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Suppression of Serum Luteinizing Hormone in Postmenopausal Women by an Orally Administered Nonpeptide Antagonist of the Gonadotropin-Releasing Hormone Receptor (NBI-42902)

Departments of Endocrinology (R.S.S.), Preclinical Development (T.C., B.C., H.P.B.), and Clinical Development (R.J., H.P.), Neurocrine Biosciences Inc., San Diego, California 92130; and Department of Reproductive Medicine (S.S.C.Y.), University of California, San Diego, San Diego, California 92093

Address all correspondence and requests for reprints to: Dr. R. Scott Struthers, Department of Endocrinology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, California 92130. E-mail: sstruthers{at}neurocrine.com.

Context: Parenteral administration of peptide GnRH analogs is widely used in clinical practice for the suppression of pituitary gonadotropins. NBI-42902 is an orally available, high-affinity nonpeptide antagonist of the human GnRH receptor.

Objective: The objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropin secretion of NBI-42902 in postmenopausal women.

Design: This was a phase I, double-blind, placebo-controlled, single-dose study with sequential dose escalation.

Participants: Fifty-six healthy, postmenopausal women were included. FSH levels were greater than 40 IU/liter, and body mass index was within 20% of ideal values for all subjects.

Interventions: Subjects were administered 5, 10, 25, 50, 75, 100, 150, or 200 mg NBI-42902 as an oral solution.

Main Outcome Measures: Safety, tolerability, and serum LH and FSH concentrations were evaluated.

Results: NBI-42902 was well tolerated. Serum LH concentrations rapidly declined, and dose-dependent suppression was observed. Maximal change from baseline LH concentrations ranged from –19 ± 5% in the 5-mg group to –55 ± 2% in the 150-mg group. Suppression of FSH was less pronounced (–15 to –22% of baseline). NBI-42902 was rapidly absorbed after oral administration with a terminal elimination half-life ranging from 2.7 ± 0.3 to 4.8 ± 0.8 h. A clear relationship between plasma NBI-42902 concentrations and LH suppression was evident.

Conclusions: Dose-dependent LH suppression was achieved by oral administration of a nonpeptide GnRH antagonist suggesting that compounds such as NBI-42902 may enable adjustable gonadotropin suppression as part of novel treatment strategies for benign gynecological conditions.

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