Pharmacodynamics and safety of the novel selective progesterone receptor modulator vilaprisan: a double-blind, randomized, placebo-controlled phase 1 trial in healthy women.

STUDY QUESTION: Does administration of vilaprisan (VPR) to healthy women for 12 weeks reduce menstrual bleeding? SUMMARY ANSWER: In this 12-week proof-of-concept phase 1 trial, most women (30/33, 90%) who received VPR at daily doses of 1-5 mg reported the absence of menstrual bleeding. WHAT IS KNOWN ALREADY: Vilaprisan (BAY 1002670) is a novel, highly potent selective progesterone receptor modulator that markedly reduces the growth of human leiomyoma tissue in a preclinical model of uterine fibroids (UFs). STUDY DESIGN, SIZE, DURATION: In this double-blind, parallel-group study, of the 163 healthy women enrolled 73 were randomized to daily VPR 0.1 mg (n = 12), 0.5 mg (n = 12), 1 mg (n = 13), 2 mg (n = 12), 5 mg (n = 12) or placebo tablets (n = 12) for 12 weeks. Participants were followed up until the start of the second menstrual bleeding after the end of treatment. Trial simulations were used to determine the minimum sample size required to estimate the non-bleeding rate (i.e. self-assessed bleeding intensity of 'none' or 'spotting') using Bayesian dose-response estimation with incorporated prior information. It was estimated that 48 participants in the per-protocol analysis population would be sufficient. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-45 years who had been sterilized by tubal ligation were enrolled between November 2011 and May 2012. Participants kept a daily diary of bleeding intensity. Blood and urine samples were taken, and transvaginal ultrasound was performed before treatment, during treatment and follow-up. Endometrial biopsies were obtained during the pretreatment cycle, at the end of the treatment period and during the follow-up phase. The primary outcome was the estimated dose-response curve of the observed non-bleeding rate during Days 10-84 of treatment, excluding the endometrial biopsy day and 2 days after biopsy. Secondary outcomes included return of bleeding during follow-up, size of follicle-like structures and serum hormone levels. Safety assessments included adverse events (AEs), endometrial thickness and histology, laboratory parameters, vital signs and 12-lead electrocardiography. MAIN RESULTS AND THE ROLE OF CHANCE: All 73 randomized participants received at least one dose of study medication and were included in safety analyses; six participants were excluded from the per-protocol analyses. A total of 69 completed the study. Observed non-bleeding rates increased with VPR dose: 0.1 mg (0%; 90% confidence interval [CI]: 0-23.8), 0.5 mg (27.3%; 90% CI: 7.9-56.4), 1 mg (80.0%; 90% CI: 49.3-96.3), 2 mg (100%; 90% CI: 77.9-100), 5 mg (90.9%; 90% CI: 63.6-99.5), compared with 0% (90% CI: 0-22.1) in the placebo group. Maximal non-bleeding rates were reached at doses of 2 mg and higher. Return of menstrual bleeding was observed in all women ≤52 days after VPR discontinuation. No treatment-emergent critical endometrial findings occurred. Follicular growth was not suppressed and minimum average estradiol levels remained above 40 pg/ml. No serious treatment-emergent AEs or study discontinuations due to AEs were reported. Clinically relevant changes in laboratory parameters or vital signs were not evident. LIMITATIONS, REASONS FOR CAUTION: The results of this small proof-of-concept study will need to be confirmed in larger trials in patients with UFs to establish the potential therapeutic benefits and safety of VPR. WIDER IMPLICATIONS OF THE FINDINGS: The high rates of non-bleeding (80-100% at VPR doses of 1-5 mg) support further evaluation of VPR in patients with UFs and heavy menstrual bleeding. STUDY FUNDING/COMPETING INTERESTS: This study was funded by Bayer Pharma AG. B.S., A.K., M.-H.S.M., C.S. and B.R. are employees of Bayer Pharma AG. B.S., A.K. and M.-H.S.M. are listed as inventors of an issued patent related to this work, and received payment for this from Bayer Pharma AG. D.B. is the founder of Biokinetic Europe Ltd, UK, which received funding for this study from Bayer Pharma AG. M.K. is an employee of Nuvisan GmbH, Germany, which received funding for this study from Bayer Pharma AG. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov identifier: NCT01816815. TRIAL REGISTRATION DATE: 20 March 2013. DATE OF FIRST PATIENT'S ENROLMENT: 28 November 2011.

