OR17-06 Clinical And Mechanistic Insight For The Therapeutic Potential Of Intranasal Kisspeptin Administration To Treat Reproductive Disorders In Humans

Abstract

Abstract Disclosure: E.G. Mills: None. M. Swedrowska: None. V. Delli: None. K. Chachlaki: None. M. Silva: None. L. Decoster: None. G. Ternier: None. L. Thurston: None. M. Phylactou: None. B. Patel: None. L. Yang: None. S.A. Clarke: None. B. Muzi: None. E.C. Alexander: None. M. Choudhury: None. P. Bech: None. A. Abbara: None. B. Forbes: None. P. Giacobini: None. V. Prevot: None. A.N. Comninos: None. W.S. Dhillo: None. Background: Kisspeptin is a key regulator of hypothalamic GnRH neurons with emerging potential to treat reproductive, psychosexual and bone disorders. However, current therapeutic application is limited to the subcutaneous or intravenous routes, which presents significant barriers to further development. Alternative delivery routes could overcome this and capitalise on the clinical utility of kisspeptin-based therapeutics. Herein, we comprehensively examine the translational potential of intranasal kisspeptin administration for the first time using a series of human, rodent and pharmaceutical studies. Methods:Human studies: Healthy men (n=12) and a patient group of women with Hypothalamic Amenorrhoea (HA) (n=5) completed a randomised, double-blind, crossover, placebo-controlled study investigating the acute effects of intranasal kisspeptin-54 administration (doses 3.2-25.6nmol/kg [healthy men] and 12.8nmol/kg [women with HA] vs 0.9% saline placebo). Plasma kisspeptin and serum reproductive hormones were measured every 15mins for 4hrs. Thereafter, we conducted rodent studies in adult C57BL/6J male mice to elucidate the possible mechanism by which intranasal kisspeptin induces reproductive hormone release, using intranasal administration of fluorescently-tagged kisspeptin-54 and a series of c-Fos experiments. From a medicines development perspective, we undertook pharmaceutical studies to evaluate the chemical stability of kisspeptin-54 in solution for nasal delivery in real-time. Results:Human studies: in healthy men, intranasal kisspeptin dose-dependently increased plasma kisspeptin at doses 6.4-25.6nmol/kg (p<0.01 for all doses vs placebo), with the maximal rises achieved within 15-30 minutes. Correspondingly, intranasal kisspeptin acutely and potently increased serum LH at doses 6.4-25.6nmol/kg (p<0.01 all doses vs placebo) with maximal rises at 30 minutes. Likewise, in women with HA, intranasal kisspeptin acutely increased plasma kisspeptin (p=0.004 vs placebo) and serum LH (p=0.004 vs placebo). Animal studies: To provide mechanistic insight, we demonstrate in male mice that GnRH neurons located in the olfactory bulb express kisspeptin receptors and that intranasal administration of fluorescently-tagged kisspeptin-54 binds to the olfactory epithelium. Pharmaceutical studies: Kisspeptin-54 in 0.9% saline remained within pharmaceutically accepted limits for stability for up to 60 days at 4°C demonstrating realistic pharmaceutical potential. Conclusion: We identify robust clinical effects and provide mechanistic and pharmaceutical data for intranasal delivery as a novel, non-invasive, safe and effective kisspeptin administration route for the management of common reproductive disorders that would be far preferable to patients and clinicians and so transform the ongoing rapid development of kisspeptin-based therapeutics. Presentation: Saturday, June 17, 2023