tak-063 and Schizophrenia

The basal ganglia regulates motor, cognitive, and emotional behaviors. Dysfunction of dopamine system in this area is implicated in the pathophysiology of schizophrenia characterized by positive symptoms, negative symptoms, and cognitive deficits. Medium spiny neurons (MSNs) are principal output neurons of striatum in the basal ganglia. Similar to current antipsychotics with dopamine D

Topics: Animals; Enzyme Inhibitors; Humans; Phosphoric Diester Hydrolases; Pyrazoles; Pyridazines; Schizophrenia; Signal Transduction

TAK-063 is a potent, selective inhibitor of phosphodiesterase 10A, an enzyme selectively expressed in medium spiny neurons of the striatum. This randomized, parallel-group study evaluated the efficacy and safety of 20-mg daily TAK-063 versus placebo in subjects with acutely exacerbated symptoms of schizophrenia (NCT02477020).. Adults aged 18 to 65 with diagnosed schizophrenia and psychotic symptoms that exacerbated within 60 days before screening were included. Subjects who discontinued psychotropic medications before screening were randomized 1:1 to 6 weeks of placebo (n = 81) or 20-mg TAK-063 (n = 83). Weekly efficacy visits were conducted during the treatment period, and dose de-escalation was allowed (blinded) to 10-mg TAK-063 for intolerability.. The primary endpoint, change from baseline in the Positive and Negative Syndrome Scale total score at week 6, was not achieved (least-squares mean difference vs placebo [standard error] = -5.46 [3.44]; p = 0.115). Secondary endpoints were generally supportive of antipsychotic efficacy. Consistent with previous phase 1 studies, TAK-063 was safe and well tolerated, and most adverse events were mild or moderate in severity and did not result in discontinuation. No deaths occurred, and the incidence of akathisia and dystonia, categories of extrapyramidal syndromes, was more frequent in the TAK-063 group than placebo.. Although the study did not meet the primary endpoint (effect size = 0.308), the effects of TAK-063 on the primary and secondary endpoints may be suggestive of antipsychotic activity. Interpretation of these results is confounded by a relatively high placebo effect and a lack of dose-ranging or active reference.

Topics: Acute Disease; Adolescent; Adult; Aged; Corpus Striatum; Humans; Middle Aged; Outcome Assessment, Health Care; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrazoles; Pyridazines; Schizophrenia; Young Adult

Phosphodiesterase 10A (PDE10A) is selectively expressed in medium spiny neurons of the striatum. TAK-063 is a selective inhibitor of PDE10A in clinical development for the treatment of schizophrenia.. Safety, tolerability, and pharmacokinetics (PK) of TAK-063 were evaluated following multiple rising oral doses, and PK/adverse event (AE) models were developed to characterize the relationship between TAK-063 exposure and incidence of specific AEs.. Healthy Japanese subjects (HJS) aged 20-55 years and subjects with stable schizophrenia (SSS) aged 18-55 years were enrolled and randomized to either TAK-063 or placebo. Study medication was administered as a tablet once daily (at night) with food over a 7-day period.. TAK-063 and placebo groups consisted of 62 and 15 subjects, respectively. A majority of subjects (71 of 77) completed the study. AEs were mostly of mild or moderate severity, and no deaths were reported. The most common AE was somnolence. For equivalent doses, the rate of extrapyramidal syndromes (EPS) was higher in SSS than in HJS. PK parameters were comparable between HJS and SSS at equivalent doses. The incidence of somnolence and EPS symptoms increased with exposure, and this was described with the PK/AE model. A maximum tolerated dose was not determined.. Multiple doses of TAK-063 were safe and well tolerated. PK/AE models characterized the incidence of somnolence and EPS with increasing TAK-063 exposure, and simulations suggested that a once-daily dose range of up to 30 mg would be suitable for future studies. CLINICALTRIALS.. NCT01879722.

