OR18-4 Beneficial Effect on Sperm Production of Leflutrozole in Men with Obesity-Associated Secondary Hypogonadotropic Hypogonadism: Results from a Phase II Study

Introduction: Excess aromatase activity in adipose tissue has been linked to increased conversion of testosterone (T) to estradiol, resulting in high estradiol levels and suppressing gonadotropins. In obese men, this can cause obesity-associated hypogonadotropic hypogonadism (OHH) with decreased fertility. T replacement therapies frequently result in negative feedback suppression of follicle stimulating hormone (FSH) and luteinizing hormone (LH), further impairing semen fertility. Aromatase inhibition avoids this complication, restoring T without impairing fertility parameters, by reducing inhibitory effects of excess estradiol on LH and FSH. We report the impact of a weekly (QW) oral aromatase inhibitor on hormone levels and semen parameters in patients with OHH. Methods: A 24-wk, multicenter, randomized, double-blind, placebo (PBO)-controlled phase IIb trial (NCT02730169) of 3 doses of leflutrozole QW in obese adult males (BMI 30-50 kg/m(2)) with morning serum T <300 ng/dL. Exclusion criteria: Type 1 or uncontrolled type 2 diabetes; clinically significant endocrinopathy; prostate disease; recently diagnosed cardiovascular conditions; treatment with confounding medications (including those affecting gonadotropin or T levels). Primary endpoint: normalization (300-1000 ng/dL) of serum T in >75% of patients by end of treatment (EOT) at Wk 24. Secondary endpoints included gonadotropin and estradiol levels; a substudy assessed change in semen parameters. Safety was monitored from 1st dose to 90 days after EOT. Results: 271 patients (means: age 50.9 (±8.7) yrs, BMI 38.1 (±5.3) kg/m(2), T 231.1 (±54.6) ng/dL) were randomized to 3 doses of leflutrozole or PBO. All 3 leflutrozole-treated arms met the primary endpoint with normalized T levels by EOT in >75% of patients vs 10% for PBO (p<0.001). Dose-dependent elevations in FSH and LH (p<0.001) and dose-dependent reductions in estradiol were observed at EOT. At Wks 12 and 20, numerical increases in sperm counts were observed in all 3 leflutrozole groups vs PBO, with statistically significant improvements (LS mean difference [95% CI]) in semen volume (1.37 [0.41, 2.34] ml, p=0.006, n=24), spermatozoa (270.084 [65.007, 475.161] x10(6)/ejaculate, p=0.011, n=23), and total motile sperm count (127.711 [12.602, 242.819] 10(6)/ejaculate, p=0.030, n=22) in leflutrozole highest dose group vs PBO. Leflutrozole was generally well tolerated; 24.7% of patients experienced related treatment-emergent adverse events (AEs). Of these, 3.0-7.5% of patients in the 3 leflutrozole dose groups experienced serious AEs, vs 5.2% of patients receiving PBO. Conclusions: In contrast to suppression of spermatogenesis seen with exogenous T therapy, leflutrozole restores normal endogenous physiologic T levels whilst increasing FSH/LH, with positive effects on semen fertility parameters in men with OHH. A 24-wk, blinded extension study is currently ongoing.