Vilaprisan for the treatment of symptomatic endometriosis: results from a terminated phase 2b randomized controlled trial.

Objective: To evaluate the efficacy and safety of 2 doses of vilaprisan vs. placebo in participants with symptomatic endometriosis. Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2b trial (NCT03573336). The initially planned sample size was 315 patients. Recruitment was paused to assess long-term toxicity findings in rodents; although the findings were assessed as likely to be of limited clinical relevance in humans, the study was closed by the sponsor. During the pause, enrolled patients completed 3 or 6 months of treatment per their assigned regimen. Setting: University hospitals, a regional hospital, and a private clinic. Patients: Premenopausal adults with confirmed endometriosis and moderate-to-severe pelvic pain (≥4/10 on a numerical rating scale) were enrolled. Inclusion required protocol adherence, including ≥24 diary entries, and an average pain score of ≥3.5. Intervention: Participants were randomly assigned 1:1:1 to receive vilaprisan (2 mg), vilaprisan (4 mg), or placebo. Main Outcome Measures: The primary outcome was a change in the 7-day mean "worst pain" (per the endometriosis symptom diary item 1) from baseline to month 3. All analyses were descriptive only. Results: Eight participants were randomly assigned to treatment before the study pause: 6 received vilaprisan (4 mg, n = 4 and 2 mg, n = 2), and 2 received placebo. The 6 vilaprisan recipients experienced an improvement in endometriosis-associated pelvic pain, whereas the 2 placebo recipients experienced no change or increased pain; all 8 participants had decreased use of pain medication. Bleeding intensity decreased from baseline in the vilaprisan group. Conclusion: The study findings suggest that vilaprisan may improve outcomes in patients with endometriosis. Further studies in larger populations would be needed to accurately assess treatment effects. Clinical Trial Registration Number: NCT03573336.

Efficacy and safety of vilaprisan in women with uterine fibroids: data from the ASTEROID 3 randomized controlled trial.

OBJECTIVE: Vilaprisan is a highly potent selective progesterone receptor modulator shown to reduce heavy menstrual bleeding, induce amenorrhea, and diminish uterine fibroid volume in phase 2 studies. The objective of ASTEROID 3 was to demonstrate the superiority of vilaprisan compared with placebo in the treatment of heavy menstrual bleeding in women with uterine fibroids. DESIGN: Randomized, double-blind, placebo-controlled, multicenter phase 3 study. SETTING: Hospitals and medical centers. PATIENT(S): Women with ≥1 uterine fibroid of ≥3 cm and heavy menstrual bleeding of >80 mL/cycle. INTERVENTION(S): Women were randomly assigned to 1 of 4 treatment arms, which were planned to comprise 2 treatment periods of 12 weeks, each with vilaprisan (2 mg/d) or placebo that were continuous or separated by a break of one bleed. MAIN OUTCOME MEASURE(S): Amenorrhea (primary end point; <2 mL in the last 28 days of treatment) and heavy menstrual bleeding response (key secondary end point; <80 mL/cycle and >50% reduction in bleeding from baseline) were measured with the alkaline hematin method. Change in volume of the 3 largest fibroids from baseline to end of treatment was assessed by ultrasound. Safety was monitored throughout the study. RESULT(S): Overall, 75 women completed the first 12 weeks of treatment. Statistically significant and clinically meaningful differences were observed between the vilaprisan- and placebo-treated groups in both the full analysis and per-protocol sets. In the per-protocol set (n = 36 and n = 12 for the vilaprisan and placebo groups, respectively), amenorrhea was observed more frequently in women treated with vilaprisan than in those who received placebo (83.3% vs. 0%, P<.0001), with a median time to onset of 3 days in the vilaprisan group. Similarly, more vilaprisan- than placebo-treated women achieved a response in heavy menstrual bleeding (91.7% vs. 25.0%, P<.0001). Serious adverse events were reported for 22 (27.8%) of 79 women and were evenly distributed among the 4 groups receiving vilaprisan and/or placebo. None of these events led to study discontinuation or were related to the liver, and no new safety findings were identified compared with the earlier phase 2 ASTEROID studies. CONCLUSION(S): Vilaprisan is efficacious and well tolerated over 12 weeks in the treatment of heavy menstrual bleeding associated with uterine fibroids. Further investigations of the long-term efficacy and safety of vilaprisan are warranted. CLINICAL TRIAL REGISTRATION NUMBER: NCT03400943 (ClinicalTrials.gov).

