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.

The effect of ulipristal acetate on tumor necrosis factor α, insulin-like growth factor 1, and plasminogen activator inhibitor-1 serum levels in patients with symptomatic uterine fibroids.

Introduction: Uterine fibroids (UFs) are benign tumors of the female reproductive system originating from the smooth muscle of the uterus. Currently, progesterone is known to play a key role in the differentiation of the myometrial tissue to form UFs and their abnormal growth. The mechanism of action of progesterone in UF tumorigenesis involves its effect on increasing the concentrations and dysregulation of selected growth factors. Material and methods: A retrospective cohort study was performed to evaluate and compare tumor necrosis factor α (TNF-α), insulin-like growth factor 1 (IGF-1), plasminogen activator inhibitor-1 (PAI-1) serum concentrations in patients with UFs without prior hormonal treatment, patients with UFs treated with a 3-month standard ulipristal acetate (UPA - a type of selective progesterone receptor modulator) scheme (5 mg/day) and in control patients without UFs. A total of 120 patients were divided into 3 groups (controls, UFs with UPA treatment, UFs without UPA treatment). Results: There were no significant differences in TNF-α serum concentrations between patients with UFs who underwent UPA treatment and patients who did not. Serum concentrations of IGF-1 and PAI-1 did not show significant intergroup differences. Conclusions: No significant differences were found between TNF-α concentrations in the serum of patients with UFs treated with UPA, and patients without UPA treatment. In addition, our data analysis did not show significant differences in the concentrations of IGF-1 and PAI-1 between patients with UFs and the control group. Further studies on the dependence of specific symptoms on selected growth factors are mandatory.

Functional evidence for two distinct mechanisms of action of progesterone and selective progesterone receptor modulator on uterine leiomyomas.

OBJECTIVE: To study the specific mechanisms through which progesterone and selective progesterone receptor modulators impact the growth, synthesis, and accumulation of the extracellular matrix in uterine leiomyomas. DESIGN: Laboratory study. SETTING: Academic Research Institutions. PATIENTS (S): This study involved reproductive-age women diagnosed with infertility associated uterine leiomyomas who underwent myomectomy either after selective progesterone receptor modulator ulipristal acetate (UA) treatment or without any pharmacological pretreatment. Control samples included healthy myometrium tissue (n = 100). Specimens were obtained from the Department of Reproduction and Gynecological Endocrinology and Biobank, Medical University of Bialystok, Poland. INTERVENTIONS: Daily (5 mg/d) UA treated for 2 months (n = 100) and untreated (n = 150) patients with uterine leiomyomas or normal healthy myometrium (n = 100) tissue samples immediately after surgery were collected for transcriptional analysis and assessments. MAIN OUTCOME MEASURES: Progesterone-induced activation of the signaling pathways related to uterine leiomyomas extracellular matrix synthesis, deposition, and growth, as well as the expression profile of progesterone receptors in uterine leiomyomas, were assessed. RESULTS: The results indicated that progesterone activated the transforming growth factor-ß and SMAD3 signaling pathways and promoted proliferation, growth, and extracellular matrix remodeling in uterine leiomyomas by up-regulating SMAD3, transforming growth factor-ß (TGF-ß) receptor type 1 and II, Ras homolog A, vascular endothelial growth factor, or increasing the fibrosis-related gene collagen, type I, ɑ-1, and procollagen, type I, ɑ-1 production. In contrast, UA had inhibitory effects on these processes. The study also showed that both nuclear and membrane progesterone receptors play distinct roles in uterine leiomyoma pathobiology. CONCLUSIONS: We showed that both nuclear and membrane progesterone receptors were relevant in the treatment of uterine leiomyomas, especially when combined with selective progesterone receptor modulators. Novel therapeutic approaches combining selective progesterone receptor modulators with or without direct and indirect extracellular matrix targeting through selected specifically TGF-ß and SMAD3 (SMAD3, TGF-ß receptor types 1 and II, Ras homolog A, vascular endothelial growth factor, collagen, type I, ɑ-1) signaling pathways could therefore be a treatment option for uterine leiomyomas.

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).

