Endocrine Abstracts

MLE4901 (previously AZD4901) is a potent and selective neurokinin 3 receptor (NK3R) antagonist being developed for the treatment of polycystic ovary syndrome (PCOS). Clinical studies indicate the compound negatively regulates the hypothalamus-pituitary-gonadotropin (HPG) axis to reduce pituitary luteinizing hormone and gonadal sex steroids. To understand the longer-term in vivo effects of MLE4901, a 13-week safety study was carried out. Groups of 3 male and female dogs received vehicle or MLE4901 at 5, 140, and 1000 mg/kg by gavage dosed once daily. Additionally, 3 dogs from each sex from the vehicle and high dose groups were maintained for a 3 month recovery period. MLE4901 was rapidly absorbed and plasma exposure increased with dose; exposures were similar at Week 4 and Week 13. MLE4901 effects were largely confined to reproductive organs. In females, reduced ovary and uterine weights as well as an increased incidence of anestrus were observed. In males, MLE4901 administration resulted in reduced testes, epididymides, and prostate weights which were associated with atrophic microscopic changes. MLE4901 effects showed evidence of reversibility following the 3 month recovery period. At doses of 140 mg/kg/day and above, MLE4901 completely suppressed the secretion of testosterone in male dogs as measured on Day 92. Some recovery of serum testosterone levels became apparent within 48 hours of the end of the dosing period. The pharmacodynamic response of MLE4901 was intact after 91 consecutive days of administration, as demonstrated by the acute reduction in plasma testosterone and its subsequent recovery to pre-dose concentrations at 24 hours in the 5 mg/kg/day dose group. These findings, which are believed to result from suppression of the HPG axis and reflect the primary pharmacology of MLE4901 as a NK3R antagonist, provide support for the development of MLE4901 as a treatment for PCOS and related endocrine diseases.