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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 10 3903-3907
Copyright © 2006 by The Endocrine Society

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

R. Scott Struthers, TaKung Chen, Bruce Campbell, Roland Jimenez, Henry Pan, Samuel S. C. Yen and Haig P. Bozigian

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DEPOT INJECTIONS OF peptide GnRH agonists have found widespread application for a range of steroid-dependent diseases (1) as well as for ovarian hyperstimulation protocols for assisted reproductive therapy (2). Currently, several GnRH peptide agonist therapeutics such as leuprolide and goserelin are commercially available for these uses. More recently, peptide GnRH antagonists have been developed (3, 4). GnRH antagonists result in an immediate reduction in gonadal steroid levels (5), which can result in the avoidance of an initial flare in testosterone in advanced prostate cancer patients (6, 7) and a more rapid reduction in uterine fibroid volume (8, 9) as well as reduction in frequency of injections and duration of treatment during in vitro fertilization protocols (4).

The requirement for daily injection or implantation of long-acting depots of peptide GnRH agonists or antagonists has led several groups to attempt to develop orally active, nonpeptide antagonists (for a recent review, see Ref. 10). Recently, a novel nonpeptide GnRH antagonist, NBI-42902, (1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil), has been developed (11). The detailed pharmacological characterization of this compound in vitro and in vivo in nonhuman primates will be presented elsewhere. Briefly, tritiated NBI-42902 binds with high affinity (Kd = 0.19 nM) to the human GnRH receptor and can be displaced by a range of peptide and nonpeptide GnRH receptor ligands, suggesting a common orthosteric binding pocket. In vitro experiments demonstrate that NBI-42902 is a potent functional, competitive antagonist of GnRH-stimulated inositol phosphate accumulation, Ca2+ flux, and ERK1/2 activation. Furthermore, this nonpeptide did not stimulate histamine release from rat peritoneal mast cells. Finally, it is effective in lowering serum LH in castrated male macaques after oral administration. Based on these pharmacological data and preclinical studies demonstrating adequate safety, we undertook to evaluate this nonpeptide GnRH antagonist in humans. In the present study, we examine the safety, tolerability, pharmacokinetics, and inhibition of gonadotropin secretion of this compound after oral administration to postmenopausal women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study protocol

This was a first-in-human, single-center, phase I, randomized, double-blind, placebo-controlled, single-dose study with sequential dose escalation to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of NBI-42902 in 56 healthy, postmenopausal women (age, 49–65 yr). FSH levels were greater than 40 IU/liter, and body mass index (BMI) was within 20% of ideal values for all subjects. We excluded subjects who used nicotine-containing products, consumed more than two alcoholic beverages per day, or took hormone replacement therapy (or alternative remedies for menopause symptoms) within 3 months of dosing. All study procedures involving human subjects were approved by the Independent Ethics Committee at the Medical Board (Ärztekammer) of Berlin and were performed at PAREXEL GmbH, Institute of Clinical Pharmacology (Berlin, Germany). Written informed consent was obtained from all subjects.

The study was conducted in eight dose cohorts (5, 10, 25, 50, 75, 100, 150, or 200 mg), each consisting of seven healthy, postmenopausal women (56 subjects). Each cohort of seven women entered the clinical unit 1 d before dosing (d 0), and a series of blood samples were collected (24, 22, 20, 16, 12, and 0.25 h before dosing) to establish baseline gonadotropin levels. Subjects were required to fast overnight (no food after midnight) before dosing and until 4 h after dosing, which occurred at approximately 0800 h. Subjects were randomized to receive either a single dose of NBI-42902 (six subjects per cohort) or a single dose of matching vehicle (one subject per cohort). Each higher-dose group was started after review of all safety and pharmacokinetic data from the preceding dose group(s). The subjects remained in-house for 48 h after dose and returned to the clinic for subsequent evaluations. Blood was collected at intervals (0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 144 h after dose) to determine NBI-42902 plasma concentrations and serum hormone levels. An additional blood sample was collected at 18 h in the 150- and 200-mg cohorts. Safety assessments were conducted at scheduled times for up to 144 h (d 7) after dose and included physical examination, safety laboratory tests, electrocardiogram and vital signs recordings, and monitoring of adverse events and concomitant medication.

