A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects

Abstract

Rationale Phosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest efficacy in schizophrenia treatment. Objective This randomized, double-blind, placebo-controlled, incomplete-crossover study investigated effects of single oral administration of TAK-063 on ketamine-induced changes in blood oxygen level-dependent (BOLD) signal in healthy males. Methods Healthy men aged 18 to 45 years with normal magnetic resonance imaging (MRI) scans and electroencephalogram measurements at screening were eligible. Each subject was randomized to one of nine treatment schedules: all subjects received placebo and two of three doses of TAK-063 followed by ketamine. The primary endpoint was ketamine-induced brain activity in select regions of the brain during resting state. Secondary endpoints included pharmacokinetic parameters of TAK-063, proportion of subjects with treatment-emergent adverse events (AEs), and percentage of subjects meeting criteria for abnormal safety laboratory tests and vital sign measurements. Results The study comprised 27 subjects. Prior to ketamine infusion, TAK-063 exerted region-specific effects on resting state functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced the Cohen's effect size for resting-state fMRI BOLD signal in key brain regions examined, and exerted similar effects on BOLD signal during the working memory task across all doses. TAK-063 was safe and well tolerated. Conclusions Our results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required.

Translational Development Strategies for TAK-063, a Phosphodiesterase 10A Inhibitor

“…To extend the phMRI findings in rodents, TAK-063 was investigated in ketamine-treated healthy human subjects ( Yurgelun-Todd et al, 2020 ). Compared with placebo, TAK-063 reduced ketamine-induced increases in BOLD signal across all brain regions analyzed during the working memory task ( Figure 2 ; Supplementary Figure S3 ) in a dose-dependent manner ( Yurgelun-Todd et al, 2020 ). The most consistent reversal of ketamine-induced effects in fMRI was observed in the 30-mg TAK-063 dose group, which approximates the steady state exposure of 20 mg ( Macek et al, 2016b ).…”

“…EEG studies were also conducted in subjects with stable schizophrenia (SSS) who were on stable antipsychotic monotherapy and received 3, 10, 30, or 100 mg TAK-063 during a 7-day multiple-rising dose study ( Macek et al, 2016a ); according to Goldsmith et al ( 2017 ), SSS can be defined as an individual on stable antipsychotic monotherapy for ≥1 month before screening, who had a Clinical Global Impression of Severity score ≤4, and a total Positive and Negative Symptom Scale score ≤70 at screening and check-in (Day -1; Macek et al, 2016a ; Goldsmith et al 2017 ). Additionally, an EEG was assessed in healthy subjects who received 3, 10, and 30 mg TAK-063 in an incomplete crossover, ketamine-challenge, functional MRI (fMRI) study ( Yurgelun-Todd et al, 2020 ); ClinicalTrials.gov ID: NCT01892189), and EEG recordings were made after the imaging battery was complete, which was approximately 5 hours after the administration of study medication (n = 14 for 3 mg and 10 mg doses; n = 15 for 30 mg dose). In the multiple-rising dose study, 10-minute samples of 19-channel EEG recordings were taken while subjects were either (1) seated with eyes closed (resting condition) or (2) presented with high-frequency auditory stimuli at 40 Hz in blocks (40-Hz condition; n = 9 for placebo; n = 7 for 100 mg dose).…”

“…EEG recordings were made after the imaging battery was complete, approximately 5 hours after the administration of study medication, and were generally similar to the EEG methods used in the multiple-rising dose study. The fMRI BOLD signal was assessed during the resting state and a working memory activation task (the expectancy AX Continuous Performance Test paradigm, for 15 minutes; Yurgelun-Todd et al, 2020 ). BOLD echo planar images were obtained during a 20-minute resting-state sequence using a 3 Tesla Siemens Verio scanner (repetition time = 2 s, echo time = 28 ms, 40 slices, 3 mm slice thickness).…”

Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments

“…Its blockage in animal models of schizophrenia using rodents and apes induces a beneficial effect in cognitive deficit [ 217 , 218 ]. TAK-063, a PDE10 inhibitor, has reached clinical trials, and although it was shown to be safe in phase 1 [ 219 ], it did not show a significant improvement in cognitive abilities in phase 2 studies with schizophrenic patients [ 119 ].…”

Phosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke

“…TAK-063 [1-[2-uoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a potent and highly selective inhibitor of PDE10A [13]. Preclinical and clinical data indicate that TAK-063 is safe and well tolerated in humans [14,15]. Harada et.…”