MLE4901, a Neurokinin 3 Receptor Antagonist, Acts Upstream of Pituitary GnRH to Reduce Testosterone Secretion in Male Dogs
Presentation Number: SUN 485
Date of Presentation: April 2nd, 2017
Andrew Gibson Spencer*1, Michelle Coulson2 and Andrew Warren Hunt III3
1Millendo Therapeutics, Ann Arbor, MI, 2AstraZeneca, Melbourne, Herts, United Kingdom, 3Millendo Therapeutics, Ann Arbor, CA
MLE4901 (previously AZD4901) is a potent and selective neurokinin 3 receptor (NK3R) antagonist being developed for the treatment of polycystic ovary syndrome (PCOS). MLE4901 is thought to act on NK3R in KNDy neurons upstream of gonadotropin releasing hormone (GnRH) and kisspeptin signaling. Clinical studies suggest that administration of MLE4901 in women with PCOS results in reduced serum LH as well as reduced LH pulse frequency and testosterone concentrations consistent with the negative modulation of the hypothalamic-pituitary-gonadal (HPG) axis via NKR3 antagonism in the KNDy neurons. In dogs, MLE4901 administration causes rapid and sustained reduction of testosterone secretion along with effects in the reproductive tract which are consistent with NK3R-mediated antagonism of HPG signaling. In a 1-month repeat-dose toxicology study in dogs, plasma testosterone was suppressed within two hours of MLE4901 administration, remained suppressed throughout the dosing period, and began recovering within 48-72 hours of a recovery period. This rapid response confirmed suppression of the HPG axis by MLE4901. To better understand where in the HPG pathway MLE4901 has its effects, we undertook a pharmacodynamic experiment aimed at determining whether male dogs (n=4) are sensitive to GnRH signaling in the presence and absence of MLE4901. In this study, plasma testosterone and LH concentrations were monitored following a single dose of MLE4901 (20 mg/kg) or vehicle. A progressive fall in serum testosterone (-80% from baseline) was observed following MLE4901 administration, confirming the expected pharmacodynamic effect which was not observed in vehicle-treated animals. Two hours later, a subcutaneous injection of the GnRH analog buserelin was administered, thereby allowing a functional assessment of HPG signaling via continued monitoring of testosterone and LH. Buserelin administration caused sharp increases in LH (from <1 ng/mL to 7-8 ng/mL) and testosterone (up to 15-20 nM from ~1–4 nM in both MLE4901 and vehicle-treated groups. The magnitude of the buserelin-induced LH and testosterone increases were similar after MLE4901 or vehicle dosing, indicating normal pituitary and gonadal activity in the presence of MLE4901. The results suggest that the pharmacological effect of MLE4901 impacts processes modulating the synthesis and/or release of neuronal GnRH, which occur prior to the interaction of GnRH with the pituitary gland, and are consistent with pharmacologic activity at the level of the NK3R in the KNDy neurons.
Disclosure: AGS: Employee, Millendo Therapeutics. MC: Employee, Astra Zeneca. AWH III: Employee, Millendo Therapeutics.