High-Affinity CRF1 Receptor Antagonist NBI-34041: Preclinical and Clinical Data Suggest Safety and Efficacy in Attenuating Elevated Stress Response

Abstract

There is an extensive evidence that corticotropin releasing factor (CRF) is hypersecreted in depression and anxiety, and blockade of CRF could have therapeutic benefit. We report preclinical data and the results of a clinical Phase I study with the novel nonpeptide CRF 1 antagonist NBI-34041/SB723620. Preclinical data conducted with different cell lines expressing human CRF receptors and in Wistar and Sprague-Dawley rats indicate that NBI-34041 is effective in reducing endocrine responses to pharmacological and behavioral challenge mediated by CRF 1 receptors. These specific properties and its well-documented safety profile enabled a clinical Phase I study with 24 healthy male subjects receiving NBI-34041 (10, 50, or 100 mg) or placebo for 14 days. Regulation of the hypothalamic-pituitaryadrenocortical (HPA) axis was evaluated by intravenous stimulation with 100 mg of human CRF. Psychosocial stress response was investigated with the Trier Social Stress Test (TSST). Treatment with NBI-34041 did not impair diurnal adrenocorticotropic hormone (ACTH) and cortisol secretion or CRF evoked ACTH and cortisol responses but attenuated the neuroendocrine response to psychosocial stress. These results suggest that NBI-34041 is safe and does not impair basal regulation of the HPA system but improves resistance against psychosocial stress. NBI-34041 demonstrates that inhibition of the CRF system is a promising target for drug development against depression and anxiety disorders.

Making a bad thing worse: adverse effects of stress on drug addiction

“…Currently, antalarmin is in phase I and phase II clinical trials for the treatment of anxiety and depression, although no results from these studies have been made public (87). In addition, R121919 has been shown in an open-label clinical trial to be effective in reducing depression and anxiety-like symptoms in humans (88,89), and more recently, the high-affinity CRFR1 antagonist NB1-34041 has demonstrated efficacy in attenuating an elevated stress response both in animals and in humans, but no studies have evaluated the therapeutic value of these compounds in treating the drug-addicted population (90).…”

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

“…Inhalation of 35% CO 2 , a model for panic discussed above, also causes increased HPA responsivity in the form of enhanced cortisol and ACTH levels in both panic patients and control subjects (van Duinen et al 2005(van Duinen et al , 2006. In human healthy volunteers, exposure to psychosocial stressors in the Trier Social Stress Test, involving a mock job interview and public speaking, induces HPA activity (Ising et al 2007;Kudielka et al 2004a, b). Given the relative ease with which HPA responsivity can be measured in animals, this would seem to be another highly translatable model.…”

Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders

“…In summary, inhibition of the CRH 1 receptor subtype has been proposed as an attractive target for medication development in anxiety, depression, and addiction [23,30,31] and promising compounds are in development [6,25,32]. On the other hand, a wide variety of safe and effective RAS-targeting medications exist, but their potential as adjuvant medications for these disorders is largely unexplored.…”