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Ulipristal acetate simultaneously provokes antiproliferative and proinflammatory responses in endometrial cancer cells.

Ulipristal acetate (UPA), a selective progesterone receptor modulator, is used for the treatment of uterine fibroids and selectively inhibits the proliferation and inflammation of leiomyoma cells. As few studies have focused on the molecular biological mechanism of UPA in Ishikawa endometrial cancer cells, we aimed to identify the effects of UPA on these cells. Ishikawa cells were treated with different concentrations of UPA. Cell viability and colony formation assays were performed to assess the growth of cancer cells, whereas invasion and migration assays were used to measure cell motility and invasiveness. Western blotting, caspase 3/7 assay, TUNEL assay, and flow cytometry were performed to analyze apoptosis. Moreover, expression levels of the proinflammatory cytokines oncostatin M, its receptor, interleukin 6, and interleukin 8 were examined using quantitative real-time PCR. UPA decreased cell viability and growth, thereby inhibiting cell migration and invasion via induction of apoptosis. Contrary to expectation, stand-alone application of UPA increased the expression of the proinflammatory cytokines but concomitant use of UPA and the estrogen receptor antagonist ICI 182,720 decreased it. These data revealed a novel dual role of UPA: It could attenuate cell growth via activation of apoptosis while simultaneously provoking the activation of proinflammatory cytokines in endometrial cancer cells. These indicate that the combination of UPA and an estrogen receptor antagonist may be useful in suppressing the secretion of proinflammatory cytokines by UPA alone.

The progesterone-receptor modulator, ulipristal acetate, drastically lowers breast cell proliferation.

PURPOSE: The proliferation of breast epithelial cells increases during the luteal phase of the menstrual cycle, when they are exposed to progesterone, suggesting that ulipristal acetate, a selective progestin-receptor modulator (SPRM), may reduce breast cell proliferation with potential use in breast cancer chemoprevention. METHODS: Women aged 18-39 were randomized 1:1 to ulipristal 10-mg daily or to a combination oral contraceptive (COC) for 84 days. Participants underwent a breast biopsy and breast MRI at baseline and at end of study treatment. Proliferation of breast TDLU cells was evaluated by Ki67 immunohistochemical stain. We evaluated the breast MRIs for background parenchymal enhancement (BPE). All slides and images were masked for outcome evaluation. RESULTS: Twenty-eight treatment-compliant participants completed the study; 25 of whom had evaluable Ki67 results at baseline and on-treatment. From baseline to end of treatment, Ki67 % positivity (Ki67%+) decreased a median of 84% in the ulipristal group (N = 13; 2-sided p (2p) = 0.040) versus a median increase of 8% in the COC group (N = 12; 2p = 0.85). Median BPE scores decreased from 3 to 1 in the ulipristal group (p = 0.008) and did not decrease in the COC group. CONCLUSION: Ulipristal was associated with a major decrease in Ki67%+ and BPE. Ulipristal would warrant further investigation for breast cancer chemoprevention were it not for concerns about its liver toxicity. Novel SPRMs without liver toxicity could provide a new approach to breast cancer chemoprevention. TRIAL REGISTRATION: NCT02922127, 4 October 2016.

Hysteroscopic and ultrasonographic evaluation of ulipristal acetate treatment for symptomatic myomas in premenopausal women: a prospective study.

OBJECTIVE: This study aimed to analyze the effects of a six-month therapy with ulipristal acetate (UPA) on myoma size and endometrial thickness in premenopausal women. MATERIAL AND METHODS: Seventy-four women undergoing conservative therapy with UPA were enrolled for this study. All women underwent transvaginal ultrasound evaluation to assess the endometrial thickness, and the number and size of myomas at the beginning and after six months. Hysteroscopy and biopsy were performed after six months, if necessary. RESULTS: After six months of treatment, sonographic examination showed a statistically significant (p < .05) reduction of the size of the largest myoma (56.3 ± 5.1 vs. 31.7 ± 10.1 mm) and a statistically significant (p < .05) increase in endometrial thickness (5.9 ± 2.1 vs. 9.7 ± 3.4 mm). Twenty-two patients with endometrial thickness >10 mm or nonhomogeneous pattern and ten patients with metrorrhagia underwent hysteroscopy: the most frequent finding was the combination of endometrial hypotrophy, floating surface, and chicken-wire vascular pattern aspect (14 cases, 43.7%). Histologic findings showed no case of complex hyperplasia. CONCLUSION: UPA is a safe, effective and assured method to decrease symptoms, reduce the need for surgery in premenopausal women suitable for the treatment.

