MLE4901 impacts the central driver of PCOS
Polycystic Ovary Syndrome (PCOS) is a disease in which HPG (hypothalamus-pituitary-gonadal) signaling is dysfunctional. In PCOS, the gonadotropin-releasing hormone (GnRH) pulse generator is overactive. GnRH hyperpulsatility leads to increased pulse frequency and levels of luteinizing hormone (LH). This dysfunctional signaling leads to downstream hormonal abnormalities (e.g., excess androgens, such as testosterone) that result in the symptoms of PCOS, including irregular menstruation and hirsutism. Current off-label treatments such as oral contraceptives and metformin only address some of the symptoms of the disease. In contrast, MLE4901 directly addresses GnRH hyperpulsatility, the central driver of PCOS, which we believe will improve the symptoms of the disease.
KNDy neurons have recently been found to mediate the activity of gonadotropin-releasing hormone (GnRH) neurons through the action of kisspeptin, which is positively regulated by neurokinin B and its receptor, NK3R. In patients lacking functional NK3R, GnRH deficiency is observed, which supports the role of KNDy neurons as upstream regulators of GnRH release.
MLE4901 antagonizes NK3R to diminish the activity of GnRH neurons and reduce LH pulsatility. In patients with PCOS, where LH pulsatility is abnormally high, it is hypothesized that decreasing LH pulsatility with MLE4901 will help normalize hormone levels and result in improvement in the symptoms of PCOS.
MLE4901 is in Phase 2b clinical development
In a Phase 2a clinical study in patients with PCOS, MLE4901 showed dose-dependent and statistically significant reductions in LH, the primary endpoint of the study1. Decreases were also seen in other key hormonal parameters, including the reduction of total testosterone levels. Millendo is currently conducting a Phase 2b dose-ranging study in PCOS with longer-term dosing, focused on the symptomatic improvement for patients. For more information, please visit clinicaltrials.gov, identifier number NCT02865915.
- George JT, et. al. Neurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial. J Clin Endocrinol Metab. 2016 Nov;101(11):4313-4321. (PMID: 27459523)