Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Neurology and Therapy
Published in: Neurology and Therapy 1/2018

Open Access 01-06-2018 | Original Research

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

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

Published in: Neurology and Therapy | Issue 1/2018

Login to get access

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.
Literature
1.
Neill JC, Barnes S, Cook S, et al. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. Pharmacol Ther. 2010;128:419–32.CrossRefPubMed
2.
Nabeshima T, Mouri A, Murai R, Noda Y. Animal model of schizophrenia: dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine. Ann N Y Acad Sci. 2006;1086:160–8.CrossRefPubMed
3.
Salisbury DF, Shenton ME, Griggs CB, Bonner-Jackson A, McCarley RW. Mismatch negativity in chronic schizophrenia and first-episode schizophrenia. Arch Gen Psychiatry. 2002;59:686–94.CrossRefPubMed
4.
Schobel SA, Chaudhury NH, Khan UA, et al. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron. 2013;78:81–93.CrossRefPubMedPubMedCentral
5.
Medoff DR, Holcomb HH, Lahti AC, Tamminga CA. Probing the human hippocampus using rCBF: contrasts in schizophrenia. Hippocampus. 2001;11:543–50.CrossRefPubMed
6.
Dorner-Ciossek C, Baum-Kroker KS, Rosenbrock H. CNS functions and diseases-Chapter 15: role of PDE9 in cognition. In: Zhang H, Xu Y, O’Donnell JM, editors. Advances in neurobiology, vol. 17. Basel: Springer International Publishing; 2017.
7.
Reneerkens OA, Rutten K, Steinbusch HW, et al. Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharmacology. 2009;202:419–43.CrossRefPubMed
8.
Schmidt CJ. Phosphodiesterase inhibitors as potential cognition enhancing agents. Curr Top Med Chem. 2010;10:222–30.CrossRefPubMed
9.
Dorner-Ciossek C, Giovannini R, Rosenbrock H. BI 409306, a novel phosphodiesterase 9A inhibitor, part I: potency, selectivity and in vitro functional characterization on synaptic plasticity. International Congress on Schizophrenia Research. Schizophrenia Bull. 2015; p. S31.
10.
Rosenbrock H, Marti A, Koros E, et al. BI 409306, a novel phosphodiesterase 9A inhibitor, part II: in vivo characterization regarding target engagement and cognition tasks in rodents. International Congress on Schizophrenia Research. Schizophrenia Bull. 2015; p. S36.
11.
12.
Moschetti V, Boland K, Hoch A, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of BI 409306 film-coated tablets given orally once or twice daily for 14 days in young and elderly healthy volunteers. Poster presented at: Alzheimer’s Association International Conference, 18–23 Jul 2015, Washington, DC, USA.
13.
Wunderlich G, Kim JM, Yum S.-Y.A., et al. Safety, tolerability, and pharmacokinetics of BI 409306: a randomized, placebo-controlled, double-blinded phase I study in Chinese and Japanese healthy male volunteers. Poster presented at: Alzheimer’s Association International Conference, 18–23 Jul 2015, Washington, DC, USA.
14.
15.
16.
Schwam EM, Nicholas T, Chew R, et al. A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer’s disease. Curr Alzheimer Res. 2014;11:413–21.CrossRefPubMed
17.
Brown A, Daniels K, Zhang S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of BI 409306 film-coated tablets given orally qd for 14 days in patients with schizophrenia. International Congress on Schizophrenia Research. Schizophrenia Bull. 2015; p. S04.
Metadata
Title
A Phase IC Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Cognitive Outcomes of BI 409306 in Patients with Mild-to-Moderate Schizophrenia
Authors
David Brown
Kristen Daniels
Solen Pichereau
Michael Sand
Publication date
01-06-2018
Publisher
Springer Healthcare
Published in
Neurology and Therapy / Issue 1/2018
Print ISSN: 2193-8253
Electronic ISSN: 2193-6536
DOI
https://doi.org/10.1007/s40120-017-0085-5

Other articles of this Issue 1/2018

Neurology and Therapy 1/2018 Go to the issue

Commentary

Practical Treatment of Lewy Body Disease in the Clinic: Patient and Physician Perspectives

Letter

Author’s Response to the Letter to the Editor Regarding: Practical Treatment of Lewy Body Disease in the Clinic: Patient and Physician Perspectives

Editorial

Editorial Regarding: Practical Treatment of Lewy Body Disease in the Clinic: Patient and Physician Perspectives

Original Research

Positive Effectiveness of Tafamidis in Delaying Disease Progression in Transthyretin Familial Amyloid Polyneuropathy up to 2 Years: An Analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS)

Brief Report

Understanding the Disease Course and Therapeutic Benefit of Tafamidis Across Real-World Studies of Hereditary Transthyretin Amyloidosis with Polyneuropathy: A Proof of Concept for Integrative Data Analytic Approaches

Case Series

Treatment with Botulinum Toxin for Refractory Fever Caused by Severe Spasticity: A Case Series