The Corticotropin Releasing Hormone-1 (CRH1) Receptor Antagonist Pexacerfont in Alcohol Dependence: A Randomized Controlled Experimental Medicine Study

Abstract

Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress-and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fiftyfour anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by 100 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcoholrelated cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.

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

“…To validate this first fMRI biomarker, we analyzed responses to fearful faces in the placebo group. This analysis identified an expected activation within the amygdala, primarily on the right side ( Figure 6, upper row), consistent with what has previously been reported for this type of stimuli (see, e.g., Hariri et al, 2002;Kwako et al, 2015). This response was blunted in the verucerfont group ( Figure 6, middle row).…”

“…The in vivo HPA-axis suppressing activity of verucerfont in patients was predicted by rat data, which showed a potent and lasting suppression of ACTH output when a maximal activation of CRF drive was induced through adrenalectomy. Utility of the adrenalectomized rat assay for predicting in vivo CRF1 antagonist activity is further supported by the observations that another CRF1 antagonist, pexacerfont (Zhou et al, 2012), lacked activity in the rat assay, and was similarly unable to block the dex-CRF response in AD patients in a previous study (Kwako et al, 2015).…”

“…In the clinical study, we used a battery that included neuroendocrine, behavioral, and brain imagingbased measures. Both the design and the outcome measures were similar to those recently used to evaluate another CRF1 antagonist, pexacerfont (Kwako et al, 2015). Verucerfont blocked HPA-axis activity in the adrenalectomized rat assay.…”

“…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. Hypothalamicpituitary adrenal (HPA) axis responses, alcohol-craving, and fMRI brain responses to aversive stimuli in anxious patients with AD were all unaffected by pexacerfont, despite ensuring adequate central nervous system exposure (Kwako et al, 2015).…”

“…We then carried out a double-blind, placebo-controlled experimental medicine study to evaluate verucerfont in treatment-seeking women with anxious AD. As primary outcome, we assessed the effects of verucerfont on stress-induced alcohol craving and on brain responses to aversive stimuli, using established procedures previously used to evaluate pexacerfont (Kwako et al, 2015). As a translational biomarker, and a measure of target engagement, we also examined whether verucerfont would block HPA axis responses in the combined dexamethasone-CRF test ('dex-CRF test'; Modell et al, 1998).…”