A Phase II study of a histamine H3 receptor antagonist GSK239512 for cognitive impairment in stable schizophrenia subjects on antipsychotic therapy

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Abstract

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H3 receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES = 0.29, CI =  0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES =  0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.

Introduction

Cognitive impairment associated with schizophrenia (CIAS) constitutes a major unmet therapeutic need for people with schizophrenia. Available antipsychotics provide little, if any, benefit for these cognitive deficits and no treatments are currently approved for CIAS. Histamine H3 receptors are widely distributed in the central nervous system and antagonism of H3 receptors is known to release acetylcholine, dopamine, norepinephrine and histamine in specific brain regions involved with cognitive function (Brown et al., 2001), including the frontal cortex, an area implicated in CIAS (Jin et al., 2009, Barch and Ceaser, 2012). Limited post-mortem evidence also suggests altered H3 receptor expression in schizophrenia in the prefrontal cortex (Jin et al., 2009). The role of histamine H3 receptor is presently being investigated for potential impact on cognition in CIAS (Egan et al., 2013, Haig et al., 2014). GSK239512, a potent, selective, orally bioavailable and brain penetrant histamine H3 receptor antagonist (Ashworth et al., 2014), has shown efficacy in several preclinical cognition models (Wilson et al., 2013a, Wilson et al., 2013b). Additionally, signals of efficacy in the episodic memory cognitive domain have been observed in Alzheimer's disease trials (Nathan et al., 2013, Grove et al., 2014). Thus, selective H3 receptor antagonists may have therapeutic benefits in CIAS, and this exploratory pilot study was designed to investigate GSK239512 in the symptomatic treatment of CIAS.

Section snippets

Trial design

This Phase II, randomized, double-blind, placebo-controlled, parallel group study (GSK H3B113147) was conducted in adult outpatients (18–55 years) with DSM IV-TR schizophrenia (American Psychiatric Association, 1994) who were symptomatically stable and taking stable doses of antipsychotic medication (Buchanan et al., 2005). Subjects were determined to be ‘stable’ if they were on a stable dose of antipsychotic medications, believed to be unlikely to require a dose change during study

Subjects

Demographic characteristics were comparable across treatment groups (Table 1). The majority of subjects completed the study (41 [82%]), with 8 of the 9 withdrawn subjects discontinuing during dose titration. Two GSK239512 subjects (8%) and one (4%) placebo subject withdrew due to adverse events. Study PK data on file suggest that dosing and compliance were adequate within the study.

Neurocognition

The CSSB Composite Score suggested a small advantage for GSK239512 versus placebo with an ES of 0.29 (90% CI − 

Conclusions

GSK239512 at a maximum dose of 80 μg per day up-titrated over a four week period and maintained for three weeks was generally well-tolerated with an AE profile consistent with the known pharmacology of the class. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population. The most consistent effects were decrements in Processing Speed for GSK23912 versus placebo in both the CSSB and MCCB measures. An important limitation of the study was the small sample size

Role of funding source

Not applicable.

Contributors

This study was designed collaboratively by GlaxoSmithKline and members of the TENETS group. Drs. Breier, Buchanan, Goff, Green, Jarskog, Keefe, Leiberman, Marder, McMahon, Ms. Ball (TENETS group members), and Dr. Lowy, Dr. Maruff, Dr. Laurelle and Mr. Grove contributed to the original design of the study. Mr. Grove undertook the statistical analyses with contributions from Dr. McMahon. Drs. Breier, Buchanan, Cameron, Jarskog, Kantrowitz, Keshavan, Leiberman, and Marder participated as study

Conflict of interest

L. Fredrik Jarskog has received/receives/research funding support from GlaxoSmithKline, Sunovion, Genentech, Auspex Pharmaceuticals and Amgen, and has served on a Data Safety and Monitoring Board for Janssen. Richard Grove and Margaret Peykamian are employees of GlaxoSmithKline and receive payment and stock remuneration as part of that employment, but have no other financial interests or conflicts of interest. Martin Lowy, Joseph P Horrigan, and Marc Laurelle were employed by GlaxoSmithKline

Acknowledgments

Research was funded by GlaxoSmithKline. Results submitted in collaboration with the Treatment and Evaluation Network for Trials in Schizophrenia (TENETS) group. The sponsor and authors of this paper would like to thank the patients and investigators who made this research possible, including study investigators Mohommad Bari, Christopher Benbow, Alan Breier, Robert W. Buchanan, Carter S. Cameron, Stephen Glass, Armen Goenjian, Morris Goldman, L. Fredrik Jarskog, Joshua Kantrowitz, Matcheri S.

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Registry Name/URL, Registration: www.ClinicalTrials.gov/Identifier NCT01009060, www.gsk-clinicalstudyregister.com/Identifier 113147.

1

Member of TENETS group.

2

Current affiliation: PPD, Morrisville, NC.

3

Current affiliation: Neuren Pharmaceuticals Limited, Auckland, NZ.

4

Current affiliation: Columbia University, New York, NY.

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