Lisa Arvanitis

Sanofi-Aventis, USA

Abstract

[O29] Clinical development of SSR149415, a selective, nonpeptide, vasopressin V1b receptor antagonist

Acting through the pituitary vasopressin V1b receptor, arginine vasopressin (AVP) modulates adrenocorticotropic hormone (ACTH) secretion and plays a critical role in maintaining the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis during periods of chronic stress. The V1b receptor is also located in extrahypothalamic brain regions and may mediate the behavioral effects of AVP.  Blockade of the central V1b receptor represents a novel strategy for the treatment of stress-related psychiatric disorders. As SSR149415, the first selective nonpeptide V1b antagonist, was active in models of depression and anxiety, development in major depressive disorder (MDD) and generalized anxiety disorder (GAD) was initiated. After assessment of the clinical profile in healthy subjects, 2 efficacy and tolerability studies in MDD and 1 study in GAD were conducted. Studies were 8-week, double-blind, placebo-controlled trials evaluating 100 mg and 250 mg BID doses of SSR149415, placebo, and escitalopram 10 mg or paroxetine 20 mg QD in 312 patients/trial (78 patients/group). Patients entered MDD trials with Montgomery-Asberg (MADRS) and Hamilton (HAM-D) Depression Rating Scale total scores of ≥24 and ≥18, respectively. A Hamilton Anxiety Rating Scale (HAM-A) total score of ≥22 was required for inclusion in the GAD trial. Efficacy was assessed using the HAM-D or HAM-A, MADRS, and Clinical Global Impression.  Changes from baseline in the HAM-D or HAM-A total scores the primary efficacy endpoints. Analysis was a mixed-effect model with repeated measures. Standard assessments of tolerability were included. A 4-week, double-blind, placebo-controlled study evaluating the effect of 100 and 250 mg BID doses of SSR149415 on HPA axis in 45 MDD patients (15 patients/group) was also conducted.  Across efficacy trials, SSR149415 was not superior to placebo on the analyses of the primary or secondary endpoints; active control was generally superior to placebo. SSR149415 was well-tolerated and had no deleterious effect on HPA axis at the doses studied.

Biography

Dr. Arvanitis received a Bachelor’s of Pharmacy degree at Washington State University and a Doctor of Medicine degree from the University of Washington School of Medicine. She completed an Internship in Internal Medicine, residency training in both Psychiatry and Neurology, and a fellowship in Neurology in the area of Movement Disorders, all at the University of Rochester School of Medicine.  Dr. Arvanitis is Board Certified in both Psychiatry and Neurology.  She also has extensive laboratory research experience in the areas of neuroendocrinology and the anatomy of the basal ganglia.

Dr. Arvanitis has 19 years of international clinical drug development experience in the area of central nervous system disorders at both AstraZeneca (formerly ICI Pharmaceuticals and Zeneca Pharmaceuticals) and Sanofi-Aventis (formerly Sanofi-Synthelabo Research). At AstraZeneca, she was responsible for the global clinical development and registration of SEROQUELÒ, an antipsychotic agent, in the treatment of schizophrenia, as well as other compounds in schizophrenia and stroke. At Sanofi-Aventis, Dr. Arvanitis directs the global clinical development of compounds from discovery through registration in the areas of depression, anxiety disorders, schizophrenia, bipolar disorder, and sleep disorders. Previously, she had responsibility for global development of compounds in Alzheimer’s and Parkinson’s disease and amyotrophic lateral sclerosis.