amino‐butyric acid type B (GABAB) receptor positive allosteric modulator currently in phase 2 development. Safety and pharmacokinetic (PK) profiles of ASP8062 were evaluated in 2 studies in healthy subjects. The first study (a first‐in‐human study) evaluated single ascending doses (SAD) of ASP8062. The second study was composed of 2 parts: part 1 evaluated multiple ascending doses (MAD) of ASP8062 for 14 days, and part 2 was a single‐dose arm to assess the PK of ASP8062 in cerebrospinal fluid (CSF). Fifty‐six men (SAD) and 56 subjects (24 women and 32 men; MAD) were enrolled. Across the SAD dosing range, area under the concentration‐time curve was dose proportional; increases in maximum plasma concentration appeared linear but were slightly less than dose proportional. Time to maximal concentration and half‐life were 1‐4 hours and ∼40‐50 hours, respectively; no food effect was observed. ASP8062 PK properties at steady state were similar to those following a single dose. Steady state was achieved by ∼day 9 with ∼2‐fold accumulation, and ASP8062 was detected in CSF. ASP8062 was well tolerated; no clear evidence of ASP8062's effects on safety, cognition, drug withdrawal, or suicidal ideation/behavior was observed. These data support the development of ASP8062 in indications where the GABAB receptor is a target.

A randomized phase 1 single-dose polysomnography study of ASP8062, a GABAB receptor positive allosteric modulator

“…In general, pharmacokinetics of ASP8062 taken following nighttime dosing were consistent with those reported in the (Walzer et al 2020). As expected, the AUC 24 for 70-mg ASP8062 was approximately double that of 35-mg ASP8062 (Table 5) and exposure following the 70-mg single dose was similar to the 30-mg once-daily dosing at steady state.…”

“…In this double-blind, placebo-and active-controlled, singledose, 4-way crossover PSG study, eligible healthy volunteers were randomly assigned to receive single oral doses of 35-mg ASP8062, 70-mg ASP8062, paroxetine 40 mg, or matching placebo 2 h before planned bedtime (Table 1). The single 70mg dose of ASP8062 was selected to match exposures to a 30mg QD dose, which was the highest dose administered in the 14-day multiple ascending dose study (Walzer et al 2020).…”

“…However, absorption was very rapid in some subjects, with T max less than 1 h, and slow in other subjects, with T max delayed to 8 h. The distribution of ASP8062 in the cerebrospinal fluid (CSF) after a single dose was also rapid, and similar to plasma, but slightly delayed; median T max times of 5 and 3 h were observed in the CSF following 10-mg (n = 4) or 70-mg (n = 4) single doses, respectively. Concentrations of ASP8062 persisted in CSF over the full 24-h sampling schedule (Walzer et al 2020).…”

“…In these studies, ASP8062 significantly decreased REM sleep, increased the power of delta waves during non-REM sleep, and significantly decreased the frequency of sleep interruptions. Therefore, ASP8062 was evaluated in a phase 1 single ascending oral dose study in healthy males administered doses of up to 70 mg (8062-CL-0001) and in a multiple ascending oral dose study in healthy male and female volunteers (8062-CL-0002) administered doses of up to 30 mg or placebo for 14 consecutive days (Murai et al 2019;Walzer et al 2020). ASP8062 had a tolerable safety profile at all doses after single and multiple administrations, and most treatment-emergent adverse events (TEAEs) were considered mild in severity.…”

“…The most common TEAEs across both studies were dizziness and headache. No deaths, serious adverse events (AEs), or TEAEs leading to withdrawal of treatment occurred throughout either study (Walzer et al 2020). After a single dose of 30mg (n = 6) or 70-mg (n = 6) ASP8062, the median time to peak plasma concentration (T max ) was 4 and 2.5 h, respectively.…”