Anti-Spermatogenic Efficacy of Nonhormonal Male Contraceptive Agent, H2-Gamendazole, in Mice, Rats, Rabbits, and Nonhuman Primates (Rhesus), and a Multiple Low Dose Oral Regimen That Gives 100% Infertility with Complete Reversibility.

The NIH, Institute of Medicine, and World Health Organization (WHO) have focused attention on the need for strategies to develop novel non-steroidal reversible male contraceptives, in part, because traditional approaches have yielded mixed results, reversibility problems, and/or unacceptable side-effects. To meet this need, we have developed H2-Gamendazole (H2-GMZ), an orally active anti-spermatogenic indazole carboxylic acid with potent antifertility effects, and no adverse side effects at doses needed to induce reversible infertility. We report efficacy results using oral doses of H2-GMZ in mice, rats, rabbits, and non-human primates (Rhesus). Single oral doses of H2-GMZ produced significant loss of spermatids (less than 5 spermatids per tubule) in all species as assessed by Spermatogenic index (SI) (Whitsett et al, 1984) assessment of testicular histology: monkeys (SI = 2.5 ± 0.5 at 1 mg/kg (P<0.004), and 2.3±0.5 (P<0.00006) at 2 mg/kg; rabbits (SI = 3.2±0.5 (P<0.000004) at 3 mg, and 2.6±0.6 (P<0.002) at 6 mg/kg) and mice (SI was 2.0±0.0 (P<0.00002) at 12 mg and 25 mg/kg (both doses identical)) The dosage required to induce comparable reductions in testicular histology, testicular mass, and SI, as those obtained to induce infertility in rat mating trials, in all species were different (1 mg/kg in monkey, ≤ 3mg/kg in rabbits, 3-6 mg/kg in rats and ≤ 12 mg/kg in mice), demonstrating that the efficacy of H2-GMZ is related to body mass index (blood volume) rather than linear with respect to body weight. In all species, at the effective doses, there were no visible adverse effects, and no significant difference in the body weight versus control groups. In non-human primates, the reductions in SI were completely recovered by 106 days after dosing. In rats, weekly doses of only 1 or 2 mg/kg caused complete loss of spermatids with excellent retention of spermatocyte and spermatogonial populations with no change in Inhibin B production. Rat mating trials (10 males per group) showed that 6 weekly oral doses of H2-GMZ at 1 or 2 mg/kg in 0.1 M Captisol in water resulted in 95% and 100% infertility (assessed by mating each male with two proven fertile females every two weeks), respectively, that lasted for 2 wks after the last dose, followed by full recovery of fertility by 8wks later in both treatment groups. Metabolic stability tests using liver microsomes from human, monkey, dog, cat, and rat showed that stability of H2-GMZ was excellent in all species (82%-100%). Mouse showed slightly lower, 75%, stability. In summary, the anti-spermatogenic efficacy in multiple species including non-human primates and complete reversibility after 100% infertility in rats of H2-GMZ has laid a promising foundation for progressing towards FDA IND and clinical trials, once ongoing tox studies are completed. This research was supported by grant U54 HD055763.

(platform)