vilaprisan and Leiomyoma

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.. 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.. 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".. 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.. 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.

Topics: Clinical Trials as Topic; Female; Humans; Leiomyoma; Receptors, Progesterone; Steroids; Uterine Neoplasms

Uterine fibroids are common in women of reproductive age and can have a significant impact on quality of life and fertility. Although a number of international obstetrics/gynecology societies have issued evidence-based clinical practice guidelines for the management of symptomatic uterine fibroids, many of these guidelines do not yet reflect the most recent clinical evidence and approved indication for one of the key medical management options: the selective progesterone receptor modulator class. This article aims to share the clinical experience gained with selective progesterone receptor modulators in Europe and Canada by reviewing the historical development of selective progesterone receptor modulators, current best practices for selective progesterone receptor modulator use based on available data, and potential future uses for selective progesterone receptor modulators in uterine fibroids and other gynecologic conditions.

Topics: Contraceptive Agents, Female; Disease Management; Estrenes; Female; Forecasting; Humans; Leiomyoma; Mifepristone; Norpregnadienes; Oximes; Population Growth; Receptors, Progesterone; Steroids; Uterine Neoplasms

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.

Topics: Animals; Female; Humans; Leiomyoma; Norpregnadienes; Receptors, Progesterone; Steroids; Time Factors; Uterine Hemorrhage; Uterine Neoplasms

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.. 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.. 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.. Daily administration of vilaprisan 2 mg induced amenorrhea, controlled bleeding, decreased UF size, and was well tolerated in women with HMB associated with UF.. ClinicalTrials.gov number: NCT02465814 https://clinicaltrials.gov/ct2/show/NCT02465814.

Topics: Adult; Female; Humans; Leiomyoma; Menorrhagia; Norpregnadienes; Steroids; Uterine Neoplasms

To assess the safety and efficacy of four vilaprisan doses (0.5-4.0 mg) in women with uterine fibroids.. Randomized, double-blind, placebo-controlled, multicenter trial.. Ninety-eight centers in 12 countries.. 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.. Treatment for 12 weeks, 24-week follow-up.. 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.. 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.. 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.. NCT02131662.

Topics: Administration, Oral; Adult; Double-Blind Method; Drug Administration Schedule; Europe; Female; Humans; Japan; Leiomyoma; Menorrhagia; Menstruation; Middle Aged; North America; Steroids; Time Factors; Treatment Outcome; Tumor Burden; Uterine Neoplasms

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.. 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.. 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.

Topics: Adolescent; Adult; Contraceptive Agents, Female; Double-Blind Method; Drug Administration Schedule; Female; Humans; Leiomyoma; Middle Aged; Norpregnadienes; Quality of Life; Research Design; Steroids; Young Adult

Topics: Female; Humans; Leiomyoma; Receptors, Progesterone; Steroids

Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the treatment of such diseases. Steroidal SPRMs, including mifepristone and ulipristal acetate, have proven effective in clinical trials. However, several steroidal SPRMs containing a dimethylamino substituent have been associated with elevated liver enzymes in patients. An earlier drug discovery program identified lonaprisan as a highly selective SPRM that did not show drug-related change in liver enzyme activity. Building on data obtained from that work, here we describe the research program that culminated in the discovery of a novel steroidal SPRM, vilaprisan, which combines an extremely high potency with very favorable drug metabolism and pharmacokinetic properties. Vilaprisan has entered clinical development and is currently undergoing phase 3 clinical trials.

Topics: Animals; Cell Line, Tumor; Drug Discovery; Estrenes; Female; Genital Diseases, Female; Humans; Leiomyoma; Molecular Structure; Pregnancy; Rabbits; Rats, Wistar; Receptors, Progesterone; Steroids; Structure-Activity Relationship

Does the novel progesterone receptor (PR) modulator BAY 1002670, based on its preclinical pharmacological profile, offer a potential novel treatment option for uterine fibroids?. The newly synthesized BAY1002670 has proved to be a very potent, highly selective PR modulator in all in vitro and in vivo pharmacodynamics assays performed: it exhibits marked efficacy in an innovative humanized fibroid disease model, suggesting BAY 1002670 to be a very promising treatment option for uterine fibroids.. PR inhibiting ligands have shown clinical utility in a range of potential indications and applications. Despite the emergence of the first PR antagonist >30 years ago, no agent of this compound class has been authorized in any indication for long-term application. Among other reasons, suboptimal selectivity and safety profiles of previous candidates have led to discontinuation and modification of development programmes.. The preclinical studies include relevant in vitro and in vivo assays to clarify the properties of the PR modulator BAY 1002670 as well as a fibroid xenograft study to show directly the efficacy of BAY 1002670 on the human target tissue.. BAY 1002670 was tested for binding and transactivational activity towards different human steroid receptors. Activity of the compound in the corresponding in vivo models (rat, rabbit) was assessed. Furthermore, BAY 1002670 was tested in a disease model for uterine fibroids utilizing primary human tumour tissues as xenograft in immunodeficient mice treated with estradiol (E2) and progesterone (P).. BAY1002670 in subnanomolar concentrations exhibits a highly selective binding profile and antagonistic activity for the PR. These properties are also reflected in its action in two progesterone-dependent animal models that assess the termination of pregnancy and endometrial transformation. Favourable selectivity towards other nuclear hormone receptors was demonstrated. No in vivo activity was found at the glucocorticoid, estrogenic and mineralocorticoid receptors with only weak anti-androgenic activity. In a human fibroid xenograft model BAY 1002670 showed a marked dose-dependent reduction of fibroid tumour weight gain of 95% at a dose of 3 mg/kg/day (P < 0.005).. Selectivity and potency of BAY 1002670 have only been determined in vitro and in animal models so far.. The PR modulator BAY 1002670 might offer a treatment option not only for uterine fibroids but also for other gynaecological indications.. The studies took place at Bayer Pharma AG. All authors are employees of Bayer Pharma AG. No external funding declared.

Topics: Animals; Estradiol; Female; Genital Diseases, Female; Heterografts; Humans; Leiomyoma; Mice; Progesterone; Rabbits; Rats; Receptors, Progesterone; Steroids; Transcriptional Activation