A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia

Murai, Norihiko; Akuzawa, Shinobu; Mihara, Takuma; Shiraishi, Nobuo; Kakimoto, Shuichiro; Matsumoto, Mitsuyuki

doi:10.1016/j.ejphar.2019.172750

Cited by 22 publications

(13 citation statements)

References 35 publications

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“…ASP8062 is a novel orally active GABA B receptor PAM in clinical development for the treatment of AUD and OUD (data on file) (Walzer et al, 2020(Walzer et al, , 2021. ASP8062 has been characterized as a GABA B receptor PAM in in vitro studies, and in in vivo studies, ASP8062 has demonstrated effects on sleep activity and in preclinical pain models (Murai et al, 2019). ASP8062 decreased alcohol reinforcement like baclofen but without nonspecific effects which are influenced by sex (Haile et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects

et al. 2022

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Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). Aims: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. Methods: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. Results/outcomes: After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and Cmax) of ASP8062 was observed, but tmax and t½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUClast and Cmax of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Conclusion/interpretation: The data support further clinical studies investigating ASP8062 in patients with AUD.

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Section: Introductionmentioning

confidence: 99%

A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects

et al. 2022

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“…ASP8062 is a novel, orally active GABA B receptor PAM, previously studied in vitro and also in vivo to evaluate its effects on the sleep/wake cycle, EEG during sleep stages, and motor coordination in rats (Murai et al 2019). 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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Walzer

Ahmad

et al. 2021

Psychopharmacology

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Rationale Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. Objectives This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). Methods Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. Results In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. Conclusions Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.

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“…Therefore, GABA B receptor PAMs may represent a promising therapeutic option for the treatment of pain and other CNS-related indications. 15 ASP8062 16 is an orally active GABA B receptor PAM recently investigated in a phase 2 trial for the assessment of analgesic efficacy in patients with fibromyalgia (NCT03092726). Preclinical studies using transfected cell lines that incorporate stable expression of human or mouse GABA B 1c/2 receptors demonstrated that ASP8062 enhanced the potency and maximal response over a wide range of GABA concentrations (data on file).…”

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confidence: 99%

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

Walzer

Marek

et al. 2020

Clinical Pharm in Drug Dev

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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.

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A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia

Cited by 22 publications

References 35 publications

A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects

A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects

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

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

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