NBI-42902 preparation

NBI-42902 (11) was administered as an oral solution (10 mg/ml) in a mixture of propylene glycol and purified water containing sorbitol (70% solution), orange cream flavor, and benzyl alcohol (as a preservative). The matching placebo oral solution was similar in form and taste.

Assays

Serum LH and FSH levels were obtained using an automated microparticle enzyme immunoassay performed on the AxSYM system (Abbott Laboratories, Abbott Park, IL). Samples from each cohort were measured in a single assay. Assay sensitivities were 0.50 and 0.37 IU/liter for LH and FSH, respectively. Interassay coefficient of variation (CV) was 1.9–6.9 and 1.1–4.8% and the intraassay CV was 4.2–6.7 and 3.7–7.6% for LH and FSH, respectively.

Plasma NBI-42902 concentrations were determined by high-pressure liquid chromatography using tandem mass spectrometry detection (LC-MS/MS). Deuterated NBI-42902 was used as an internal standard. The bioanalytical procedure involves extraction of analytes and added internal standard by protein precipitation with 0.8 ml acetonitrile from a 0.2-ml aliquot of plasma sample. After the extraction, the supernatant was collected, dried under vacuum, and reconstituted with 0.11 ml of 25:75 (vol/vol) acetonitrile/water solution before being introduced into an LC-MS/MS system (Waters 2690 HPLC system in tandem with a Micromass Quattro mass spectrometer) for quantification. The external calibration curve of the assay has a linear range of 0.5–500 ng/ml with a lower limit of quantification at 0.5 ng/ml. The study-wide accuracy and precision (percent CV) of the bioanalytical assay are within ±13.5% of the theoretical concentrations from spiked quality control samples. Descriptive pharmacokinetic parameters were calculated from noncompartmental analysis (model 200) using WinNonlin software (version 4.1; Pharsight Corp., Mountain View, CA) and summarized using descriptive statistics.

Data analysis

Data are expressed as mean ± SEM. To evaluate treatment effects, serum gonadotropin levels were expressed as percent change from the average gonadotropin concentration for each individual baseline during the 24 h before administration of antagonist. Data were analyzed by two-way, repeated-measures ANOVA with time and drug dose as the treatment conditions. Holm-Sidak post hoc comparisons were used to determine drug group differences from placebo at each time point. All statistical analyses were done using SigmaStat (SPSS, Inc., Chicago, IL). Differences were considered significant if P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Body weight and BMI ranged from 48.0–80.0 kg and from 18.2–27.0 kg/m2, respectively. A summary of characteristics of all subjects by dose group is presented in Table 1Go. There were no relevant differences in the mean age, height, weight, and BMI among the nine groups.


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  		TABLE 1. Characteristics of 56 postmenopausal women according to treatment group assignment

 
Single doses of 5–200 mg NBI-42902 were well tolerated and did not evoke any safety concerns. A total of 24 mild to moderate treatment-emergent adverse events were reported from 19 (33.9%) of the 56 subjects, all of which resolved by the final examination. The most common adverse events regardless of treatment were myalgia (n = 6; 11%, six events) and headache (n = 5; 9%, seven events). There were no meaningful treatment-emergent laboratory findings. There were no allergic reactions.

