A Phase IC Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Cognitive Outcomes of BI 409306 in Patients with Mild-to-Moderate Schizophrenia

David Brown, Kristen Daniels, Solen Pichereau, Michael Sand, David Brown, Kristen Daniels, Solen Pichereau, Michael Sand

Abstract

Introduction: This randomized, double-blind, parallel-group study investigated the safety, tolerability, pharmacokinetics (PK), and cognitive outcomes of BI 409306-a selective phosphodiesterase 9A (PDE9A) inhibitor-in patients with schizophrenia.

Methods: Patients with mild-to-moderate schizophrenia were randomized (1:1:1:1) to receive BI 409306 at 25, 50, or 100 mg or placebo once daily over 14 days. The primary endpoints were safety and tolerability; the secondary endpoints were PK and cognitive outcomes.

Results: Of the 40 randomized patients, 38 (95%) completed the study. Patients were predominantly male (87.5%; mean age, 40.2 years). After a single dose, C max was reached within 30-45 min. The geometric mean (gMean) C max and AUC0-∞ ranged from 138 to 998 nmol/L and 217 to 2020 nmol∙h/L, respectively. Elimination was rapid (gMean t 1/2 range 1.10-1.85 h). After multiple doses, C max,ss was reached within 1 h; elimination was similar to that observed after a single dose. Total exposure at steady state and after a single dose were similar (accumulation ratio range: AUC, 0.758-1.13 and Cmax, 0.768-1.40). No deaths, adverse events (AEs) leading to discontinuation, or serious AEs were observed. Treatment-emergent AEs were mild, with no apparent dose-related trends. There was no worsening of schizophrenia symptoms (Positive and Negative Syndrome Scale) and no trends in suicidality (Columbia Suicide Severity Rating Scale). The Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) showed no effect on cognitive function.

Conclusion: Administration of BI 409306 in patients with mild-to-moderate schizophrenia resulted in satisfactory safety and tolerability. BI 409306, PK was characterized by rapid absorption, monophasic to biphasic elimination, and minor accumulation with multiple dosing.

Trial registration: ClinicalTrials.gov identifier NCT01892384.

Funding: Boehringer Ingelheim Pharma GmbH & Co. KG.

Keywords: BI 409306; Cognitive outcome; PDE9A; Pharmacokinetics; Phase I; Phosphodiesterase inhibitor; Safety; Schizophrenia; Tolerability.

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Patient disposition
Fig. 3
Fig. 3
Geometric mean plasma concentration–time profiles after single and multiple doses of BI 409306 (25, 50, and 100 mg)

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