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

Abstract

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 R1.0 mg vilaprisan versus 9% with placebo. Heavy menstrual bleeding stopped (but returned at a lower volume after treatment cessation) with R1.0 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.

Effect of hepatic impairment on the pharmacokinetics of vilaprisan: An open‐label, single‐dose, parallel‐group study

“…In this study, a single oral dose of vilaprisan 2 mg was well tolerated by participants of both sexes with mild or moderate hepatic impairment, and in participants with normal hepatic function. Safety findings in this study were comparable with observations from previous phase 1 and phase 2 studies in which vilaprisan was well tolerated, with no drug‐related serious AEs even at the maximal daily doses used in females . Here, the most frequently observed TEAEs were headache and nausea, which were also among the most common drug‐related AEs reported alongside ovarian and cervical cyst (identified at ultrasound), fatigue, abdominal or pelvic pain, other gastrointestinal disorders (flatulence, constipation), hot flushes, and dizziness in previous studies …”

“…This phase 1, single‐dose, open‐label, parallel‐group study evaluated the impact of mild (CP‐A) or moderate (CP‐B) hepatic impairment on the pharmacokinetics of vilaprisan in adult White/Caucasian participants. A single oral vilaprisan 2 mg dose was given, in line with the dose that was selected for the phase 3 trials in UF . Participants with severe hepatic impairment were not included in this study as they are not part of the target patient population for vilaprisan.…”

“…Safety findings in this study were comparable with observations from previous phase 1 and phase 2 studies in which vilaprisan was well tolerated, with no drug-related serious AEs even at the maximal daily doses used in females. 4,5,7,21,23 Here, the most frequently observed TEAEs were headache and nausea, which were also among the most common drug-related AEs reported alongside ovarian and cervical cyst (identified at ultrasound), fatigue, abdominal or pelvic pain, other gastrointestinal disorders (flatulence, constipation), hot flushes, and dizziness in previous studies. 4,5,7,21,23 A limitation of this study, which is inherent in the primary objective to investigate the pharmacokinetics of vilaprisan, is that safety data were only collected in a small participant population and after single oral dosing (n = 36).…”

“…In 2 phase 2 clinical studies in women with UF, treatment with vilaprisan resulted in effective bleeding control and reductions in fibroid volume, and demonstrated a favourable safety profile . Based on these promising results, vilaprisan is currently being investigated in phase 3 studies in patients for long‐term treatment of UF…”

“…2,3 In 2 phase 2 clinical studies in women with UF, treatment with vilaprisan resulted in effective bleeding control and reductions in fibroid volume, and demonstrated a favourable safety profile. 4,5 Based on these promising results, vilaprisan is currently being investigated in phase 3 studies in patients for long-term treatment of UF. 6 Previous clinical drug-drug interaction studies with the potent cytochrome P450 3A4 (CYP3A4) inhibitor itraconazole and the potent CYP3A4 inducer rifampicin showed a mean increase by 6.2-fold and a reduction by 96% of the vilaprisan exposure, respectively, confirming preclinical investigations that vilaprisan is extensively metabolised by CYP3A4.…”