Basal concentrations (mean ± SD) of serum LH (37 ± 11 IU/liter) and FSH (83 ± 24 IU/liter) were consistent with the hypogonadal state in all 56 subjects. Figure 1Go shows the time course of gonadotropin responses to oral administration of 5, 25, 100, and 200 mg NBI-42902. All dose groups resulted in a rapid decline in LH levels, the extent of which was dose dependent. Statistically significant suppression (P < 0.05) was achieved in the 100-mg group at 1 h and by 2 h in the remaining groups. Maximal suppression of LH levels was achieved 4–8 h after dosing. Maximal change from baseline in LH ranged from –19 ± 5% (mean ± SEM) in the 5-mg group to –55 ± 2% in the 150-mg group. The duration of suppression also related to dose with more rapid recovery of LH levels in the lower-dose groups. All groups returned to baseline LH levels by 24 h. The initial rate of LH decline (Fig. 2Go) was dose dependent at the lower doses (5–50 mg) and reached a plateau at doses of 75 mg and above. Suppression of FSH levels was slower and less pronounced than LH (Fig. 1Go). All NBI-42902 dose groups showed similar levels of FSH suppression (15–22%) 6 h after administration with the exception of the 10-mg dose, which did not show suppression (data not shown).


Figure 1
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  		FIG. 1. Time course of LH and FSH suppression in 56 postmenopausal women in response to oral administration of NBI-42902. Subjects were administered 5 mg ({blacktriangleup}; n = 6), 25 mg ({square}; n = 6), 100 mg ({triangledown}; n = 6), or 200 mg (•; n = 6) NBI-42902 or vehicle ({circ}; n = 8) at time 0. Serum was collected for gonadotropin determinations at the times indicated. Values shown are mean (± SEM) percent changes from the average gonadotropin concentrations for each individual baseline during the 24 h before administration of antagonist. A mean baseline gonadotropin curve for all subjects (n = 56) is shown ({blacksquare}). Gonadotropin responses of subjects receiving 10, 50, 75, and 150 mg of NBI-42902 are omitted for clarity. Arrows indicate the time at which antagonist was administered.

 

Figure 2
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  		FIG. 2. Initial LH decline during the first 6 h after oral administration of NBI-42902. Subjects received 5 mg ({blacktriangleup}; n = 6), 25 mg ({square}; n = 6), 100 mg ({triangledown}; n = 6), or 200 mg (•; n = 6) NBI-42902 at time 0, and serum was collected for LH determinations at the times indicated. Values shown are mean (± SEM) percent changes from the average gonadotropin concentrations for each individual baseline during the 24 h before administration of antagonist. Curves are fitted by a single-exponential decay model.

 
NBI-42902 was rapidly absorbed after oral administration (Fig. 3Go). A summary of pharmacokinetic parameters for the range of dose groups is presented in Table 2Go. Median time to peak plasma NBI-42902 concentration ranged from 0.38–1.125 h. Maximal concentration and area under the curve increased proportionally to dose. The terminal elimination half-life ranged from 2.7 ± 0.3 to 4.8 ± 0.8 h.


Figure 3
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  		FIG. 3. Plasma NBI-42902 concentrations after oral administration of 5 mg ({blacktriangledown}; n = 6), 25 mg ({square}; n = 6), 100 mg ({triangledown}; n = 6), or 200 mg (•; n = 6). Values shown are mean ± SEM. The dashed line indicates the limit of quantitation (0.5 ng/ml).

 

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  		TABLE 2. Pharmacokinetic parameters of NBI-42902 in 56 postmenopausal women after oral administration

 
The time-dependent relationship between pharmacokinetics and pharmacodynamic response (LH suppression) is shown for the 200-mg dose group in Fig. 4AGo. To illustrate better the relationship between antagonist and LH concentrations, these same data are shown as a hysteresis plot in Fig. 4BGo. In the first blood sample taken after administration of the antagonist (15 min), high plasma NBI-42902 concentrations were obtained (226 ± 76 ng/ml) without alterations of LH levels. In the subsequent blood sample (30 min), antagonist plasma concentrations continue to rise (500 ± 131 ng/ml) and LH concentrations begin to decline reflecting a suppression of secretion. This decline continued until the 4-h time point when a plateau in LH suppression was achieved (–49 ± 4.9%). This was maintained through the 12-h time point. Between 12 and 24 h, LH concentrations returned to baseline associated with a decline in plasma NBI-42902 concentrations from 28 ± 9.7 to 5.9 ± 2.2 ng/ml.


