Endocrine safety of ulipristal acetate, a selective progesterone receptor modulator (SPRM): results from two phase II randomised, placebo-controlled studies
Lynnette Nieman1, Nathalie Chabbert-Buffet3 & Philippe Bouchard2
Objective: Ulipristal acetate or UPA (PGL4001, formerly CDB-2914) is an oral SPRM with the potential to be the first in a new treatment class for uterine fibroids. As treatment with first-generation SPRMs led to modification of adrenal and thyroid function and changes in prolactin secretion and because UPA binds to the glucocorticoid receptor, we report here a detailed investigation of the endocrine effects of UPA.
Methods: Endocrine function was assessed for women included in two studies of UPA. In Study A, women with symptomatic fibroids received UPA 10 mg (n=13), 20 mg (n=13) or placebo (PLC; n=12) for the equivalent of three menstrual cycles (phase [ph] 1), after which they were offered surgical treatment or a 3-month continuation of UPA (ph2; n=12). Hormone levels were measured approximately every 2 weeks. In Study B (partially reported by Chabbert-Buffet et al. J Clin Endocrinol Metab 2007 92 3582), healthy women received UPA 2.5 mg (n=11), 5 mg (n=11), 10 mg (n=10) or PLC (n=11) for 84 days. Hormone levels were measured before treatment and on Days 59, 63, 67, 70, 74, 77, 80 and 84.
Results: Of the women in Study A receiving UPA, 23/26 in ph1 and 11/12 in ph2 had amenorrhea or spotting. Similarly, 18/21 women receiving UPA 5 or 10 mg in Study B had amenorrhea during month 3. In both studies, serum oestradiol levels fluctuated within physiological premenopausal limits. In Study A, values were similar for PLC and UPA groups in ph1, but were lower in ph2 in the UPA group (mean±S.D. 103.7±62 vs 74.4±35.2 ng/ml; delta change P=0.008). In Study B, oestradiol levels were similar in UPA and PLC women. In Study A, elevated prolactin levels (≥25 and <90 μg/l) were found in six women in both PLC and UPA groups; two had high baseline levels (excluding a relationship to treatment), the rest had occasional minor increases. There was no evidence for adrenal blockade; two PLC- and one UPA-treated women had transient mild adrenocorticotrophin elevations (>49 pg/ml), with normal cortisol levels. In Study B, prolactin, cortisol and testosterone levels did not vary significantly between baseline and Day 84. During treatment, thyroid function was normal in all but two patients (5 mg UPA group) who had subclinical disease before enrolment.
Conclusions: These results demonstrate no endocrine safety concerns with UPA, with no evidence of oestrogen suppression of relevance to bone health and no antiglucocorticoid effects.