A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-group Study to Assess the Safety and Efficacy of ASP4345 as Add-on Treatment for Cognitive Impairment in Subjects With Schizophrenia on Stable Doses of Antipsychotic Medication

The purpose of this study was to evaluate the efficacy of ASP4345 on cognitive impairment compared to placebo using change from baseline in MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score (excluding social cognition domain). The primary estimand used a Hypothetical Strategy and compared participants as though the participant had continued on the assigned treatment and to evaluate the safety and tolerability of ASP4345 compared to placebo. This study also evaluated the effects of ASP4345 compared to placebo on functional capacity using the University of California San Diego Performance-based Skills Assessment-2 Extended Range (UPSA-2-ER) total score and evaluated the pharmacokinetic profile of ASP4345.

Start Date13 Jul 2018

Sponsor / Collaborator

Astellas Pharma Global Development, Inc.

NCT02720263 / CompletedPhase 1

A Phase 1 Multiple Ascending Oral Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ASP4345 in Patients With Schizophrenia

The purpose of this study is to evaluate the safety and tolerability of multiple ascending oral doses of ASP4345 in patients with schizophrenia. In addition, this study will evaluate the pharmacokinetics of multiple ascending oral doses of ASP4345 in patients with schizophrenia.

Start Date28 Mar 2016

Sponsor / Collaborator

Astellas Pharma Global Development, Inc.

100 Clinical Results associated with ASP-4345

100 Translational Medicine associated with ASP-4345

100 Patents (Medical) associated with ASP-4345

Literatures (Medical) associated with ASP-4345

01 May 2021·NeuropsychopharmacologyQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

AbstractASP4345, 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.

01 Jan 2021·Clinical PharmacokineticsQ2 · MEDICINE

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies

Q2 · MEDICINE

Article

Author: Gertsik, Lev ; Desai, Amit ; Uz, Tolga ; Wu, Ruishan ; Zhu, Tong ; Benner, Lauren ; Marek, Gerard J

BACKGROUNDCognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D₁) receptor that selectively binds to, and enhances the activity of, D₁ receptors. ASP4345 has the potential to be an effective and well-tolerated treatment option for cognitive impairment associated with schizophrenia.OBJECTIVEThe objective of this study was to determine the pharmacokinetics of ASP4345 in two phase I single ascending-dose and multiple ascending-dose studies.METHODSBoth phase I studies were randomized, double blind, and placebo controlled. The single dose-ascending study assessed pharmacokinetics of single oral doses of 3-900 mg of ASP4345 or placebo in the fasted state in healthy adult volunteers. This study also assessed cerebrospinal fluid pharmacokinetics, as well as the effects of food on pharmacokinetic parameters. The multiple ascending-dose study (NCT02720263) assessed the pharmacokinetics of multiple oral doses of 3-150 mg of ASP4345 in patients with schizophrenia or schizoaffective disorder receiving stable antipsychotic drug treatment. The pharmacokinetic data from both studies were summarized using descriptive statistics.RESULTSThe plasma concentration-time profile in both studies showed a rapid increase in concentrations of ASP4345. The median time to maximum concentration range was 1.00-2.26 h in the single ascending-dose study in the fasted state and 1.25-3.02 h in the multiple ascending-dose study at steady state. There were less than dose-proportional increases in maximum concentration and area under the curve in the single ascending-dose study, where doses had a range from 3 to 900 mg, and in the multiple ascending-dose study in patients with stabilized schizophrenia or schizoaffective disorder, where doses had a range from 3 to 150 mg. The mean terminal elimination half-life was dose independent and had a range from 9.12 to 14.3 h in the single ascending-dose study and from 11.1 to 26.8 h in the multiple ascending-dose study. Additionally, in the single ascending-dose study, absorption of 300 mg of ASP4345 was slightly delayed when administered in the fed state compared with the fasted state; median time to maximum concentration was 1.5 h under the fasting state and 4.0 h under fed states. All other pharmacokinetic parameters were comparable for both conditions. ASP4345 appeared in the cerebrospinal fluid with some delay; time to maximum concentration range was from 2.48 to 7.98 h in cerebrospinal fluid compared with 0.75 to 1.03 h in plasma (median cerebrospinal fluid/plasma = 0.188). The ratio of cerebrospinal fluid to total plasma for area under the curve from 0 to 24 h (0.157-0.573%) and maximum concentration (0.0899-0.311%) and the ratio of cerebrospinal fluid to unbound plasma for maximum concentration (25.0-86.4%) confirm the distribution of ASP4345 into the brain.CONCLUSIONSThe pharmacokinetics of ASP4345 suggest that single daily dosing is appropriate for ASP4345. Furthermore, the concentration of ASP4345 in cerebrospinal fluid compared to free drug concentrations in plasma provides evidence of penetration of ASP4345 into the brain.

100 Deals associated with ASP-4345

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Cognitive Dysfunction	Phase 2	US	Astellas Pharma Global Development, Inc.	13 Jul 2018
Schizophrenia	Phase 2	US	Astellas Pharma Global Development, Inc.	13 Jul 2018

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03557931 (CTgov)	Phase 2	Cognitive Dysfunction \| Schizophrenia	233	risperidone+aripiprazole+placebo+paliperidone+olanzapine+lurasidone+brexpiprazole+ziprasidone+Quetiapine (Placebo)	gwcwwchdrx(jbsotxvgtt) = fmzhebcfpx fhqeuswatt (lppnakmqgc, gvyejmuqmw - jrwdpbjkga) View more	-	27 Oct 2020
				risperidone+aripiprazole+paliperidone+olanzapine+lurasidone+ASP4345+brexpiprazole+ziprasidone+Quetiapine (ASP4345 150 mg)	gwcwwchdrx(jbsotxvgtt) = pzepszkcoc fhqeuswatt (lppnakmqgc, cywgeqgoky - zrknujzktj) View more

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