SUN-LB042 The Novel Androgen 11β-Methyl-19-Nortestosterone Dodecylcarbonate (11β-MNTDC) Effectively Suppresses Gonadotropins and Testosterone in Healthy Men: A Potential Oral Male Hormonal Contraceptive

Background: 11β-MNTDC is an orally bioavailable prodrug of 11β-methyl-19-nortestosterone (11β-MNT). It is a modified testosterone (T) with androgenic and progestational activity being developed as a male contraceptive. 11β-MNTDC suppressed serum T and gonadotropin production while maintaining androgenic functions in preclinical studies. Single oral doses of 11β-MNTDC (up to 800 mg) were well-tolerated in healthy men and reversibly suppressed serum T. Methods: We conducted a placebo-controlled, double-blind study at two academic medical centers. 40 healthy men (18-50 years) were randomized to receive either oral placebo (P, n=10) or 11β-MNTDC 200 (n=14) or 400 (n=16) mg dosed daily for 28 consecutive days and completed the study. Participants presented twice weekly for assessment of the primary outcome measures, namely safety parameters (vital signs, hematocrit, liver function tests, lipids, EKG, QTc interval, adverse events). Subjects also underwent serial blood sampling over 24h on Day 1 and 28 to assess the pharmacokinetic and pharmacodynamic effects of oral 11β-MNTDC, including 24h serum drug concentrations, T, LH and FSH suppression (secondary outcomes). Potential effects on mood (PHQ-9) and sexual function (PDQ) were evaluated at baseline, day 28, and end of study via standardized questionnaires. Results: 11β-MNTDC was well tolerated. There were no serious adverse events or significant clinical concerns. None of the participants discontinued due to an adverse event. Administration of 11β-MNTDC resulted in a dose-proportional increase in serum 11β-MNTDC and 11β-MNT concentrations over 24h. This was accompanied by a dose-related profound suppression of serum Cavg24h T (median P 461.1 vs 200mg 22.3, 400mg 7.6 ng/dL), LH (median P 6.0 vs 200mg 1.9, 400mg 0.3 IU/L) and FSH (median P 3.1 vs 200mg 1.2, 400mg 0.2 IU/L) on day 28. Treatment related adverse events occurred in 3 participants in the placebo compared to 22 participants administered 11β-MNTDC including 4 with fatigue, 6 with headache, 5 with acne, 5 with decreased libido and 2 with mild erectile dysfunction. There were no significant changes in blood pressure, liver enzymes, EKG, and QTc. Depression (PHQ-9) scores did not change. On a scale of 0-7, sexual desire score was reduced (median -0.80) without changes in sexual activity in the 400 mg group. As anticipated, there were significant dose-related increases in weight (median change P 0.6 vs 200mg 1.3 and 400mg 1.9 kg), hematocrit (median change