A 39-week oral toxicity study of ulipristal acetate in cynomolgus monkeys

Abstract

Ulipristal acetate (UPA) is a novel Progesterone Receptor Modulator (PRM) and registered for the pre-operative treatment of symptomatic uterine fibroids during 3 months. In a study which assessed the potential toxicity of UPA in female cynomolgus monkeys following daily oral administration of 1, 5, or 25 mg/kg for 39 weeks, UPA was well tolerated with dose-dependent macroscopic and microscopic observations limited to the uterus and oviducts. These findings were considered to be related to the pharmacological action of UPA and showed evidence of partial reversibility. Findings in the endometrium were similar to PRM-associated-endometrial-changes (PAEC) described in PRM-treated women. No adverse effects were found that would raise concerns about potential pre-malignancy. Although the translation of these findings to human is limited by the small study size and species differences, these results from animals chronically exposed to up to 150 times the clinical UPA exposure are considered significant and supportive to the chronic administration of UPA for more than 3 months in women of reproductive age.

Introduction

Progesterone plays a pivotal role in reproduction in many species. It is involved in the control of ovulation, implantation, and maintenance of pregnancy, and withdrawal of progesterone at the end of a non-fertile cycle results in menstruation in humans and nonhuman primates (Reel et al., 1979, Csapo and Pulkkinen, 1978). In the uterus, progesterone controls the growth and differentiation of endometrial and myometrial cells and directly regulates a variety of cell functions; it also acts indirectly by functionally opposing various estrogen effects. The recognition of the important role of progesterone in reproduction led to the development of synthetic progesterone receptor ligands, also known as Selective Progesterone Receptor Modulators (SPRMs). The synthesis of mifepristone (RU486), the first progesterone receptor antagonist, which also acted as a glucocorticoid receptor antagonist, was a starting point of drug discovery for progesterone receptor modulators throughout the world. Research focused on finding compounds with increased progesterone antagonistic potency and reduced antiglucocorticoid activity compared with mifepristone (Teutsch and Philibert, 1994, Spitz and Bardin, 1993, Bouchard et al., 2011). Ulipristal acetate (UPA) is a result of this search. This paper reports the design and results of a 39-week multiple dose study with an 8-week recovery period, conducted in cynomolgus monkeys. UPA is currently registered as a 3-month pre-operative treatment of uterine fibroids (ESMYA®), at a dose of 5 mg/day (PregLem, 2012). This long term regulatory toxicology study is part of the non-clinical safety program conducted to evaluate the potential toxicity of UPA for chronic use in women for more than 3 months. In the interest of animal welfare, this study was designed to use the fewest number of animals possible, consistent with the objective of the study, contemporary scientific standards, and in consideration of applicable regulatory requirements (ICH, 2009, ICH, 1998). In accordance with these requirements, the study size was sufficient for meaningful statistical analysis of data, identification of target organ toxicity and symptom recovery. Female cynomolgus monkeys were chosen as the animal model since the physiology of reproduction in this species is very similar to that in human (van Esch et al., 2008a, van Esch et al., 2008b). The cynomolgus undergoes a menstrual cycle of almost identical length (28–30 days) to the human (28–32 days), and the morphological appearances in endometrium of the normal follicular, luteal and menstrual phases show close similarities (van Esch et al., 2008a, van Esch et al., 2008b). As well as having close parallels in reproductive cycle physiology, macaques and humans also share a range of endometrial abnormalities of similar histological appearances, including endometrial polyps, hyperplasia and malignant neoplasms. For example, the endometrial response to short term unopposed estrogenic stimulation is similar in both species, with the development of simple non-atypical hyperplasia. In this context, Cline et al. (2008) noted that there is a tendency for regulators to regard the use of the term “endometrial hyperplasia” to represent complex hyperplasia with atypia, which may not be the case. Furthermore, these authors drew attention to important differences in the vocabulary of diagnostic terms used by veterinary and medical pathologists. The common human postmenopausal appearance of thickened endometrium with dilated but inactive glands is termed “cystic atrophy” by medical pathologists, but the similar appearance in macaques is described by veterinary pathologists as “cystic endometrial hyperplasia”. We therefore considered it important that the endometrial changes on treatment were described in detail, rather than simply being given a diagnostic label.

In clinical studies, endometrium exposed to progesterone receptor modulators (PRMs) including UPA shows a range of histological changes referred to as PRM-associated endometrial changes (PAEC) (Mutter et al., 2008, Williams et al., 2007, Williams et al., 2012). The main histological findings of human PAEC are as follows: 1. Endometrial glands show architectural irregularity, and there is often extensive cystic dilatation. 2. Glandular epithelium appears inactive with low cuboidal, non-stratified epithelial cells showing infrequent mitoses. 3. There is a non-physiological secretory appearance, in which glands are coiled or tortuous (resembling those of the secretory phase), but with poorly developed secretory activity. 4. Glands are irregularly scattered throughout compact cellular stroma without pre-decidual change. Not all endometrial specimens exhibit every histological feature, but it is usually possible to recognize PRM-exposed endometrium by identifying several of the characteristic changes. It was of particular interest in this study of UPA-exposed monkey endometrium to determine whether an overall drug effect analogous to human PAEC could be recognized in treated animals, and whether effects were dose-related and reversible. It was also important to determine whether any of the morphological changes raised any concerns in terms of atypical or pre-malignant endometrial conditions.