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

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.

Modulating D1 rather than D2 receptor-expressing spiny-projection neurons corresponds to optimal antipsychotic effect

“…Over the past decade, much of the focus on D1Rs in schizophrenia has been on augmenting their signaling to promote cognition [56][57][58][59] . This idea is largely based on foundational work showing that, in schizophrenia, dopamine transmission is decreased within the prefrontal cortex, p. 16 where D1Rs are enriched and their signaling is crucial for cognitive function 60,61 .…”

A Patent Review on the Current Developments of Benzoxazoles in Drug Discovery

“…[90] Besides, they are found to show decreased or no receptor desensitisation compared to orthosteric agonists. [90] This class of drug is important in preventing and/or treating cognitive impairment, [89] schizophrenia, [91] depression, [92] Parkinson's disease, [93] Alzheimer's disease, [92] Huntington's disease [88] and attention deficit hyperactivity disorder. [94] Astellas Pharma Inc. discovered benzoxazole derivatives that are useful as dopamine D1 receptor PAMs.…”

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

“…For instance, in transgenic mice over-expressing D1 receptors, the D1-receptor PAM DETQ led to improved performance in an object recognition task and in cortical ACH release [392]. A phase 1 clinical trial with the D1receptor PAM ASP4345 showed improvements in psychomotor function, visual attention and corresponding improvements in neurophysiological markers [393].…”