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First-in-class mechanism of action leveraging novel biology

Millendo Therapeutics is currently advancing the development of MLE4901 for the treatment of polycystic ovary syndrome (PCOS) and vasomotor symptoms (VMS). MLE4901 leverages recent biological insights that elucidated the central regulator of reproductive hormonal signaling, the KNDy (kisspeptin/neurokinin B/dynorphin) neuron. MLE4901 is a potent and reversible antagonist of the human neurokinin 3 receptor, NK3R, and shows >150x selectivity over NK2 and NK1 receptors. MLE4901 has been well-tolerated in preclinical studies and showed expected pharmacology in short- and long-term studies. MLE4901 has also been studied in Phase 1 and Phase 2 clinical trials.  

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 PCOS

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.


  1. 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)

MLE4901 impacts the central driver of VMS

Vasomotor symptoms (VMS) are defined as hot flashes and night sweats in menopausal women. As estrogen levels fall in menopausal women, the neurons believed to be the key modulators of the heat dissipation response become hyperactive. This leads to VMS, including sensations of heat and/or perspiration that generally last several minutes and are often preceded or followed by sensations of cold and/or shivering. Current standards of therapy do not address the underlying hormonal dysregulation associated with VMS. MLE4901 directly targets the key neurons that are thought to control heat dissipation, which we believe will alleviate vasomotor symptoms.

Estrogen is known to be a negative regulator of KNDy neurons, which act upstream of heat dissipation effectors. As estrogen levels fall in peri-menopausal women, the absence of estrogen negative feedback causes KNDy neurons to become hypertrophic and hyperactive. Hyperactivity of KNDy neurons is believed to initiate the process that causes VMS.
By inhibiting NK3R signaling on KNDy neurons, MLE4901 is intended to reduce KNDy neuron hyperactivity, thereby restoring normal functioning of heat dissipation effectors and resolving the dysregulation that results in VMS. The NK3R is also believed to be a key regulator of heat dissipating neurons, which we believe further supports the potential of MLE4901 to treat VMS.

MLE4901 is in Phase 2 clinical development in VMS

Positive data from a Phase 2 investigator-initiated clinical trial of MLE4901 for the treatment of VMS, conducted by Waljit S. Dhillo, Ph.D. at Imperial College London, were recently published online in The Lancet1.


  1. Prague JK, et. al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. Advance online publication: April 03 2017.