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. 2025 Jul 22;5(1):279.
doi: 10.1038/s43856-025-01004-4.

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

Nadja Mannowetz  1 , Stewart W McCallum  2 , Sharan Sidhu  3 , Karen H Mena  2 , Eric P Ruby  2 , Ramiro Castro-Santamaria  4 , Emily Dodds  3 , Dennis Henderson  3 , Gareth Whitaker  3 , Heather Wright  3 , Sarah Beaudoin  3 , Akash Bakshi  5
Affiliations

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

Nadja Mannowetz et al. Commun Med (Lond). .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Overall, YCT-529 was well tolerated in this single ascending dose study (ClinicalTrials.gov registration: NCT06094283), which is a substantial requirement in contraceptive development.

Plain language summary

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.

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Conflict of interest statement

Competing interests: The authors declare the following competing interests: N.M. is co-founder and CSO of YourChoice Therapeutics. A.B. is co-founder and CEO of YourChoice Therapeutics. K.M. is an employee of YourChoice Therapeutics. S.W.M. and E.P.R. are paid consultants of YourChoice Therapeutics. N.M., S.W.M., K.H.M., E.P.R., R.C.S., A.B. conceived, designed and oversaw the study. N.M. wrote the first draft.

Figures

Fig. 1
Fig. 1. Phase 1a study design.
Schematic overview of Part 1 (10 and 30 mg, fasted), Part 2 (90 and 180 mg, fasted) and Period 3 (30 mg, fed).
Fig. 2
Fig. 2. Holter ECG exposure-response and timepoint analyses.
Concentration-response analysis: (a) Individual changes in QTcF from baseline at the respective plasma concentrations of YCT-529 after single dose administration of YCT-529. Shown are individual changes at 10 mg (dark grey triangles; n = 49), 30 mg (black squares; n = 60), 90 mg (pink diamonds; n = 60) and 180 mg (blue circles; n = 60), or matching placebo (light grey stars; n = 80) in the fasting state. Also shown are the model-predicted regression line (solid line) with upper and lower bounds of the two-sided 90% confidence interval (dashed lines). b Estimated ΔΔQT and two-sided 90% CIs based on geometric mean Cmax and β as the slope of the power model. Timepoint analysis (QTcF interval). c Placebo-corrected changes of QTcF from baseline as least square means ± 2-sided 90% CI after single dose administration of YCT-529 at 10 mg (light grey), 30 mg (dark grey), 90 mg (black) and 180 mg (blue) in the fasting state. The dotted line depicts the upper bound of the two-sided 90% confidence interval that was required to be <10 msec to conclude the absence of a clinically relevant effect of YCT-529 on QTcF. Shown are means ± SEM of n = 8 subjects (placebo), n = 5 subjects (10 mg YCT-529) and n = 6 subjects (30, 90 and 180 mg YCT-529) per time point. d Largest estimated ΔΔQTcF intervals with 90% CI at the fasted dose levels studied.
Fig. 3
Fig. 3. Exposure-time relationship after single oral dose administration of YCT-529 in the fasting and fed state.
a 336-hour PK profile of YCT-529 after oral administration of YCT-529 at 10 mg (light grey), 30 mg (black), 90 mg (blue) and 180 mg (orange) in the fasting state. Shown are individual data points and geometric mean concentrations ± geometric SD of n = 5 subjects (10 mg YCT-529) and n = 6 subjects (30, 90 and 180 mg YCT-529) per time point. b 336-hour PK profile of YCT-529 after oral administration of YCT-529 at 30 mg in the fasting (grey) and fed (blue) state. Shown are individual data points and geometric mean concentrations ± geometric SD of n = 6 subjects (fasting) and n = 8 subjects (fed). c Geometric mean concentrations ± geometric SD over 336 hours in all treatment groups.
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