Ulipristal acetate compared with leuprorelin acetate for Japanese women with symptomatic uterine fibroids: a phase III randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of ulipristal acetate (UPA) for uterine fibroids (UFs), a phase III study was conducted with leuprorelin (LEU) as a comparator. This is the first confirmatory trial of UPA for UFs among Asians. DESIGN: Multicenter, randomized, double-blind, double-dummy, parallel-group study. SETTING: Thirty-two sites in Japan. PATIENT(S): Patients were assigned to 2 arms, with 82 patients in the UPA group and 79 patients in the LEU group. INTERVENTION(S): In the UPA group, 10 mg of UPA was orally administered once a day for 12 weeks. In the LEU group, 1.88 mg or 3.75 mg of LEU was subcutaneously administered at weeks 0, 4, and 8. MAIN OUTCOME MEASURE(S): The primary endpoint was the percentage of patients with amenorrhea for 35 days. For safety evaluation, adverse events (AEs) were recorded. RESULT(S): The percentage of patients with amenorrhea for 35 days was 87.0% in the UPA group and 81.8% in the LEU group, and the efficacy of UPA for causing amenorrhea for 35 days was confirmed to be noninferior to that of LEU. AEs occurred in 78.0% of the patients in the UPA group and 88.8% of the patients in the LEU group. CONCLUSION(S): The effect of UPA on heavy menstrual bleeding was shown to be comparable with that of LEU in Japanese patients with symptomatic UFs. No notable AEs occurred because of the UPA treatment, and the incidence of AEs in the UPA group was comparable with that of AEs in the LEU group. This result demonstrates the clinical utility of UPA for Asians.

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.

The effects of vilaprisan on the pharmacodynamics and pharmacokinetics of a combined oral contraceptive-A randomized controlled trial.

AIMS: The primary objective was to explore whether the suppression of ovarian activity induced by a combined oral contraceptive (COC) is influenced by the simultaneous intake of the selective progesterone receptor modulator (SPRM) vilaprisan (VPR). METHODS: In this exploratory randomized, double-blind, parallel-group study, 71 healthy premenopausal women were randomized (1:1) to receive either 2 mg/d VPR or placebo for 3 months. Concomitantly, a COC (0.15 mg levonorgestrel, 0.03 mg ethinyloestradiol) was administered in a cyclic regimen. Ovarian activity (Hoogland score based on follicle size and hormone concentrations), cervical function (Insler score), bleeding pattern and endometrial thickness/histology were assessed before treatment, in treatment cycle 3 and during follow-up. RESULTS: The known COC-driven suppression of ovarian activity was mildly affected by VPR. COC+VPR group: 22, 0 and 6% of the subjects had Hoogland scores of 4 (active follicle-like structures), 5 or 6 (ovulation). COC+placebo group: 14% of the subjects had a score of 4 and none a score of 5 or 6 (Bayesian analysis for Hoogland score = 4, median difference in response rate: 7.5%; 90% credible interval [-8.5; 23.5%]). COC effects on cervical function were moderately affected (mucus more sperm permeable under COC+VPR). COC withdrawal bleeding, in contrast, was absent in 81% of the subjects receiving COC+VPR vs 0% receiving COC+placebo. CONCLUSION: The SPRM VPR interfered with the pharmacodynamic effects of the COC. Therefore, full contraceptive effectiveness cannot be assumed without final judgement by a Pearl index study. Women on SPRMs should be advised to use nonhormonal contraception methods.

Laparoscopic myomectomy after or without pre-treatment with ulipristal acetate.