Topics: Administration, Oral; Adolescent; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Japan; Middle Aged; Models, Biological; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrazoles; Pyridazines; Schizophrenia; Young Adult

TAK-063 is an inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the striatum. PDE10A hydrolyzes both cyclic adenosine monophosphate and cyclic guanosine monophosphate and modulates dopamine signaling downstream of receptor activation in both direct and indirect pathways of the striatum. TAK-063 exhibited antipsychotic-like effects in animal models; however, the translatability of these models to the clinical manifestations of schizophrenia and the meaningfulness for new targets such as PDE10A has not been established.. The TAK-063 phase 1 program included a comprehensive translational development strategy with the main objective of determining whether the antipsychotic-like pharmacodynamic effects seen in nonclinical models would translate to human subjects. To evaluate this objective, we conducted a single-rising dose study (84 healthy subjects), a positron emission tomography (PET) study (12 healthy subjects), a functional magnetic resonance imaging blood oxygen level-dependent (BOLD) study (27 healthy subjects), and a multiple-rising dose study that included people with schizophrenia (30 healthy Japanese subjects and 47 subjects with stable schizophrenia). In addition, assessments of cognition and electroencephalography (27 healthy subjects and 47 subjects with stable schizophrenia) were included.. PDE10A engagement by TAK-063 was verified with a novel PET radiotracer for use in primates and humans. TAK-063 showed favorable pharmacokinetic and safety profiles in humans, and TAK-063 reduced ketamine-induced changes in electroencephalography and BOLD signaling in animal models and healthy human subjects. In addition, analogous effects on cognition were observed in animal models and human subjects.. Overall, the phase 1 results showed some consistent evidence of antipsychotic activity. This translational strategy may be valuable for the future development of novel therapeutic approaches, even when relevant nonclinical models are not available.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Brain; Clinical Trials as Topic; Cognition; Electroencephalography; Europe; Humans; Japan; Magnetic Resonance Imaging; Models, Animal; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Positron-Emission Tomography; Pyrazoles; Pyridazines; Radioligand Assay; Schizophrenia; Schizophrenic Psychology; Translational Research, Biomedical; Treatment Outcome; United States

Cognitive deficits in various domains, including recognition memory, attention, impulsivity, working memory, and executive function, substantially affect functional outcomes in patients with schizophrenia. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a potent and selective phosphodiesterase 10A inhibitor that produces antipsychotic-like effects in rodent models of schizophrenia. We evaluated the effects of TAK-063 on multiple cognitive functions associated with schizophrenia using naïve and drug-perturbed rodents. TAK-063 at 0.1 and 0.3 mg/kg p.o. improved time-dependent memory decay in object recognition in naïve rats. TAK-063 at 0.1 and 0.3 mg/kg p.o. increased accuracy rate, and TAK-063 at 0.3 mg/kg p.o. reduced impulsivity in a five-choice serial reaction time task in naïve rats. N-methyl-d-aspartate receptor antagonists, such as phencyclidine and MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], were used to induce working memory deficits relevant to schizophrenia in animals. TAK-063 at 0.3 mg/kg p.o. attenuated both phencyclidine-induced working memory deficits in a Y-maze test in mice and MK-801-induced working memory deficits in an eight-arm radial maze task in rats. An attentional set-shifting task using subchronic phencyclidine-treated rats was used to assess the executive function. TAK-063 at 0.3 mg/kg p.o. reversed cognitive deficits in extradimensional shifts. These findings suggest that TAK-063 has a potential to ameliorate deficits in multiple cognitive domains impaired in schizophrenia.

Topics: Animals; Cognition; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred ICR; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrazoles; Pyridazines; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Schizophrenia

Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP phosphodiesterase highly expressed in medium spiny neurons (MSNs) in the striatum. We evaluated the in vivo pharmacological profile of a potent and selective PDE10A inhibitor, TAK-063 (1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one). TAK-063 at 0.3 and 1 mg/kg p.o., increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP- and cGMP-dependent protein kinases. TAK-063 at 0.3 and 1 mg/kg p.o., strongly suppressed MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]-induced hyperlocomotion, which is often used as a predictive model for antipsychotic-like activity in rodents. Upregulation of striatal cAMP/cGMP levels and the antipsychotic-like effect of TAK-063 were not attenuated after 15 days of pretreatment with TAK-063 in mice. The potential side effect profile of TAK-063 was assessed in rats using the clinical antipsychotics haloperidol, olanzapine, and aripiprazole as controls. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg p.o. At 3 mg/kg p.o., TAK-063 elicited a weak cataleptic response compared with haloperidol and olanzapine. Evaluation of pathway-specific markers (substance P mRNA for the direct pathway and enkephalin mRNA for the indirect pathway) revealed that TAK-063 activated both the direct and indirect pathways of MSNs. These findings suggest that TAK-063 represents a promising drug for the treatment of schizophrenia with potential for superior safety and tolerability profiles.

Topics: Animals; Antipsychotic Agents; Male; Mice; Mice, Inbred ICR; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrazoles; Pyridazines; Rats; Rats, Sprague-Dawley; Schizophrenia