A phase 1b study to investigate the potential interactions between ASP8062 and buprenorphine/naloxone in patients with opioid use disorder

Abstract

Background: There is an unmet need for therapeutics with greater efficacy and tolerability for the treatment of opioid use disorder (OUD). ASP8062 is a novel compound with positive allosteric modulator activity on the γ-aminobutyric acid type B receptor under development for use with standard-of-care treatment for patients with OUD. Aims: To investigate the safety, tolerability, interaction potential, and pharmacokinetics (PK) of ASP8062 in combination with buprenorphine/naloxone (B/N; Suboxone®). Methods: In this phase 1, randomized, double-masked, placebo-controlled study, patients with OUD began B/N (titrated to 16/4 mg/day) treatment upon enrollment (induction, Days 1–4; maintenance, Days 5–18; downward titration, Days 19–26; and discharge, Day 27). On Day 12, patients received a single dose of ASP8062 60 mg or placebo with B/N and underwent safety and PK assessments. Primary endpoints included frequency and severity of treatment-emergent adverse events (TEAEs), clinical laboratory tests, respiratory depression, and suicidal ideation. Secondary endpoints investigated the impact of ASP8062 on B/N PK. Results: Eighteen patients were randomized and completed the study (ASP8062, n = 12; placebo, n = 6). With this sample size typical for phase 1 drug–drug interaction studies, ASP8062 was well tolerated; most TEAEs were mild in severity, and none led to treatment withdrawal. ASP8062 did not enhance substance use-related TEAEs, respiratory depression, or suicidal ideation and did not have a clinically significant impact on the PK of B/N. Conclusions: In this phase 1 study, ASP8062 was safe, well tolerated, and did not enhance respiratory suppression induced by buprenorphine. Trial registration: Clinicaltrials.gov identifier: NCT04447287.

A phase 1 randomized, placebo-controlled study to investigate potential interactions between ASP8062, a positive allosteric modulator of the GABAB receptor, and morphine in recreational opioid users

“…Similarly, there was a numerically lower mean absolute ETCO 2 level for participants after receiving ASP8062 plus one morphine dose compared with participants receiving placebo plus one morphine dose, indicating ASP8062 potentially attenuated morphine-induced respiratory depression. These results are similar to those from a previous phase 1 study of ASP8062 and buprenorphine/naloxone treatment in participants with OUD, which found no increase in respiratory depression or potential drug abuse- or withdrawal-related TEAEs (Ito et al, 2023), suggesting a potentially low risk for respiratory depression due to drug–drug interactions for these compounds.…”

“…The PK properties of ASP8062 were similar to those reported in previous phase 1 studies (Ito et al, 2022(Ito et al, , 2023Walzer et al, 2020). The mean half-life of ASP8062 in this study was 53.6 h, similar to that reported in healthy volunteers (50-64 h) (Walzer et al, 2020), healthy volunteers who consumed alcohol regularly (65-68 h) (Ito et al, 2022) and participants with OUD (47 h; Ito et al, 2023).…”

“…The mean half-life of ASP8062 in this study was 53.6 h, similar to that reported in healthy volunteers (50–64 h) (Walzer et al, 2020), healthy volunteers who consumed alcohol regularly (65–68 h) (Ito et al, 2022) and participants with OUD (47 h; Ito et al, 2023). AUC 0–24h and C max results for ASP8062 only in this study (mean (SD): 1640 (619) and 124 (41.1), respectively) were similar to that for ASP8062 plus buprenorphine/naloxone in the previous phase 1 study in participants with OUD (1800 (497) and 152 (36.7), respectively; Ito et al, 2023). These similar data suggest that the PK profile of ASP8062 is consistent and predictable across studies in healthy volunteers, in participants with OUD, or in people who use opioids recreationally.…”

“…The incidence of dizziness in participants treated with ASP8062 (range, 6.7-12.5%) was similar to the rates observed in previous studies in healthy volunteers (range, 5-22%) (Ito et al, 2022;Walzer et al, 2020Walzer et al, , 2021. A similar rate of dizziness (8.3%) was also reported in a phase 1 OUD study investigating the interaction between a single dose of ASP8062 and buprenorphine/ naloxone, the standard-of-care treatment for OUD (Ito et al, 2023). However, the rate of dizziness was 30% in a previous phase 2 study investigating the use of ASP8062 in participants with fibromyalgia (NCT03092726).…”

“…ASP8062 is an orally available, γ-aminobutyric acid B (GABA B ) receptor positive allosteric modulator (PAM) (Murai et al, 2019) being investigated for the treatment of moderate to severe OUD and alcohol use disorder as defined by Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition (Haile et al, 2021; Ito et al, 2022, 2023). The GABA B receptor mediates suppression of self-administration and craving across several drug modalities; it decreases drug self-administration and drug-seeking behavior by either directly or indirectly affecting dopamine levels in the ventral tegmental, striatal, and prefrontal cortical areas of the brain (Filip and Frankowska, 2007; Filip et al, 2007).…”