Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia

Amit Desai,Ruishan Wu,Tong Zhu,Gerard J Marek,Paul Maruff,Lauren Benner,Tolga Uz,Gregory A Light,Lev Gertsik

doi:10.1038/s41386-020-00908-0

Abstract

ASP4345, a novel dopamine D1 receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150 mg; n = 9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.

Highlights

The central role of dopamine in working memory within the nonhuman primate prefrontal cortex was discovered by demonstrating that depleting dopamine reprised the working memory deficits produced by complete ablation of the prefrontal cortex [1]
Disruption to dopaminergic neurotransmission is a central characteristic of schizophrenia, and while overactivity of distributed dopamine networks with influences of the dopamine D2-like receptor family (e.g., D2, D3, and D4 receptors) is putatively involved in the primary psychotic manifestations of the disease, activation of dopamine D1 receptors has been recommended as a target for the investigation of treatment of cognitive impairment associated with schizophrenia (CIAS) [7]
ASP4345 did not induce any apparent suicidality as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)

Summary

Introduction

The central role of dopamine in working memory within the nonhuman primate prefrontal cortex was discovered by demonstrating that depleting dopamine reprised the working memory deficits produced by complete ablation of the prefrontal cortex [1]. Subsequent research findings have confirmed that dopamine and D1 receptors have a strong regulatory role in dorsolateral prefrontal cognitive function (i.e., cognition, emotion, and motor function) [4,5,6]. Disruption to dopaminergic neurotransmission is a central characteristic of schizophrenia, and while overactivity of distributed dopamine networks with influences of the dopamine D2-like receptor family (e.g., D2, D3, and D4 receptors) is putatively involved in the primary psychotic manifestations of the disease, activation of dopamine D1 receptors has been recommended as a target for the investigation of treatment of cognitive impairment associated with schizophrenia (CIAS) [7]. More recent work identifying increases in prefrontal cortical dopamine D1 receptors in antipsychotic-naive patients with schizophrenia has added further interest to physiologically relevant modification of presumed decreased dopamine in the dorsolateral prefrontal cortex of patients with schizophrenia [8]. Dopamine D1 agonists were previously investigated in CIAS; their use is limited by off-target safety concerns, seizures, and orthostatic hypotension [5]

Methods

Results

Conclusion