Sex Steroid Receptors in Polycystic Ovary Syndrome and Endometriosis: Insights from Laboratory Studies to Clinical Trials.

Polycystic ovary syndrome (PCOS) and endometriosis are reproductive disorders that may cause infertility. The pathology of both diseases has been suggested to be associated with sex steroid hormone receptors, including oestrogen receptors (ER), progesterone receptors (PRs) and androgen receptors (ARs). Therefore, with this review, we aim to provide an update on the available knowledge of these receptors and how their interactions contribute to the pathogenesis of PCOS and endometriosis. One of the main PCOS-related medical conditions is abnormal folliculogenesis, which is associated with the downregulation of ER and AR expression in the ovaries. In addition, metabolic disorders in PCOS are caused by dysregulation of sex steroid hormone receptor expression. Furthermore, endometriosis is related to the upregulation of ER and the downregulation of PR expression. These receptors may serve as therapeutic targets for the treatment of PCOS-related disorders and endometriosis, considering their pathophysiological roles. Receptor agonists may be applied to increase the expression of a specific receptor and treat endometriosis or metabolic disorders. In contrast, receptor antagonist functions to reduce receptor expression and can be used to treat endometriosis and induce ovulation. Understanding PCOS and the pathological roles of endometriosis sex steroid receptors is crucial for developing potential therapeutic strategies to treat infertility in both conditions. Therefore, research should be continued to fill the knowledge gap regarding the subject.

Comparing the pharmacokinetic and pharmacodynamic qualities of current and future therapies for uterine fibroids.

INTRODUCTION: Uterine fibroids are the most common benign gynecological tumors affecting women of reproductive ages. Although surgery is the definitive treatment choice, several medical approaches have been investigated to control their symptoms. The main issue of currently employed drugs for uterine fibroids is the long-term safety and tolerability profile. Today, new emerging options represent hopeful alternatives that could potentially overcome these limitations. AREAS COVERED: This manuscript aims to give an updated overview of the pharmacodynamic and pharmacokinetic properties of current and new investigational medical drugs for the treatment of symptomatic uterine fibroids. The bibliographic research was conducted by searching alone or combined keywords on the following electronic databases: Medline, PubMed, Embase, Science Citation Index via Web of Science. EXPERT OPINION: The most recent therapeutic strategies for uterine fibroids are represented by gonadotropin-releasing hormone antagonists (GnRH-ants; elagolix and relugolix) and selective progesterone receptor modulators (SPRM; ulipristal acetate). After early promising results, studies on innovative drugs, such as linzagolix (GnRH-ant) and vilaprisan (SPRM) are demanding. In the near future, a deeper knowledge of biological mechanisms at the basis of the genesis and growth of uterine fibroids could pave the way for the development of innovative targeted therapies.

Pharmacokinetics and Safety of the Selective Progesterone Receptor Modulator Vilaprisan in Chinese Healthy Postmenopausal Women.

Vilaprisan is a novel selective progesterone receptor modulator for the long-term treatment of uterine fibroids and endometriosis. This study investigated the pharmacokinetics, safety, and tolerability of vilaprisan in healthy Chinese postmenopausal women. Twelve participants received multiple doses of vilaprisan once daily over 14 days as a 2-mg tablet. Plasma vilaprisan concentrations were determined using liquid chromatography-tandem mass spectrometry. The main pharmacokinetic parameters of vilaprisan were assessed with noncompartmental analysis, including maximum observed concentration (Cmax ), systemic exposure (area under the plasma concentration-time curve), time to reach Cmax and terminal half-life. Safety assessments include the documentation of adverse events, measurement of clinical/anthropometric parameters and vital signs, electrocardiogram, and physical and gynecologic examination. The participants had a mean age of 53.3 (± 4.2) years and a body mass index of 23.8 ± 2.8 kg/m2 . Median time to reach Cmax was 1.5 hours after both single and multiple vilaprisan administration. Mean Cmax values obtained after multiple dosing (23.3 µg/L [standard deviation (SD) = 6.73]) were 1.92-fold (SD = 0.554) higher compared to single dosing (12.5 µg/L [SD = 3.04]). Mean area under the plasma concentration-time curve in the dosing interval increased with an accumulation factor of 2.98 (SD = 0.767) between single (91.3 µg · h/L [SD = 20.4]) and multiple dosing (276 µg · h/L [SD = 109]). The mean terminal half-life of vilaprisan was 44.5 hours (SD = 10.3) after multiple dosing. Mild to moderate adverse events were observed similar to previous studies. Overall, daily oral administration of the therapeutic dose of 2 mg of vilaprisan over 14 days was safe and well tolerated by all participants.

