Selective Progesterone Receptor Modulator Development and Use in the Treatment of Leiomyomata and Endometriosis

0163-769X/05/$20.00/0 Printed in U.S.A. Endocrine Reviews 26(3):423– 438 Copyright © 2005 by The Endocrine Society doi: 10.1210/er.2005-0001 Selective Progesterone Receptor Modulator Development and Use in the Treatment of Leiomyomata and Endometriosis Kristof Chwalisz, Maria Claudia Perez, Deborah DeManno, Craig Winkel, Gerd Schubert, and Walter Elger TAP Pharmaceutical Products, Inc. (K.C., M.C.P., D.D.), Lake Forest, Illinois 60045; School of Nursing (C.W.), Georgetown University, Washington, D.C. 20007; Jenapharm GmbH & Co. (G.S.), 07745 Jena, Germany; and EnTec GmbH (W.E.), 07745 Jena, Germany Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11␤-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroids, asoprisnil suppressed both the duration and intensity of uterine bleeding in a dose-dependent manner and reduced tumor volume in the absence of estrogen deprivation. In subjects with endometriosis, asoprisnil was effective in reducing nonmenstrual pain and dysmenorrhea. Asoprisnil may, therefore, provide a novel, tissue-selective approach to control endometriosis-related pain. SPRMs have the potential to become a novel treatment of uterine fibroids and endometriosis. (Endocrine Reviews 26: 423– 438, 2005) I. Introduction II. Terminology, Definitions, and Mechanism of Action of SPRMs A. SPRM definition B. 11␤-Benzaldoxime-substituted SPRMs C. Other SPRMs D. Molecular basis of tissue selectivity of SPRMs III. Reproductive Pharmacology of Asoprisnil and Structurally Related SPRMs A. Biochemical characterization B. PR-mediated effects in animal models C. AR-, GR-, and ER-mediated effects IV. Pharmacodynamic Effects of 11␤-Benzaldoxime-Substituted SPRMs in Nonhuman Primates V. Metabolism and Pharmacokinetics of Asoprisnil VI. Pharmacodynamic Effects of Asoprisnil in Healthy Women VII. SPRMs in the Treatment of Uterine Leiomyomata A. Rationale B. Clinical studies with asoprisnil VIII. SPRMs in the Treatment of Endometriosis A. Rationale B. Clinical studies with asoprisnil IX. Outlook and Concluding Remarks I. Introduction P ROGESTERONE IS THE natural ligand of the progesterone receptor (PR), which is a member of the superfamily of nuclear receptors. The nuclear receptor superfamily comprises a large and diverse group of eukaryotic transcription factors that control many biological functions through regulation of specific genes involved in embryonic development, reproduction, tissue growth and differentiation, and hormone-mediated homeostasis (1, 2). Progesterone plays a pivotal role in female reproduction. It is involved in the control of ovulation, prepares the endometrium for implantation, regulates the implantation processes, and in later stages of pregnancy is responsible for its maintenance by suppressing uterine contractility (3). The withdrawal of progesterone at the end of the nonfertile cycle leads to changes in the endometrial extracellular matrix and constriction of spiral arteries, resulting in menstruation in humans and nonhuman primates. In the uterus, progesterone controls the growth and differentiation of endometrial and myometrial cells and directly regulates a variety of cell functions by either stimulating or inhibiting structural and functional proteins; it also acts indirectly by functionally opposing various estrogen effects. In the nonpregnant uterus, progesterone exerts both inhibitory and stimulatory effects on cell proliferation in a cell- and tissue-specific manner. For example, in First Published Online April 27, 2005 Abbreviations: AF, Activation function; AR, androgen receptor; COX, cyclooxygenase; Dex, dexamethasone; E2, estradiol; EGF, epidermal growth factor; ER, estrogen receptor; GnRH-a, GnRH agonist; GR, glucocorticoid receptor; LBD, ligand binding domain; PA, PR antagonist; PR, progesterone receptor; SERM, selective estrogen receptor modulator; SPRM, selective PR modulator; SRC, steroid receptor coactivator; SRM, selective receptor modulator. Endocrine Reviews is published bimonthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community. 423 424 Endocrine Reviews, May 2005, 26(3):423– 438 primates during the luteal phase, progesterone inhibits estrogen-induced mitotic activity in the functional zones of the endometrial epithelium but shows some stimulatory effect on both the basalis and endometrial angiogenesis (4). Progesterone is an important mitogen in breast epithelial cells (5). Mitotic activity in normal breast tissue peaks during the luteal phase (6). Synthetic progestins clearly increase mammographic breast density (7), an effect that is accompanied by an increase in the expression of proliferation markers (8). Furthermore, continuous administration of estrogen/ progestin regimens, but not estrogen treatment alone, was associated with a slight, but significant, increase in breast cancer risk as reported by the Women’s Health Initiative study and other clinical studies in postmenopausal women (9, 10). Progesterone mediates its physiological effects through interaction with the PR, expressed in multiple tissues as two isoforms, hPR-A and hPR-B. These isoforms are derived from the same gene by the action of two different promoters (11, 12). The full-length hPR-B and N-terminus truncated hPR-A have highly conserved DNA and ligand binding domains (LBDs). Both isoforms have a similar architecture composed of the ligand-dependent activation function (AF)-2 present in the carboxyl terminus, and AF-1, a transcription domain present in the amino terminus (13). The constitutive AF-1 can function independently of AF-2 or with AF-2 in a liganddependent fashion. The LBD participates in interaction of the inactive receptor with heat shock proteins and immunophilins as well as promoting receptor dimerization (13, 14). A third activation domain, the AF-3 domain, is located in the upstream sequence region of hPR-B (13, 14). AF-3 is composed of approximately 164 amino acids and is present only in the hPR-B isoform. Functional evaluation studies of the AF-3 domain suggest (...truncated)