Abstract
Background: Current treatments for schizophrenia generally have significant side effects and show limited efficacy across symptom domains. TAK-063 is a novel, potent, and selective inhibitor of phosphodiesterase 10A, an intracellular enzyme selectively expressed in the medium spiny neurons of the striatum. TAK-063 has shown efficacy in animal models of schizophrenia, and was shown to be safe and well tolerated in Phase 1 studies of healthy subjects and subjects with stable schizophrenia. This study evaluated the efficacy and safety of 20-mg daily TAK-063 vs placebo in subjects with acutely exacerbated symptoms of schizophrenia.
Methods: Adults aged 18 to 65 with diagnosed schizophrenia and psychotic symptoms that exacerbated within 60 days before screening were randomized 1:1 to 6 weeks of placebo or 20-mg TAK-063 (taken once daily at night with food). Dose de-escalation was allowed (blinded) to 10-mg TAK-063 for intolerability. Efficacy was measured with the Positive and Negative Syndrome Scale (PANSS) total score. The primary endpoint was the least-squares (LS) mean change from baseline in total PANSS score at week 6. The study was powered (80%) to detect a difference on the total PANSS of 10 points at week 6, with a common SD of 20 points (effect size = 0.5).
Results: Of the 164 subjects enrolled (n = 81, placebo; n = 83, TAK-063), 106 subjects completed the study. Except for an imbalance in race distribution (43 and 65 black subjects were enrolled in the placebo and TAK-063 groups, respectively), the treatment groups were similar. The number of dose de-escalations was equivalent in each group (1 each). The change from baseline at week 6 was approximately −14 points in the placebo group and approximately −19.5 points in the TAK-063 group (LS mean = −5.46; SE = 3.44; P = .115, effect size = 0.308) from the mixed model repeated measures analysis. Secondary endpoints were generally supportive of antipsychotic efficacy. The rates of all-cause discontinuation were similar between groups. In this study, TAK-063 was safe and generally well tolerated, and consistent with Phase 1 findings.
Conclusion: In this study, 20 mg of TAK-063 did not show statistical superiority to placebo in total PANSS at week 6. Secondary endpoints, however, were supportive of overall antipsychotic efficacy. TAK-063 was safe and well-tolerated. The interpretation of these results is confounded by the lack of dose-ranging and active reference.