Abstract

Abstract Background Dimethandrolone undecanoate (DMAU) is under development as a single agent hormonal male contraceptive. DMAU is a prodrug hydrolyzed by esterase(s) to the active metabolite dimethandrolone (DMA) which has dual androgenic and progestogenic actions. Phase 1 clinical trial results show DMAU to be well‐tolerated as an oral contraceptive in healthy men; however, delivery of DMAU as a long‐acting injectable rather than a daily oral formulation would provide user compliance benefits and address oral bioavailability concerns. Objective To assess the safety, pharmacokinetics (PK), and long‐acting contraceptive potential of DMAU in male non‐human primates (NHP) when delivered as an injectable or oral formulation. Materials and methods DMAU was administered to cynomolgus macaques orally for 9 months or as five weekly intramuscular (IM) injections and to rhesus macaques as a single IM injection. Evaluations of safety, fertility indicators, and serum levels of DMAU and DMA were followed > 2 years post‐dose. Results Repeat dose oral and IM administrations were well‐tolerated with no significant toxicological findings. Dramatic reductions in serum testosterone concentration occurred within days of administration followed by sustained suppression of additional fertility indicators (e.g., serum inhibin B, sperm count, and testicular spermatogenesis). Slight body weight increases and reductions in testes weight also occurred. Repeat DMAU injections resulted in DMA serum concentrations above the lower limit of quantification (1 ng/mL) for > 500 days. DMAU PK parameters increased with increasing IM dose, while dose dependence was not seen for serum DMA concentrations suggesting a depot effect with a reservoir of non‐circulating prodrug remaining at the injection site which gets slowly hydrolyzed to DMA and absorbed into circulation. Testosterone levels and spermatogenesis returned by the end of the recovery period. Conclusions Nonclinical safety, PK, and pharmacodynamic data in male NHP demonstrate the safe, well‐tolerated, long‐acting, and reversible contraceptive potential of injectable DMAU.