Figure 4
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  		FIG. 4. Pharmacokinetic/pharmacodynamic relationship of plasma NBI-42902 and serum LH concentrations in subjects (n = 6) receiving 200 mg NBI-42902. Points shown are mean ± SEM. A, Concentration-time profile of plasma NBI-42902 ({circ}) and serum LH (•). The vertical arrow indicates the time at which NBI-42902 was administered. B, Hysteresis plot of LH change as a function of plasma NBI-42902 concentration.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The effectiveness of an orally administered, nonpeptide GnRH antagonist to suppress circulating LH is demonstrated by these data. NBI-42902 was safe and well tolerated, orally bioavailable, and a potent inhibitor of LH secretion in postmenopausal women. The suppression of LH was dose dependent from 5–200 mg, suggesting a high degree of control over pituitary LH secretion. The relationship of LH suppression to plasma antagonist concentration suggests that the compound is highly potent in vivo, and concentrations above 20 ng/ml maintain maximal suppression of pituitary LH secretion. Therefore, even though the pharmacokinetic half-life of the compound is relatively short (2.7 ± 0.3 to 4.8 ± 0.8 h), concentrations sufficient to maintain LH suppression are present for 12 or more hours after administration, depending on the dose.

Suppression of FSH was less pronounced and not dose dependent. Although the mechanisms of this differential suppression of LH and FSH are not well understood, previous studies with peptide GnRH antagonists have reported similar responses (5, 12, 13, 14). In part, this may be because of the longer half-life of FSH in the circulation, which thereby requires longer duration of suppression of pituitary secretion in order for changes in circulating levels to be observed (12).

Currently, GnRH agonists are typically used in benign gynecological disorders such as endometriosis and uterine fibroids to achieve medical castration in conjunction with various add-back regimens to avoid bone-loss and hypoestrogenic symptoms (15). In a pilot study of a draw-back therapy with the peptide agonist nafaralin, full-dose or half-dose nafaralin treatment was compared in endometriosis patients (16). Pain relief was similar in the two dose groups, but estrogen levels were higher in the half-dose group, and vasomotor symptoms and bone loss were reduced, suggesting that partial gonadal suppression may provide an alternative to medical castration with add-back. Similarly, treatment of follicular-phase premenopausal women with two different doses of the peptide antagonist ganirelix showed that partial gonadal suppression could be achieved by varying the dosage of antagonist (17). The ability to conveniently vary the degree of pituitary suppression by varying the oral dosage of NBI-42902 demonstrated in this study suggests that oral GnRH antagonists may enable adjustable pituitary suppression in premenopausal women as part of novel treatment strategies for benign gynecological conditions with reduced side effects such as bone loss and vasomotor symptoms.


   Acknowledgments
 
We thank France La Pierre-Holme, Hilde Williams, and Dr. Stacy Markison for helpful advice and discussions. We also thank Dr. Georg Golor and co-workers at Parexel GmbH (Berlin, Germany) for their assistance in the conduct of this study.


   Footnotes
 
This work was supported, in part, by National Institutes of Health Grants 1-R43-HD38625-01 and 2-R44-HD38625-02.

Present address for B.C.: Department of Pharmacology, Guys Campus, Kings College, London, United Kingdom.

Disclosure summary: R.S.S., T.C., B.C., R.J., H.P., H.P.B. are or were employed by and have equity interests in Neurocrine Biosciences. S.S.C.Y. consults for Neurocrine Biosciences, Inc.

First Published Online July 18, 2006

Abbreviations: BMI, Body mass index; CV, coefficient of variation.

Received May 23, 2006.

