A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia.

aimsTAK-041 (NBI-1065846), an orally available, investigational, small molecule agonist of GPR139, an orphan G-protein-coupled receptor, has shown promise in preclinical studies for the treatment of symptoms associated with schizophrenia. Here, we report the results from a phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy adults and exploratory efficacy assessment of TAK-041 as adjunctive therapy to antipsychotics in adults with stable schizophrenia (ClinicalTrials.gov: NCT02748694).

methodsThe study comprised 4 parts: parts 1-3 were undertaken in healthy adults and part 4 in patients with stable schizophrenia. Part 1 was a single-rising-dose study, part 2 was a multiple-rising-dose study that assessed plasma exposure and accumulation, part 3 evaluated the bioavailability of tablet formulation versus oral suspension, and part 4 was a repeat multiple-dose study in patients with stable schizophrenia.

resultsNo serious adverse events were reported. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Bioavailability was similar between the tablet formulation and oral suspension, and no meaningful food effect was detected. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. A potential signal of improvement was detected in the anxiety-depression scale of the Positive and Negative Syndrome Scale (P = .0002, not corrected for multiplicity) and the Temporal Experience of Pleasure Scale in patients with schizophrenia.

conclusionTAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia. Further investigation of TAK-041 in individuals with schizophrenia is supported.