A novel male contraceptive compound that targets the retinoic acid receptor alpha has demonstrated effective and reversible inhibition of spermatogenesis in both mice and nonhuman primates, potentially paving the way for the first oral nonhormonal male birth control option.
In the research, published in Communications Medicine, investigators from the University of Minnesota, Columbia University, and YourChoice Therapeutics reported that YCT-529, a highly selective retinoic acid receptor alpha (RARα) antagonist, achieved nearly 100% contraceptive efficacy in mice with complete recovery of fertility after treatment cessation.
YCT-529 works by selectively inhibiting RARα signaling (IC50 = 6.8 nM), which is essential for proper sperm development, without affecting related receptors RARβ and RARγ. In male mice treated with 10 mg/kg/day for 4 weeks, the compound was 99% effective in preventing pregnancies during mating trials, and fertility was fully restored within 6 weeks posttreatment. A higher dose regimen of 20 mg/kg/day for 2 weeks was 93% effective but required 12 weeks for full recovery.
In nonhuman primates (cynomolgus macaques), sperm production was significantly reduced to below fertility threshold within 2 to 5 weeks of oral dosing at 2.5 to 5 mg/kg/day and returned to normal within 78 to 148 days (10 to 15 weeks) after treatment ended.
"These results lay the groundwork for evaluating YCT-529 in human clinical trials," the researchers concluded in their report.
The research addresses a significant unmet need in contraceptive options. According to the study, "Since nearly half of all pregnancies in the U.S. and worldwide are unintended, a critical need exists for additional contraceptive options applicable throughout the reproductive lifespans of both women and men." While women have multiple contraceptive methods available, men are currently limited to condoms and vasectomy.
YCT-529 demonstrated favorable safety characteristics in both studies. No significant changes were observed in hormone levels (testosterone, FSH, inhibin B) or in hematology and clinical chemistry parameters in nonhuman primates. Importantly, neutrophil granulocyte counts remained normal despite RARα's known role in neutrophil maturation.
The compound showed "excellent metabolic stability in mouse and human liver microsomes and hepatocytes, a Log D = 3.4, and good solubility," the researchers reported. Safety screening revealed no inhibition of cardiac hERG channels, no cytotoxicity, and no mutagenic or genotoxic potential.
Lead authors Nadja Mannowetz, CSO of YourChoice Therapeutics, and Sanny S.W. Chung of Columbia University Medical Center, wrote with colleagues that the absence of significant side effects is particularly noteworthy.
The group of investigators included researchers from YourChoice Therapeutics, which holds the exclusive license for the intellectual property related to YCT-529. The research was funded by NIH/NICHD and YourChoice Therapeutics.
Disclosures can be found in the study.