CeNeRx is advancing an HPA axis modulator program. CXB722 and its prodrug Ayrene (CXB724) are hypothalamic-pituitary-adrenal (HPA) axis modulators being developed for the treatment of a variety of CNS disorders including anxiety and depression. In a recent clinical trial, CXB722 showed potential as a novel anxiolytic, demonstrating a significant effect on both endocrine and cardiovascular biomarkers associated with stress. Based on clinical and preclinical studies, the CeNeRx HPA axis modulator drugs are not expected to show the impairment of motor performance seen with traditional anxiolytic drugs.
Anxiety disorders are disabling conditions that afflict sizeable, diverse patient populations, but current anxiolytic therapies are associated with a range of limiting side effects, including sedation and addictive potential. A novel approach to treating anxiety and other mood disorders focuses on the hypothalamic-pituitary-adrenal (HPA) axis. Activation of the HPA axis increases the levels of the neuroendocrine hormones that are associated with anxiety and stress. CeNeRx is developing CXB722 and its prodrug Ayrene (CXB724), novel mechanism drugs for the treatment of anxiety and depression that act by modulating the HPA axis.
A large preclinical and clinical database suggests that HPA axis modulators have the potential to effectively treat anxiety while avoiding the adverse effects of other anxiolytic drugs. CXB722 has previously been studied in approximately 800 patients and has demonstrated safety and efficacy in a range of anxiety and mood disorders. Unlike traditional anxiolytic drugs such as benzodiazepines, CXB722 has shown no impairment of motor performance in either preclinical or clinical studies.
CeNeRx recently reported the results of a new study specifically designed to assess the effects of CXB722 on HPA axis-related responses to psychosocial stress. In the study, which was presented at a major neuroscience meeting, 24 healthy volunteers participated in a Trier Social Stress Test (TSST) experiment, a well-validated approach to measuring changes in physiologic and endocrine endpoints in response to acute psychosocial stress. Approximately half of the subjects received CXB722 and half received a placebo for seven days prior to participating in highly structured stress-inducing activities, such as a mock job interview.
Neuroendocrine biomarkers that typically rise in response to stressful situations, including plasma cortisol, salivary cortisol and plasma ACTH, were measured before and after exposure to the stress-inducing activities. While the placebo group exhibited the expected elevations in these stress-related biomarkers, they were significantly attenuated in the subjects randomized to receive CXB722. In addition, an analysis of continuous pulse rate data demonstrated an attenuation of heart rate elevation in the CXB722 group compared to the placebo group. Consistent with the large existing clinical database for CXB722, the drug was safe and well‐tolerated, with no drop-outs due to an adverse event.
The ability of CXB722 to modulate stress-related neuroendocrine activity evidenced in this study highlights its unique mechanism of action and provides important insight on how CXB722 lowers key stress hormones associated with chronic anxiety and other mood disorders. These clinical data also are consistent with the findings from preclinical studies that show that CXB722 may modulate corticotrophin-releasing factor-containing neurons associated with activation of the HPA axis.
The results of the Trier Social Stress Test add to the growing clinical database supporting the potential of the novel mechanism of CXB722 and Ayrene to treat a range of mood and anxiety disorders, without the performance limitations associated with traditional anxiolytics. Potential applications may include prevention of post-traumatic stress disorder and treatment of social anxiety disorder. The data also set the stage for further development of Ayrene, CeNeRx’s prodrug that fully converts to CXB722 in plasma and offers potential pharmacokinetic advantages compared to its parent compound.