A phase II study of BGS649, an aromatase inhibitor for the treatment of men with obesity-associated secondary hypogonadotropic hypogonadism

Introduction: Excess aromatase activity in adipose tissue has been linked to androgen deficiency. This can give rise to hypogonadotropic hypogonadism in obese men, with potentially deleterious metabolic consequences. Here we report on the efficacy and safety/tolerability of BGS649, an oral, once-weekly aromatase inhibitor as treatment of obesity-associated secondary hypogonadotropic hypogonadism (OHH). Methods: This Phase II study comprised: a 12-wk, non-randomized, open-label, BGS649 dose-finding study (Part 1); and a randomized, double-blind study of BGS649 vs placebo (Part 2). Adult males with BMI ≥30 kg/m2 , testosterone (T) <300 ng/dL, and abnormal levels of other sex hormone (normal-high estradiol / low LH and FSH) without endocrinopathy/pituitary disease were enrolled. Part-1 starting dose was 0.03 mg, titrated until total and free T were within normal levels. Part-1 PK/PD analyses determined BGS649 dosing in Part 2. The primary endpoint was total T levels in Part 1, and insulin sensitivity in Part 2. Secondary endpoints included levels of other sex hormones, metabolic parameters, and safety. Results: Part 1 enrolled 14 patients (mean ± SD age 50.3 ± 9.5 yrs, BMI 34.0 ± 3.2 kg/m2) and 13 completed the study. Part 2 included 15 patients (age 50.3 ± 10.3 yrs, BMI 37.9 ± 4.9 kg/m2), 7 on BGS649 vs 8 on placebo; of these, 5 on BGS649 vs 3 on placebo completed 12 wks of treatment. In Part 1, during BGS649 dose titration, there was an increase from baseline to Wk 12 in total T to within normal levels (mean ± SD: 239 ± 52 to 514 ± 188 ng/dL [n=14]). Increases in T levels were seen at Wk 1, with all 14 patients reaching normal levels by Wk 4, and 13 (93%) maintaining normal levels by Wk 12. In Part 1, there was a 30% reduction from baseline to Wk 12 in estradiol levels, and increases of 135% in FSH and 100% in LH levels, consistent with the increases in T levels with BGS649. Based on Part-1 PK/PD analyses, BGS649 was dosed in Part 2 at 0.3 mg (Wk 1), then 0.1 mg (Wks 2-11), in order to maintain drug plasma levels above the IC90 for aromatase inhibition. Normal T levels were sustained with BGS649 from baseline to Wk 12 in Part 2 (mean ± SD: 273 ± 142 to 423 ± 70 ng/dL [n=5]), but not with placebo (366 to 309 ng/dL [n=1]). Part 2 was stopped early when proof of concept for T normalisation was observed and re-evaluation showed the study was underpowered for insulin sensitivity analyses. In Part 1, 10 patients experienced treatment-related adverse events (AEs) (all mild/moderate). In Part 2, three patients on BGS649 reported treatment-related AEs (all mild) vs two on placebo. None of these events were considered serious. Conclusions: BGS649 restored normal physiological T levels, with positive effects on other sex hormones, and a favourable safety/tolerability profile over 12 wks of treatment in men with OHH. Further to these promising results, a larger Phase IIb dose-ranging study is ongoing.