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Medical Options for Uterine Fibroids in the Context of Reproduction
Published in Botros R.M.B. Rizk, Yakoub Khalaf, Mostafa A. Borahay, Fibroids and Reproduction, 2020
Hoda Elkafas, Mona Al Helou, Qiwei Yang, Ayman Al-Hendy
Vilaprisan (BAY 1002670) is a novel and highly effective SPRM with oral administration. Because of its pharmacological profile, this molecule is a promising drug in the regimen of many gynecological conditions. It is currently under evaluation for the long-term treatment of symptomatic fibroids [61]. In preclinical in vitro studies, vilaprisan showed strong selective binding activity to PR, exerting strong antagonism without agonistic activity. Vilaprisan can weakly bind glucocorticoid receptors (GRs), with a slight antiglucocorticoid effect (approximately 100 times less than mifepristone). Neither agonistic nor antagonistic activity has been observed on PR, and a very weak binding affinity has been detected for the androgen receptor (AR) [61,62]. Vilaprisan passed a 12-week phase I clinical trial successfully, in which most of the women who administrated the prescription daily at the dosage of 0.5–5 mg were able to reduce mean maximum serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and decrease mean and mean maximum estradiol concentrations [63]. Amenorrhea occurred in 75% of women at the doses of 1, 2, and 4 mg. These results confirmed the preliminaries of advanced clinical trials to evaluate vilaprisan in women with symptomatic fibroids [61,64]. In phase II, vilaprisan has been estimated at the doses of 0.5, 1, 2, and 4 mg daily for 12 weeks, in a double-blind, placebo-controlled study, and it was shown to manage bleeding within 3 days in most of the women at doses equal to or greater than 1 mg, and to obtain amenorrhea in 87%–92% of cases. Furthermore, improvements in symptoms related to fibroids and the quality of life were observed in all treatment groups and a dose-dependent volume reduction of fibroids up to 40% at the highest doses [65]. The same study shows that the reduction of bleeding and amenorrhea have been recoded within 3 days from the start of vilaprisan treatment [65]. The phase II study ASTEROID 2 (ClinicalTrials.gov Identifier: NCT02465814), for the first time, evaluated the efficacy and safety of different treatment regimens with vilaprisan at the daily doses of 2 mg (12 weeks of repeated cycles or 24 weeks of continuous treatment) compared to both placebo and UPA. The study was performed in patients with massive bleeding associated with uterine fibroids [60]. The study was completed at the end of 2016. Vilaprisan is currently under study in phase III for the long-term treatment of uterine fibroids, with the trials ASTEROID5 and ASTEROID6 (ClinicalTrials.gov Identifier: NCT03240523 and NCT03194646, respectively). The study plan recommends evaluation of the efficiency and safety of vilaprisan 2 mg at different regimens, recruiting more than 3600 women worldwide; efficacy outcomes will be bleeding control, shrinkage in fibroid volume, and enhancement in the quality of life [61].
Hysteroscopic treatment of submucosal fibroids in perimenopausal women: when, why, and how?
Published in Climacteric, 2020
S. G. Vitale, G. Riemma, M. Ciebiera, S. Cianci
Recently, the use of ulipristal acetate (UPA), a selective progesterone receptor modulator, has been discussed in terms of controlling fibroid-related symptoms52. Moreover, a 3-monthly preoperative treatment with UPA was proposed to facilitate the hysteroscopic myomectomy of submucosal fibroids. Several studies were conducted to validate the hypothesis53. It was reported that, unlike GnRHs, hysteroscopic myomectomy was not negatively affected by UPA pretreatment. Also, it was associated with a high probability of performing a complete resection of fibroids in complex cases, with a decreased duration of the surgical procedure, as well as improved patient satisfaction after 3 months54,55. However, the main problem connected to UPA is that it is not available in all countries. Moreover, some cases were reported to develop liver failure that was possibly related to the use of this drug56. Nevertheless, numerous authors are still supporting this drug and believe that it may be considered a valuable option in the treatment of uterine fibroids57. Vilaprisan, a new selective progesterone receptor modulator, was the subject of extensive research in endometriosis and uterine fibroids and could be a new agent in this indication, especially if the role of UPA changed. However, new results concerning its toxicity in animals halted current research in this matter58.
Successes and failures of uterine leiomyoma drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Mohamed Ali, Zunir Tayyeb Chaudhry, Ayman Al-Hendy
Telapristone acetate (CDB4124), branded under the name of Proellex, is a newer SPRM undergoing trials for UFs and endometriosis [49]. It showed promising results in preliminary studies, successfully inducing apoptosis in fibroid cells while leaving normal adjacent myometrium unaltered [49]. Investigators were hopeful that telapristone could potentially become a chronic therapy for long-term symptom control. Unfortunately, multiple large studies, including a phase III trial, were prematurely terminated owing to concerns for safety while testing telapristone in symptomatic fibroids [50]. At present time, there is an ongoing phase II clinical trial started on 2014 aiming to evaluate both safety and efficacy of lower oral as well as vaginal doses of Telapristone acetate [51]. Vilaprisan, a novel SPRM that recently passed a 12 week phase I clinical trial successfully, in which most of the women who took the medication at daily dose of 1–5 mg reported absence of menstrual bleeding. These results supported the initiation of advanced clinical trials to evaluate vilaprisan in women with symptomatic UFs [52].
Vilaprisan for treating uterine fibroids
Published in Expert Opinion on Investigational Drugs, 2018
Gian Benedetto Melis, Manuela Neri, Bruno Piras, Anna Maria Paoletti, Silvia Ajossa, Monica Pilloni, Maria Francesca Marotto, Valentina Corda, Alessandra Saba, Elena Giancane, Valerio Mais
Data derived from preclinical and clinical studies on vilaprisan have outlined this drug as a potent SPRM, candidate for treatment of gynecological conditions sustained by progesterone. The administration of 2 mg daily is sufficient to obtain control of bleeding and to induce amenorrhea in most of women with heavy bleeding related to myomas. These results are consistent with UPA and the other SPRMs tested in human clinical trials [41–44], indicating that this effect is typical of this pharmacological class. Although the study that compares UPA with vilaprisan is still unpublished [59], a preliminary placebo controlled study shows that the reduction of bleeding and amenorrhea have been obtained within 3 days from the start of vilaprisan treatment [58]. This is a shorter time in comparison with that observed with UPA treatment [45,47], likely dependent on the powerful antagonistic activity of vilaprisan on PR [53]. The pharmacodynamic effects on hypothalamic–pituitary–ovarian axis regress in a short time from the vilaprisan assumption to discontinuation [57], reassuring with regard to the possibility to conceive soon after the improvement of myoma’s signs and symptoms. Furthermore, the high selectivity of action on PR and the preservation of low estradiol plasma concentrations allow a good tolerability profile. For all of these considerations, vilaprisan might be a promising option for uterine fibroids long-term medical treatment. Results from phase III trials could better define the most appropriate treatment regimens of vilaprisan, and further research could confirm its efficacy in the long-term treatment of heavy bleeding associated with uterine fibroids and its safety profile.