PII-LBA7 IN TWO PHASE III STUDIES, ENDROXAL™ (ENCLOMIPHENE CITRATE) SIGNIFICANTLY IMPROVES TOTAL TESTOSTERONE LEVELS COMPARED TO ANDROGEL 1.62%, WITHOUT SUPPRESSION OF SPERMATOGENESIS AND TESTICULAR FUNCTION IN OVERWEIGHT MALES WITH SECONDARY HYPOGONADISM.

Abstract

INTRODUCTION AND OBJECTIVES: Epidemiological studies of hypogonadism have unequivocally shown that themajority of menwith clinically low testosterone levels have secondary hypogonadism. This disorder is primarily associated with being overweight (BMI > 25) or obese (BMI > 30) and is neither idiopathic nor due to normal aging. The secondary hypogonadal male has functional but under stimulated testes. These men are typically fertile but exhibit low total testosterone that results from sub-optimal stimulation of the Leydig cells due to suppressed LH secretions by the pituitary. The reduced LH release in turn is due to negative feedback of estrogen on the hypothalamus-pituitary axis. METHODS: Two double-blind, double-dummy, placebocontrolled, 16week studies in 256men.Men less than 60years of age, with BMI> 25 were enrolled if they exhibited sperm counts in the normal range at baseline (> 15 million/mL) and morning testosterone of< 300 ng/dL) RESULTS: Endroxal was found to restore T levels in the majority of secondary hypogonadal men (Table 1). The magnitude of the effect was much greater and more consistent than with Androgel. In contrast to the characteristic and well-documented suppression of spermatogenesis with Androgel, Endroxal exhibited no negative effect on spermatogenesis compared to placebo. CONCLUSIONS: Endroxal is a high affinity estrogen antagonist (IC50:16nM) with substantially higher antagonist activity than its isomer zuclomiphene (IC50:610nM). The zu isomer, comprising up to 40% of commercial clomiphene, is poorly metabolized and accumulates (10 fold greater than enclomiphene). These pharmacological and pharmacokinetic differences between the two isomers could lead to and improved therapeutic window for Endroxal over clomiphene. Overall, the data show that T restoration with Endroxal could provide an advantageous clinical profile over gel-induced T replacement.