INTRODUCTION: The aim was to compare the surgical experience and the clinical results of laparoscopic myomectomy (LM) with or without pre-treatment with ulipristal acetate (UPA). MATERIAL AND METHODS: Fifty-four women who underwent LM for intramural myomas and were pre-treated with three months of UPA were matched with 54 patients with the same procedure but no hormonal pre-treatment. All operations were performed by one team. The technical features of the procedures were reviewed and evaluated by two other laparoscopists, unaware of the eventual use of UPA. The clinical, histological, and reproductive outcomes of each patient were assessed and the results of both groups were compared. RESULTS: The groups did not significantly differ in operation time, intra-operative blood loss, drop in hemoglobin concentration, number of complications, pregnancy rate, and delivery rate. Women pre-treated with UPA had significantly longer hospital stays, higher numbers of histologically abnormal leiomyomas, and higher rates of fibroids peri-procedurally assessed as soft and disintegrating. The other four technical parameters of LM were comparable in both groups. CONCLUSIONS: The surgeons performing LM in women pre-treated with UPA should be aware of the abnormal texture of enucleated myomas. Nevertheless, this does not negatively affect the other surgical and clinical outcomes of these patients.

Ulipristal Acetate for Treatment of Premenstrual Dysphoric Disorder: A Proof-of-Concept Randomized Controlled Trial.

OBJECTIVE: Premenstrual dysphoric disorder (PMDD) is a common mood disorder, characterized by distressing affective, behavioral, and somatic symptoms in the late luteal phase of the menstrual cycle. The authors investigated continuous treatment with a selective progesterone receptor modulator, ulipristal acetate (UPA), as a potential treatment for PMDD. METHODS: The authors conducted an investigator-initiated, multicenter, double-blind, randomized, parallel-group clinical trial in which women with PMDD (N=95) were treated with either 5 mg/day of UPA or placebo during three 28-day treatment cycles. The primary outcome was the change in premenstrual total score on the Daily Record of Severity of Problems (DRSP) from baseline to end of treatment. DRSP scores were captured by daily ratings using a smartphone application and were analyzed with linear mixed models for repeated measures. RESULTS: The mean improvement in DRSP score after 3 months was 41% (SD=18) in the UPA group, compared with 22% (SD=27) in the placebo group (mean difference -18%; 95% CI=-29, -8). Treatment effects were also noted for the DRSP depressive symptom subscale (42% [SD=22] compared with 22% [SD=32]) and the DRSP anger/irritability subscale (47% [SD=21] compared with 23% [SD=35]), but not for the DRSP physical symptom subscale. Remission based on DRSP score was attained by 20 women in the UPA group (50.0%) and eight women in the placebo group (21.1%) (a statistically significant difference). CONCLUSIONS: If these results are replicated, UPA could be a useful treatment for PMDD, particularly for the psychological symptoms associated with the disorder.

Asoprisnil, a Selective Progesterone Receptor Modulator (SPRM), Inhibits Melanosome Export in B16F10 Cells and HEMn-DP Melanocytes.

Previous studies have reported that estrogen hormone promotes melanogenesis while progesterone inhibits it. A selective estrogen receptor modulator (SERM), tamoxifen, has been shown to promote melanogenesis; however, to date, there have been no reports on the effects of a selective progesterone receptor modulator (SPRM) on melanogenesis. In the present study, we hypothesized that asoprisnil (AP), a SPRM, inhibits melanogenesis. AP was tested for cytotoxicity to B16F10 mouse melanoma cells for screening the nontoxic concentrations using MTS cytotoxicity assay. Extracellular and intracellular melanin levels were estimated at nontoxic concentrations of AP. To evaluate the direct effect of AP on tyrosinase enzyme, tyrosinase activity and copper chelating activities were measured. Next, the effects of AP on melanogenesis were tested in normal human melanocytes, neonatal, darkly pigmented (HEMn-DP). Our results demonstrate that AP was nontoxic at a concentration range of 10-50 µM in B16F10 cells; AP at 50 µM significantly suppressed extracellular melanin levels comparable to kojic acid at 500 µM, with no significant effect on intracellular melanin levels. The mechanism of melanogenesis inhibition was studied to assess if AP downregulated tyrosinase activity in cell lysates or in a cell-free system. However, AP was found to increase intracellular tyrosinase activity without any effect on tyrosinase enzyme activity or copper chelating activity in a cell-free system, indicating that AP inhibits melanogenesis by mechanisms other than direct effects on tyrosinase enzyme activity. The capacity of AP to inhibit melanosome export was further validated in HEMn-DP cells; AP significantly suppressed dendricity at concentrations of 20 and 30 µM in the absence of effects on melanin synthesis or intracellular tyrosinase activity. In addition, AP was nontoxic to human keratinocytes (HaCaT) at these concentrations, validating its safety for topical use. Taken together, our preliminary results demonstrate that AP might be repurposed as a candidate therapeutic for treatment of hyperpigmentation disorders via a unique mechanism, which encompasses a selective inhibition of melanosome export.

