Safety and pharmacokinetics of the non-hormonal male contraceptive YCT-529

Abstract

Since nearly half of all pregnancies in the US and worldwide are unintended, there is a critical need for additional contraceptive options for men and women. After a hiatus in non-hormonal male contraceptive development of about half a century, the new chemical entity YCT-529 – a retinoic acid receptor-α antagonist - is being developed as a non-hormonal oral male contraceptive to decrease sperm count by impairing retinoic acid signaling in the testes. Here, we report the results of the first in human Phase 1a clinical trial with YCT-529 to assess its safety, tolerability, pharmacokinetics and pharmacodynamics, and its potential effects on heart rate, inflammatory biomarkers, sexual desire and mood. Sixteen male volunteers were enrolled to receive single oral doses of 10, 30, 90 or 180 mg of YCT-529 in the fasted state. Volunteers also received 30 mg in the fed state to study the effect of food on the pharmacokinetics of YCT-529. Single doses of up to 180 mg of YCT-529 had no effects on heart rate, hormone (follicle-stimulating hormone, luteinizing hormone, and testosterone), sex hormone-binding globulin or inflammatory biomarker levels, sexual desire or mood. Further, there was no clear food effect on the pharmacokinetics of YCT-529. Overall, YCT-529 was well tolerated in this single ascending dose study (ClinicalTrials.gov registration: NCT06094283), which is a substantial requirement in contraceptive development. Since nearly half of all pregnancies in the world are unintended, there is a critical need for additional contraceptive options for men and women. The small molecule YCT-529 stops sperm production, and we are developing YCT-529 as a non-hormonal oral contraceptive for men. To study the safety of YCT-529 in humans, we conducted a Phase 1a clinical trial where 16 healthy men received either placebo or escalating single doses of YCT-529 to assess its safety and tolerability. YCT-529 was well tolerated, and no adverse effects were noted. The positive results from this first clinical trial laid the groundwork for a second trial, where men receive YCT-529 for 28 days and 90 days, to study safety and changes in sperm parameters. Mannowetz et al. evaluate the safety and tolerability of the small molecule YCT-529 and show that single doses of up to 180 mg were well tolerated in healthy male subjects of this Phase 1a clinical trial. YCT-529 is developed as a non-hormonal, oral male contraceptive pill with the intention to reduce the risk of unplanned pregnancies.

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