Effect of Food Intake on the Pharmacokinetics of the Selective Progesterone Receptor Modulator Vilaprisan: A Randomized Clinical Study in Healthy Postmenopausal Women.

This exploratory, open-label, randomized, 3-period crossover study in 12 healthy postmenopausal women investigated the effects of food intake on the pharmacokinetics of vilaprisan. Single doses of vilaprisan (2 mg) were administered under fasting conditions, after intake of a high-fat, high-calorie meal, and after intake of a moderate-fat, moderate-calorie meal. The intake of food had only a marginal impact on the oral bioavailability of vilaprisan. The mean exposure of vilaprisan (area under the plasma concentration-time curve [AUC]) was increased by approximately 20% when the drug was taken after a meal and not on an empty stomach (point estimate for AUC ratios [%] and 90% confidence interval: high-fat and -calorie meal/fasting 121 [114-128]; moderate-fat and -calorie meal/fasting 118 [111-125]). The rate of absorption was slightly decreased when the drug was taken after a meal as indicated by approximately 10% lower mean maximum concentrations (Cmax ) of vilaprisan in plasma (Cmax ratios: high-fat and -calorie meal/fasting 87.9 [75.6-102]; moderate-fat and -calorie meal/fasting 89.4 [76.9-104]) and a prolonged time to Cmax (fasting: 1.5 hours; fed conditions; ∼4 hours). Overall, the results of this study indicate that vilaprisan can be administered equally well with or without food.

Highlights on Medical Treatment of Uterine Fibroids.

Uterine fibroids (leiomyomas or myomas) are the most frequent benign tumors in women. Heavy menstrual bleeding with resultant anemia, dysmenorrhea, chronic pelvic pain, infertility, urinary symptoms and constipation are generally associated with uterine fibroids (UFs). Although strategies mainly resort to surgical intervention, medical treatments are considered the first-line treatment to preserve fertility and avoid surgery. The aim of this review is to offer available and the newest medical treatment options for symptomatic UFs. Various medical therapies are now available for women with uterine fibroids, although each therapy has its own advantages and disadvantages. Our topic specifically explores gonadotropin-releasing hormone (GnRH) analogs and selective progesterone receptor modulators (SPRMs), but also provides the reader with useful advice on the therapies for fibroids available after the recent European Medicines Agency (EMA) warning (EMA/160220/2020). The treatment options depend on the personal treatment objectives of the patients, in addition to treatment effectiveness and necessity for recurrent interventions.

Pharmacokinetics and Safety of the Novel Selective Progesterone Receptor Modulator Vilaprisan in Participants With Renal Impairment.

This open label, parallel-group study investigated the pharmacokinetics and safety of a single oral 2-mg dose of the novel selective progesterone receptor modulator vilaprisan in participants with impaired renal function compared with age, weight, sex, and race matched controls with normal renal function. Systemic exposure (area under the plasma concentration-time curve [AUC]) and maximum observed concentrations (Cmax ) were compared among 9 participants with moderate renal impairment and matched controls by ANOVA. An additional 4 participants, each with severe renal impairment or normal renal function, contributed to a linear regression analysis exploring any monotone relationship between individual variables and the estimated glomerular filtration rate. The geometric mean AUC was increased by a factor of 1.35 in renally impaired participants compared to normal controls (not statistically significant: least squares mean, 1.346; 90% confidence interval, 0.918-1.973). Cmax was similar in participants with moderate renal impairment and normal renal function (least squares mean, 1.026; 90% confidence interval, 0.779-1.351). Considering the overall variability, there was no correlation between renal function (estimated glomerular filtration rate) and Cmax or AUC of vilaprisan. Single oral administration of vilaprisan 2 mg was well tolerated by all participants, both men and women and irrespective of renal function. The incidence of treatment-emergent adverse events was similar across all groups. Results from this study do not indicate that a dose adjustment will be necessary for vilaprisan when treating patients up to moderate renal impairment.