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.

Gonadotropin-releasing hormone antagonist (linzagolix): a new therapy for uterine adenomyosis.

OBJECTIVE: To compare the efficacy of a selective progesterone receptor modulator, ulipristal acetate, and a gonadotropin-releasing hormone antagonist, linzagolix, in a case of severe uterine adenomyosis. DESIGN: Case report. SETTING: Private clinic and infertility research unit. PATIENT: One patient born in 1981 who presented because of heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis confirmed by magnetic resonance imaging (MRI). INTERVENTION: The patient received a first treatment of 5 mg UPA daily for one course of 3 months. This therapy was discontinued because MRI revealed a worsened aspect. One year later, a once-daily dose of 200 mg linzagolix administered orally was initiated for 3 months, followed by another 3-month course of 100 mg once daily. MAIN OUTCOME MEASURES: Clinical symptoms and MRI aspect. RESULTS: During treatment with UPA, the symptoms (pelvic pain, dysmenorrhea, bulk symptoms) worsened and MRI revealed aggravation of the adenomyotic lesions. During the 12-week course of once-daily 200 mg linzagolix, the patient remained in amenorrhea and noted a very significant improvement in symptoms. On MRI, the uterine volume had fallen from 875 cm3 to 290 cm3, and the adenomyotic lesions had significantly regressed. During the 100-mg linzagolix course (weeks 13-24), the patient reported continued alleviation of her symptoms. CONCLUSION: To our knowledge, this is the first reported use of linzagolix, a new oral gonadotropin-releasing hormone antagonist that significantly reduced lesion size and improved quality of life in a patient with severe adenomyosis, who was previously nonresponsive to treatment with a selective progesterone receptor modulator, ulipristal acetate.

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.

Ulipristal acetate for Japanese women with symptomatic uterine fibroids: A double-blind, randomized, phase II dose-finding study.

PURPOSE: A multicenter, randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy, safety, and appropriate dose of ulipristal acetate (UPA) in Japanese women with symptomatic uterine fibroids (UFs). METHODS: A total of 121 premenopausal women with UFs were enrolled to receive either placebo, UPA-2.5 mg, UPA-5 mg, UPA-10 mg, or leuprorelin acetate (LEU), a reference drug, for 12 weeks. The primary end point was the rate of patients having achieved amenorrhea for 35 days at Week 12. RESULTS: The rates for amenorrhea were 4.5%, 60.0%, 72.7%, 88.0%, and 76.2% in the placebo, UPA-2.5 mg, UPA-5 mg, UPA-10 mg, and LEU groups, respectively. The median times to amenorrhea were 20.0, 5.0, 5.0, and 23.0 days for treatment with UPA-2.5 mg, UPA-5 mg, UPA-10 mg, and LEU, respectively. A significant dose-response of UPA for the rate of amenorrhea was observed. The overall incidence rates of adverse events were 45.8% in the placebo group, 56.5%-80.0% in the UPA groups, and 100.0% in the LEU group. There were no notable safety issues with UPA. CONCLUSIONS: Ulipristal acetate was effective and well tolerated in Japanese women with UFs. The recommended dose of UPA is considered to be 10 mg.

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.

The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor.

CONTEXT: The selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors. OBJECTIVE: To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types. DESIGN: Immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body. RESULTS: Dexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary. CONCLUSIONS: These studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent.