The company’s data supports the notion that the negative feedback of exogenous testosterone administered by any route suppresses the hypothalamic–pituitary axis and hence spermatogenesis.
The discussion with the FDA focused on two issues. Firstly, the FDA requested that the company propose a label that better defines the population of individuals for whom Repros believes will benefit from the use of Androxal. Secondly, the FDA requested the company conduct a literature review of the incidence of infertility associated with the use of exogenous testosterone as supportive of its data. The FDA requested that the company provide such information and, if the FDA finds the submission appropriate, no additional clarifying meeting regarding the indication for Androxal may be required.
During the course of the meeting, Repros noted that if the FDA concurred with the indication proposed by it, the company would like to request a special protocol assessment (SPA). The FDA responded that the issues noted above should be resolved first before undertaking a protocol review.
In a study previously completed by Repros, blinded Androxal 12.5mg and 25mg were compared to open label Androgel used per manufacturers recommendations, and blinded placebo in hypogonadal men that met the criteria of secondary hypogonadism (T<300ng/dl, LH<15mIU/ml).
In this balanced 200 patient trial, at six months of exposure, exogenous testosterone (Androgel) suppressed both luteinizing hormone (LH) and follicle stimulating hormone (FSH) in a statistically significant manner. Each of these hormones was suppressed by greater than 60% compared to baseline (p value < 0.0001). By contrast Androxal improved both LH and FSH in this population in a dose dependent manner with the 25mg dose of Androxal showing a median change of greater than 90% for both important reproductive related hormones (p value <0.0001).
In a subsequent study, Repros correlated the reductions of FSH seen with exogenous testosterone with suppression of sperm counts. In this second small trial, two of five subjects on exogenous testosterone had no detectable sperm at three and six months and an additional subject had less than five million sperm per milliliter of semen. Four of five men at three months and three of five at six months were oligospermic (<20 million sperm per milliliter) during the trial.
By contrast the six men on Androxal exhibited sperm concentrations with a mean of >150 million sperm per milliliter, with all six of the subjects exhibiting concentrations well above the generally accepted level of fertility of 20 million sperm per milliliter. The difference between the Androxal group and the Testim group achieved statistical significance (p<0.01), even though this was a small pilot study. As expected, Androxal improved FSH, the hormonal driver of spermatogenesis and Testim suppressed FSH as evidenced by the suppression of spermatogenesis. The difference in FSH between the two treatment groups also achieved statistical significance at months three and six (p<0.02).