Selective Progesterone Receptor Modulators-Mechanisms and Therapeutic Utility.

Selective progesterone receptor modulators (SPRMs) are a new class of compounds developed to target the progesterone receptor (PR) with a mix of agonist and antagonist properties. These compounds have been introduced for the treatment of several gynecological conditions based on the critical role of progesterone in reproduction and reproductive tissues. In patients with uterine fibroids, mifepristone and ulipristal acetate have consistently demonstrated efficacy, and vilaprisan is currently under investigation, while studies of asoprisnil and telapristone were halted for safety concerns. Mifepristone demonstrated utility for the management of endometriosis, while data are limited regarding the efficacy of asoprisnil, ulipristal acetate, telapristone, and vilaprisan for this condition. Currently, none of the SPRMs have shown therapeutic success in treating endometrial cancer. Multiple SPRMs have been assessed for efficacy in treating PR-positive recurrent breast cancer, with in vivo studies suggesting a benefit of mifepristone, and multiple in vitro models suggesting the efficacy of ulipristal acetate and telapristone. Mifepristone, ulipristal acetate, vilaprisan, and asoprisnil effectively treated heavy menstrual bleeding (HBM) in patients with uterine fibroids, but limited data exist regarding the efficacy of SPRMs for HMB outside this context. A notable class effect of SPRMs are benign, PR modulator-associated endometrial changes (PAECs) due to the actions of the compounds on the endometrium. Both mifepristone and ulipristal acetate are effective for emergency contraception, and mifepristone was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of Cushing's syndrome due to its additional antiglucocorticoid effect. Based on current evidence, SPRMs show considerable promise for treatment of several gynecologic conditions.

Vilaprisan, a New Selective Progesterone Receptor Modulator in Uterine Fibroid Pharmacotherapy-Will it Really be a Breakthrough?

BACKGROUND: Vilaprisan (VPR) is a new orally available selective progesterone receptor modulator (SPRM), with anti-proliferative activity against uterine fibroids (UFs). It definitively causes suppression of ovulation and inhibition of proliferation of endometrial, myometrial and UF cells. PURPOSE: This review aims to summarize current knowledge on VPR from all studies, including clinical trials, conducted to date and to contextualize the potential role of VPR in future medical regimens for the treatment of UFs. METHODS: We performed a literature search in PubMed US National Library of Medicine and Google Scholar databases. Both databases were extensively searched for all original and review articles/book chapters as well as congress abstracts published in English until July 2019. The use of VPR for UF therapy was identified by using the keywords: "uterine fibroids" and "vilaprisan". RESULTS: In phase I and II clinical trials, VPR was shown to be effective in ameliorating UF-related clinical symptoms, especially abnormal or excessive uterine bleeding and in shrinking UFs. The tolerability of VPR is roughly similar to that of ulipristal acetate (UPA) and it tends to be more favorable than that of GnRH-agonists. CONCLUSION: Presently, all trials examining the utility of VPR for the treatment of UF are halted; likely, due to the recently reported cases of hepato-toxicity with UPA, in addition to non reassuring toxicology results from preclinical long-term testing on rodents, carried out in parallel with late stage testing on humans. An accurate summary of robust data related to the safety of VPR is urgently needed to draw definitive conclusions on the future clinical development of this drug for UF therapy.

Efficacy and safety of vilaprisan in women with uterine fibroids: Data from the phase 2b randomized controlled trial ASTEROID 2.

