Effects of PRX-00023, a Novel, Selective Serotonin 1A Receptor Agonist on Measures of Anxiety and Depression in Generalized Anxiety Disorder

Abstract

PRX-00023, a serotonin 1A receptor agonist, was designed to provide high potency and selectivity for its target. To assess the possible therapeutic utility in anxiety, a randomized, double-blind, placebo-controlled trial was conducted in 311 subjects who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for generalized anxiety disorder. All subjects underwent a 1-week placebo run-in and were randomized to receive once-daily capsules containing either PRX-00023 (80 mg/d) or placebo for an additional 8 weeks. The primary outcome measure was the Hamilton Anxiety Scale (HAM-A). The Montgomery-Asberg Depression Rating Scale was used as a secondary endpoint to measure depressive symptoms. Statistical testing was performed with analysis of covariance, between baseline and week 8, with baseline values as a covariate. The anxiolytic effect of PRX-00023, compared with placebo, showed trends across all anxiolytic measures but failed to reach significance on the primary endpoint (HAM-A total score). Among the components of the HAM-A total score, the anxious mood item was significantly different from placebo in the PRX-00023-treated group (-1.015 vs -0.748; P = 0.02). The scores of the Montgomery-Asberg Depression Rating Scale were significantly improved compared with placebo at week 8 (-4.5 vs -1.6; P = 0.0094 in the last observation carried forward analysis). PRX-00023 was well tolerated; of note, there were no drug-related serious adverse events, and more patients discontinued due to adverse events in the placebo group (2.9%) than in the PRX-00023 group (1.4%). The most common adverse event was headache, observed in 15.7% and 10.9% of PRX-00023- and placebo-treated patients, respectively. Furthermore, there was no evidence of impaired sexual function, as measured by the Massachusetts General Hospital Sexual Function Scale. Collectively, these results support further clinical investigation of higher doses of PRX-00023 in anxiety and depression.

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

“…There are also no recent or active, ongoing studies of other azapirones such as ipsapirone or lesopitron. In terms of non-azapirone 5-HT 1A agonists, PRX-00023 was studied in GAD in a RCT and, despite good tolerability, it did not show separation from placebo on endpoint anxiety (106). Additionally, there are other selective 5-HT 1A partial agonists, such as TGFK08AA, in development for GAD (89), and TGW00AA (FKW00GA) in Phase 2 studies for GAD and SAD (107).…”

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision

“…Á Propranolol did not show sufficient evidence in GAD (Meibach et al 1987)(E). Á PRX-00023, a 5-HT 1A receptor agonist, failed to show superiority over placebo (Rickels et al 2008) (E).…”

New Prospects for the Drug Treatment of Generalized Anxiety Disorder — A Systematic Review

“…tolerability or efficacy) is in the degree of partial agonism: buspirone has ~50% the agonist activity of the natural ligand (serotonin), whereas gepirone has ~80% agonist activity [10]. A recent 8-week double blind placebo-controlled study reported the effects of PRX-00023, a non-azapirone 5HT1A partial agonist with high (~90% intrinsic activity) in GAD [11]. PRX-00023 produced a 9.8 point reduction in HAM-A scores, whereas an 8.5 point reduction was noted in the placebo arm.…”