Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder

Abstract

Background: Antagonism of corticotropin‐releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF‐1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double‐blind, placebo‐controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half‐powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2‐2016) with the HAM‐A psychic subscale score for the entire cohort at baseline (FDR‐adjusted P=.015). Conclusions: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects

“…Finally, reports are accumulating in which studies have failed to detect activity of CRF1 antagonists in disease populations where animal work has predicted it, such as depression (Binneman et al, 2008;GlaxoSmithKline, 2010), anxiety disorders (Coric et al, 2010), or AD (Kwako et al, 2015;present study). If target engagement has, in fact, been achieved in these studies, appropriate patient populations have been targeted, and informative outcomes have been assessed, then the possibility must be considered that a consistent activity pattern of CRF1 antagonists in preclinical behavioral assays does not translate between rodents and humans.…”

“…The first CRF1 antagonist to be evaluated in humans, R121919, showed promise in depression (Zobel et al, 2000), but was terminated owing to safety issues widely shared by first-generation CRF1 antagonists. CRF1 antagonists with improved safety followed, but yielded negative results both in depression (Binneman et al, 2008) and anxiety disorders (Coric et al, 2010). Recently, we evaluated the effects of pexacerfont, a potent, selective, orally available and brain penetrant CRF1 antagonist, on a battery of experimental outcomes in AD.…”

Role of corticosteroids in the antidepressant response

“…153 A reversible increase in liver enzymes in a separate Phase I study 154 led to discontinuation of its clinical development. There has been a series of other compounds that have generated promising animal data, but a number of these have led to abandoned 155 or negative Phase II trials, 156 eg, CP-316,311 in a recurrent depression trial, 157 pexacerfont (BMS-562,086) in a generalized anxiety disorder trial, 158 and GSK561679 in a depression study. 159 The results of a depression trial 160 using SSR125543, the SanofiAventis compound, are not yet available.…”

HPA Axis Modulation in the Treatment of Mood Disorders

“…In the largest study to date (n=260), Coric et al conducted an 8-week multicenter, randomized, double-blind, placebo-controlled clinical trial with Pexacerfont (BMS-562,086) for generalized anxiety disorder. No significant anxiolytic effect was observed compared to placebo though the comparator in the study, escitalopram, was efficacious [38][39]. It is important to note that these studies have not used narrowly defined patient sub-types such as psychotic, anxious or atypical depression, but instead have utilized the broader MDD inclusion criterion.…”