OBJECTIVE: To assess the efficacy of vilaprisan compared with placebo in the management of the symptoms of uterine fibroids (UF), with a secondary objective to provide a descriptive comparison with ulipristal acetate. STUDY DESIGN: The randomized, parallel-group, double-blind, placebo- and active-controlled, multicenter ASTEROID 2 trial assessed the efficacy and safety of vilaprisan versus placebo and ulipristal acetate for two 12-week treatment periods in women with ≥1 UF experiencing heavy menstrual bleeding (HMB). The primary endpoint compared the efficacy of vilaprisan with placebo at 12 weeks, assessed as the absence of bleeding/spotting by bleeding diary. Secondary endpoints compared the efficacy of vilaprisan with ulipristal acetate. Results of the first 12-week treatment period are reported here. RESULTS: Women (mean age 42.5 years) were enrolled from 1 June 2015. At baseline, mean menstrual blood loss per 28 days was 214.1 mL and the volume of the three largest UF was 106.2 mL. In total, 155 women completed the initial 12-week treatment period. Complete absence of bleeding/spotting until the end of the 12-week treatment period was achieved by 62.9 % of women receiving vilaprisan versus 0.0 % with placebo (p < .001); 55.4 % of women treated with ulipristal acetate reported absence of bleeding/spotting. The predefined HMB response (<80 mL and >50 % reduction from baseline during the last 28 days of treatment) was observed in 95.7 % of subjects treated with vilaprisan and 86.5 % of subjects treated with ulipristal acetate. Vilaprisan and ulipristal acetate treatment reduced the sum of the volume of the three largest UF by 29.9 % and 23.8 %, respectively, whereas an increase of 6.3 % was observed in the placebo group. No safety concerns, including multiple laboratory parameters, were identified. CONCLUSION: Daily administration of vilaprisan 2 mg induced amenorrhea, controlled bleeding, decreased UF size, and was well tolerated in women with HMB associated with UF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02465814 https://clinicaltrials.gov/ct2/show/NCT02465814.

Vilaprisan in women with uterine fibroids: the randomized phase 2b ASTEROID 1 study.

OBJECTIVES: To assess the safety and efficacy of four vilaprisan doses (0.5-4.0 mg) in women with uterine fibroids. DESIGN: Randomized, double-blind, placebo-controlled, multicenter trial. SETTING: Ninety-eight centers in 12 countries. PATIENT(S): Women aged 18-50 years with uterine fibroids and heavy menstrual bleeding were randomized equally to oral vilaprisan at 0.5, 1.0, 2.0, or 4.0 mg or placebo once daily. INTERVENTION(S): Treatment for 12 weeks, 24-week follow-up. MAIN OUTCOME MEASURE(S): Primary end point was absence of scheduled or unscheduled bleeding/spotting. Key secondary efficacy end points included volume of menstrual blood loss and change in fibroid volume. RESULT(S): A total of 309 patients were randomized, and 300 received treatment. Complete absence of bleeding/spotting was observed in 30%, 56%, 54%, and 60% of patients in the vilaprisan 0.5, 1.0, 2.0, and 4.0 mg groups, respectively, versus 1.7% with placebo. After 12 weeks, >83% of women achieved amenorrhea (<2 mL/28 days) with ≥1.0 mg vilaprisan versus 9% with placebo. Heavy menstrual bleeding stopped (but returned at a lower volume after treatment cessation) with ≥1.0 mg vilaprisan treatment. Reductions in fibroid volume of up to 41% were observed. Most patients receiving vilaprisan reported improvements in symptom severity. No safety concerns were identified in general safety, endometrial safety (by biopsy), laboratory values, and ultrasound examinations. CONCLUSION(S): ASTEROID 1 supports the efficacy of vilaprisan for the treatment of heavy menstrual bleeding associated with uterine fibroids. Daily oral treatment with vilaprisan 0.5-4.0 mg was well tolerated, and vilaprisan 2.0 mg once daily has been selected for further investigation. CLINICAL TRIAL REGISTRATION NUMBER: NCT02131662.

Vilaprisan for treating uterine fibroids.

