ASP-8062

Recent increases in opioid use and subsequent opioid use disorder are a major public health crisis in the United States.

This phase 1 randomized, placebo-controlled study investigated the safety, tolerability, and pharmacokinetics (PKs) of ASP8062, a γ-aminobutyric acid B receptor-positive allosteric modulator, with and without administration of morphine in participants who used opioids recreationally.

Participants were randomly assigned (2:1) to daily dosing with ASP8062 25 mg or placebo on days 1–10. On day 10, all participants received morphine as a single oral dose of 45 mg; assessments were performed on days 11–16. The primary end point was safety, evaluated as the nature, frequency, and severity of adverse events, and end-tidal CO 2 levels. PK end points were a secondary outcome measure.

A total of 24 participants (aged 21–54 years) received ASP8062 ( n  = 16) or placebo ( n  = 8). There were no deaths or serious adverse events leading to treatment discontinuation during the study. Most adverse events were mild, with numerically lower absolute number of adverse events reported with ASP8062 plus morphine versus placebo plus morphine. ASP8062 plus morphine did not increase respiratory depression, potential drug abuse- or withdrawal-related adverse events. There were no significant PK interactions.

In this phase 1 study, we did not observe any unexpected safety signals or notable PK interactions with concomitant morphine administration. These data suggest a potentially low risk for an increase in drug abuse- or withdrawal-related adverse events or respiratory distress in participants exposed to ASP8062 and morphine.

ASP8062 is an orally available GABA_B receptor positive allosteric modulator (PAM). This study assessed the potential of ASP8062 for treating opioid use disorder (OUD). Three rhesus monkeys were pretreated with ASP8062 (0.3, 1 or 3 mg/kg) by oral administration 1 h prior to a 2-h morphine self-administration session (0.03 mg/kg, iv, per injection) under a fixed-ratio 5 schedule. We further examined the potential worsening of morphine-induced respiratory suppression by ASP8062 after coadministration of morphine (10 mg/kg, sc) and ASP8062 (10 mg/kg, po) in cynomolgus monkeys using a custom-made whole-body plethysmograph. Plasma concentrations of ASP8062 (3 or 10 mg/kg, po) were assessed in cynomolgus monkeys using liquid chromatography-tandem mass spectroscopy (LC-MS/MS). ASP8062 at 3 mg/kg, po decreased the morphine self-administrations with significant differences from the vehicle-treated group (IC₅₀ = 0.97 ± 0.36 mg/kg). Exposure levels at 3 mg/kg observed in monkeys were comparable to the clinical exposure levels which positive pharmacodynamic effects were previously shown. Further, ASP8062 did not potentiate morphine-induced respiratory suppression up to exposure levels higher than the clinically relevant dose. ASP8062 may reduce opioid use in OUD patients without affecting respiratory system, providing justification for further ASP8062 development as a potential treatment option for OUD.