Accepted July 10, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Conn PM, Crowley Jr WF 1991 Gonadotropin-releasing hormone and its analogues. N Engl J Med 324:93–103[Medline]
  2. Barlow DH 1998 GnRH agonists and in vitro fertilization. J Reprod Med 43:245–251[Medline]
  3. Felberbaum RE, Ludwig M, Diedrich K 2000 Clinical application of GnRH-antagonists. Mol Cell Endocrinol 166:9–14[CrossRef][Medline]
  4. Huirne JA, Lambalk CB 2001 Gonadotropin-releasing-hormone-receptor antagonists. Lancet 358:1793–1803[CrossRef][Medline]
  5. Cetel NS, Rivier J, Vale W, Yen SS 1983 The dynamics of gonadotropin inhibition in women induced by an antagonistic analog of gonadotropin-releasing hormone. J Clin Endocrinol Metab 57:62–65[Abstract]
  6. McLeod D, Zinner N, Tomera K, Gleason D, Fotheringham N, Campion M, Garnick MB 2001 A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. Urology 58:756–761[CrossRef][Medline]
  7. Trachtenberg J, Gittleman M, Steidle C, Barzell W, Friedel W, Pessis D, Fotheringham N, Campion M, Garnick MB 2002 A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol 167:1670–1674[CrossRef][Medline]
  8. Kettel LM, Murphy AA, Morales AJ, Rivier J, Vale W, Yen SS 1993 Rapid regression of uterine leiomyomas in response to daily administration of gonadotropin-releasing hormone antagonist. Fertil Steril 60:642–646[Medline]
  9. Felberbaum RE, Germer U, Ludwig M, Riethmuller-Winzen H, Heise S, Buttge I, Bauer O, Reissmann T, Engel J, Diedrich K 1998 Treatment of uterine fibroids with a slow-release formulation of the gonadotrophin releasing hormone antagonist cetrorelix. Hum Reprod 13:1660–1668[Abstract/Free Full Text]
  10. Zhu YF, Chen C, Struthers RS 2004 Nonpeptide gonadotropin releasing hormone antagonists. Annu Reports Med Chem 39:99–110[CrossRef]
  11. Tucci FC, Zhu YF, Struthers RS, Guo Z, Gross TD, Rowbottom MW, Acevedo O, Gao Y, Saunders J, Xie Q, Reinhart GJ, Liu XJ, Ling N, Bonneville AK, Chen T, Bozigian H, Chen C 2005 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization. J Med Chem 48:1169–1178[CrossRef][Medline]
  12. Andreyko JL, Monroe SE, Marshall LA, Fluker MR, Nerenberg CA, Jaffe RB 1992 Concordant suppression of serum immunoreactive luteinizing hormone (LH), follicle-stimulating hormone, {alpha}-subunit, bioactive LH, and testosterone in postmenopausal women by a potent gonadotropin releasing hormone antagonist (detirelix). J Clin Endocrinol Metab 74:399–405[Abstract]
  13. Rabinovici J, Rothman P, Monroe SE, Nerenberg C, Jaffe RB 1992 Endocrine effects and pharmacokinetic characteristics of a potent new gonadotropin-releasing hormone antagonist (ganirelix) with minimal histamine-releasing properties: studies in postmenopausal women. J Clin Endocrinol Metab 75:1220–1225[Abstract]
  14. Mortola JF, Sathanandan M, Pavlou S, Dahl KD, Hsueh AJ, Rivier J, Vale W, Yen SS 1989 Suppression of bioactive and immunoreactive follicle-stimulating hormone and luteinizing hormone levels by a potent gonadotropin-releasing hormone antagonist: pharmacodynamic studies. Fertil Steril 51:957–963[Medline]
  15. Barbieri RL 1992 Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol 166:740–745[Medline]
  16. Tahara M, Matsuoka T, Yokoi T, Tasaka K, Kurachi H, Murata Y 2000 Treatment of endometriosis with a decreasing dosage of a gonadotropin-releasing hormone agonist (nafarelin): a pilot study with low-dose agonist therapy ("draw-back" therapy). Fertil Steril 73:799–804[CrossRef][Medline]
  17. Nelson LR, Fujimoto VY, Jaffe RB, Monroe SE 1995 Suppression of follicular phase pituitary-gonadal function by a potent new gonadotropin-releasing hormone antagonist with reduced histamine-releasing properties (ganirelix). Fertil Steril 63:963–969[Medline]



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