INTRODUCTION: The medical strategy to antagonize myoma size and related-symptoms is to reduce estrogen and progesterone activity on myomas. This can be obtained with the GnRH agonist (GnRHa) or with compounds that antagonize progesterone stimulatory activity on myomas. Selective progesterone receptor modulators (SPRMs) bind progesterone receptor (PR), leading to both agonist and antagonist effects. The result of SPRMs's action is tissue-specific and it depends on the particular affinity and strength of each SPRM. Area covered: Ulipristal acetate (UPA) is the first SPRM registered for myoma treatment. UPA reduces heavy uterine bleeding within 7 days from the onset of treatment, whereas a longer time is required with GnRHa treatment. Vilaprisan is a novel powerful SPRM. Phase I and II studies give encouraging results on the efficacy of vilaprisan at different doses. Like other SPRMs, vilaprisan induces benign changes of endometrium (PR modulator-associated endometrial changes, PAECs). These disappear as treatment is discontinued. Unlike GnRHa treatment, neither UPA nor vilaprisan induce hypoestrogenism and associated symptoms. Phase III studies are ongoing to confirm efficacy and safety of vilaprisan in long-term treatment of symptomatic fibroids. Expert opinion: It is fundamental to underline the rapidity of action (only 3 days) in the control of myoma-related bleeding.

Effect of the Novel Selective Progesterone Receptor Modulator Vilaprisan on Ovarian Activity in Healthy Women.

This randomized, double-blind, parallel-group study in healthy young women investigated the effect of treatment with vilaprisan (0.5, 1, 2, or 4 mg/day for 12 weeks) on ovarian function by assessing the Hoogland score, which is based on the size of follicle-like structures as determined by transvaginal ultrasound and on estradiol and progesterone serum concentrations. Ovulation inhibition (ie, Hoogland score <6 in treatment weeks 1-4 and 8-12) was observed in >80% of the subjects receiving vilaprisan ≥1 mg/day. The effect was dose dependent. With a Bayesian approach, the percentage of subjects with ovulation inhibition was estimated to increase from 37% in subjects receiving 0.5 mg/day vilaprisan to 76%, 86%, and 88% in subjects receiving 1, 2, and 4 mg/day, respectively. Follicle growth was not suppressed during treatment. The majority of subjects receiving ≥1 mg/day had a Hoogland score of 4 (active follicle-like structures, ie, follicle diameter >13 mm, estradiol >27.2 pg/mL, no progesterone increase) both at beginning and end of treatment. Mean average estradiol as well as mean maximum progesterone concentrations were noticeably decreased during treatment with vilaprisan ≥1 mg/day compared to pretreatment, but estradiol concentrations remained >80 pg/mL. Both hormones returned to pretreatment levels after the end of treatment, indicating a rapid resumption of normal ovarian activity. Amenorrhea occurred in the majority of subjects during treatment at dosages ≥1 mg/day. The adverse events observed in this study confirm the known safety profile of vilaprisan. All in all, the results of this study support the development of vilaprisan for the long-term treatment of uterine fibroids.

Rationale and design of ASTEROID 2, a randomized, placebo- and active comparator-controlled study to assess the efficacy and safety of vilaprisan in patients with uterine fibroids.

BACKGROUND: Uterine fibroids (UFs) may be treated with progesterone receptor modulators (PRMs), which have been shown to reduce heavy menstrual bleeding and the size of UFs. To date, one PRM (ulipristal acetate) has received regulatory approval for the treatment of UFs; therapy comprises intermittent treatment courses of up to 3months each, followed by a break to allow two menstruations to occur. We report the design of ASTEROID (Assess Safety and efficacy of vilaprisan in patients with uTERine fibrOIDs) 2, a phase 2 study examining the efficacy and safety of a novel PRM, vilaprisan, in women with UFs. METHODS/DESIGN: In this randomized multi-arm study, vilaprisan (2mg daily) will be administered in different regimens: continuous treatment for 12 or 24weeks, or two 12-week treatment periods separated by a break to allow one menstruation to occur. Efficacy and safety will be compared with that of ulipristal acetate (5mg daily) and placebo. Patients randomized to receive placebo for 12weeks will also be given active treatment for 12weeks. The primary measure of efficacy will be amenorrhoea rate; secondary measures include time to normalized menstrual bleeding and percentage change in UF volume. Endometrial changes will be monitored throughout the study. DISCUSSION: The placebo- and active comparator-controlled trial ASTEROID 2 is the first study to evaluate systematically the efficacy and safety of different treatment regimens of PRMs in women with UFs. The findings of this study will direct the planning of future clinical trials of vilaprisan.