Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs)

Abstract

Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterusselective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil.

Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety

“…Exposure of mammary glands from progesterone-primed virgin mice to ZK114043 led to a reduction in epithelial cell proliferation and differentiation of alveolar cells (140). In primates, too, treatment with asoprisnil or mifepristone results in antiproliferative effects in breast tissue (48,141), and the antiproliferative effects of mifepristone have been described in the normal human breast (141). These data suggest that treatment with SPRMs may lower the risk for breast cancer, although further studies are necessary to investigate this potentially beneficial effect.…”

“…A wealth of data has demonstrated that SPRMs inhibit endometrial proliferation. In nonhuman primates, a number of SPRMs, including ulipristal acetate, asoprisnil, PRA-910, and onapristone suppress endometrial proliferation, resulting in endometrial atrophy (48,(89)(90)(91). Similar suppression has been described in human cell lines after treatment with ulipristal acetate or mifepristone (92,93), and in subjects treated with SPRMs including asoprisnil, lonaprisan, mifepristone, or telapristone acetate (50,94,95,(96)(97)(98).…”

“…It is important, however, that despite their effects on ovulation, SPRMs do not result in the down-regulation of ovarian estrogen levels, allowing estrogen concentrations to remain within physiologic levels (43)(44)(45)(46)(47)(48)(49)(50)(51). Administration of a single dose of mifepristone or ulipristal acetate also delays ovulation (52-56), a property that allows the use of these compounds for emergency contraception.…”

A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata

“…Asoprisnil exhibits mixed P agonist and antagonist activities and a high degree of uterine selectivity in animals and human beings (14,15). In nonhuman primates and human beings, it induces amenorrhea and suppresses endometrial growth via local, PR-mediated effects that occur in the presence of follicular phase concentrations of estradiol (E 2 ) (13). However, in contradiction to the so-called pure (e.g., onapristone) and almost pure (e.g., mifepristone) P antagonists, asoprisnil shows only marginal abortifacient activities in guinea pigs as a result of partial P agonist activity (14,16).…”

“…On the basis of functional definition, SPRMs are P receptor (PR) ligands that exert clinically relevant tissue-selective P agonist, antagonist, partial, or mixed agonist and antagonist effects on various P target tissues in an in vivo situation (13). Asoprisnil exhibits mixed P agonist and antagonist activities and a high degree of uterine selectivity in animals and human beings (14,15).…”