Pharmacodynamics and safety of the novel selective progesterone receptor modulator vilaprisan: a double-blind, randomized, placebo-controlled phase 1 trial in healthy women.
Does administration of vilaprisan (VPR) to healthy women for 12 weeks reduce menstrual bleeding?



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.



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).



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.



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.



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.



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.



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.



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.



Clinicaltrials.gov identifier: NCT01816815.



20 March 2013.



28 November 2011.
Bayer Pharma AG, Clinical Pharmacology, 13342 Berlin, Germany.
Barbara
B
Schütt
Bayer Pharma AG, Research & Clinical Science Statistic, 13342 Berlin, Germany.
Andreas
A
Kaiser
Bayer Pharma AG, Clinical Pharmacology, 13342 Berlin, Germany marcus.schultze-mosgau@bayer.com.
Marcus-Hillert
MH
Schultze-Mosgau
Bayer Pharma AG, Global Development Therapeutic Area General Medicine, 13342 Berlin, Germany.
Christian
C
Seitz
Biokinetic Europe Ltd, Belfast BT2 7BA, UK.
David
D
Bell
Nuvisan GmbH, 89231 Neu-Ulm, Germany.
Manuela
M
Koch
Bayer Pharma AG, Clinical Pharmacology, 13342 Berlin, Germany.
Beate
B
Rohde
D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008598:Menstruation / Q000187:drug effects*; D008875:Middle Aged; D011980:Receptors, Progesterone / Q000378:metabolism; D013256:Steroids / Q000009:adverse effects / Q000494:pharmacology*; D016896:Treatment Outcome; D016387:Women's Health; D055815:Young Adult
D011980:Receptors, Progesterone; D013256:Steroids; C586669:vilaprisan
bleeding pattern; clinical trial, phase 1; selective progesterone receptor modulator; uterine fibroids; vilaprisan