Linzagolix for Japanese women with uterine fibroids: a randomized, double-blind, placebo-controlled, phase 3 trial.

Objective: To evaluate the efficacy, safety, and pharmacodynamics of linzagolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, in patients with heavy menstrual bleeding (HMB) and pain because of uterine fibroids. Design: Phase 3, multicenter, placebo-controlled, randomized, double-blind, parallel-group, confirmatory study (NCT05445167). Subjects: Premenopausal Japanese women with HMB and moderate-to-severe pain because of uterine fibroids. Intervention: Patients were randomized 1:1 to once-daily linzagolix 200 mg (n = 48) or placebo (n = 41) for 12 weeks. Main Outcome Measures: The primary endpoints were the proportion of patients with a total pictorial blood loss assessment chart (PBAC) score <10 from week 6-12, and the proportion of patients with a maximum numeric rating scale (NRS) score ≤1 during the 28 days before the end of treatment. Secondary endpoints included time to a total PBAC score <10 or maximum NRS score ≤1, analgesic use, blood hemoglobin, myoma and uterine volumes, patient-reported symptom severity and quality of life, and plasma estradiol levels. Safety endpoints included adverse events (AEs) and time to menstrual recovery. Results: The superiority of linzagolix vs. placebo was demonstrated for both the proportion of patients with a total PBAC score <10 from week 6-12 (91.5% vs. 2.5%; difference [95% confidence interval], 89.0% [76.0-96.2]), and the proportion of patients with a maximum NRS score ≤1 during the 28 days before the end of treatment (70.8% vs. 9.8%; difference, 61.1% [42.1-75.8]). Reductions in HMB and pain with linzagolix were rapidly achieved, occurred alongside improvements in other efficacy endpoints (e.g., analgesic use, blood hemoglobin, myoma and uterine volumes, patient-reported outcomes), and coincided with rapid and sustained reductions in plasma estradiol levels. The incidence of AEs was 91.7% in the linzagolix group and 75.6% with placebo; the most common AE in the linzagolix group was hot flush (47.9%). At the end of study treatment, mean plasma estradiol in the linzagolix group returned to pretreatment levels within 4 weeks, and the median time to menstrual recovery was 29 days. Conclusion: These data reaffirm that GnRH receptor inhibition with linzagolix is a tolerable and efficacious strategy to manage the signs and symptoms of uterine fibroids. Trial Registration: This trial was registered in clinicaltrials.gov, ID number NCT05445167. URL: https://clinicaltrials.gov/study/NCT05445167. Date of registration: 6/27/2022. Date of first enrollment: 10/11/2022.