OR14-08 Clinical Potential of Novel Kisspeptin Receptor Agonists in Reproductive Health

Abstract Disclosure: E. Torres Jimenez: None. I. Lopez: None. J. Zhuo: None. R. Talbi: None. M. Schrag: None. D. MacNeil: None. L. Reddy: None. Y. Wang: None. R. Drakas: None. S. Seminara: None. D. Kobayashi: None. V.M. Navarro: None. Kisspeptin is the primary regulator of reproductive hormones and plays a essential role in the proper functioning of the reproductive system. As a result, research is increasingly focused on exploring the therapeutic potential of targeting the kisspeptin system to treat reproductive disorders. Herein, we investigate the effect of peptidic kisspeptin receptor (KISS1R) agonists (CPD-221 and CPD-77) on gonadotropin release. We conducted in vivo studies to characterize the stimulatory effect of these agonists in comparison with native kisspeptin-10 (Kp10). Further, we investigated their potential use to treat diverse reproductive impairments by using pre-clinical mouse models of hypothalamic amenorrhea and hypogonadotropic hypogonadism (HH). Dose response studies in adult WT male and female mice revealed a powerful stimulatory effect on luteinizing hormone (LH) secretion after the subcutaneous (sc) administration of both compounds. Due to the long-acting effect of CPD-221, its ability to attenuate signaling was studied in a model of hyperstimulated hypothalamic-pituitary-gonadal (HPG) axis, such as one week ovariectomized (OVX) mice, through continuous delivery using Alzet minipumps. One day of treatment was sufficient to significantly attenuate mean LH content. After 7 days of treatment, LH attenuation was evident in mean LH, amplitude of LH pulses and a trend to decrease the number of pulses per hour in comparison to control OVX mice was also observed. Taken together, the pre-clinical data discussed above identify these KISS1R agonists as potential therapeutic tools to activate the reproductive axis in conditions of insufficient GnRH release, i.e. HH and HA, or to decrease axis activity in conditions of excessive activation, with potential applications in PCOS. These agonists represent a novel approach to treat reproductive conditions that significantly affect Women’s Health with high unmet medical needs. Presentation: Sunday, July 13, 2025