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.