Linzagolix versus leuprorelin in Japanese women with uterine leiomyomas: a phase 3, randomized, active-controlled, non-inferiority trial.

study questionHow does the efficacy of linzagolix (a gonadotropin-releasing hormone [GnRH] receptor antagonist) compare with leuprorelin (a GnRH agonist) for the treatment of heavy menstrual bleeding (HMB) in patients with uterine leiomyomas? SUMMARY ANSWER: Reductions in menstrual bleeding with linzagolix were rapidly achieved, non-inferior to leuprorelin at Weeks 6-12, and maintained over 24 weeks of treatment. WHAT IS KNOWN ALREADY: GnRH agonists are commonly used to manage the symptoms of uterine leiomyomas; however, they are also associated with bone mineral density (BMD) loss, an initial worsening of symptoms (flare-up effect), and delayed pituitary recovery after treatment cessation. Linzagolix is a GnRH receptor antagonist that may overcome the limitations of GnRH agonists, though comparative safety and efficacy have not yet been evaluated. STUDY DESIGN, SIZE, DURATION: This was a phase 3, active-controlled, multicentre, randomized, double-blind, parallel-group, non-inferiority study, conducted in Japan between October 2022 and August 2024. In total, 287 patients were randomized 1:1 to oral linzagolix 200 mg once daily (plus leuprorelin placebo; n = 143) or subcutaneous leuprorelin 1.88 mg every 4 weeks (plus linzagolix placebo; n = 144) for 24 weeks. Patients were randomized using an interactive web response system, stratified by the presence of pain symptoms. PARTICIPANTS/MATERIALS, SETTING,

methodsEligible patients were premenopausal women (aged ≥20 years) with uterine leiomyomas and HMB. Key assessments throughout the treatment period included menstrual bleeding (measured using the Pictorial Blood Loss Assessment Chart [PBAC]), pain (measured using a numeric rating scale), blood haemoglobin, myoma and uterine volumes (measured by transvaginal ultrasound), patient-reported symptom severity and quality of life, plasma oestradiol, adverse events (AEs), and BMD. At the end of treatment, patients entered a follow-up period of up to 24 weeks, during which plasma oestradiol, BMD, and menstrual recovery were assessed. The primary endpoint was the proportion of patients with a total PBAC score <10 from Weeks 6 to 12 of the treatment period (non-inferiority margin, -15%). MAIN RESULTS AND THE ROLE OF CHANCE: From Weeks 6 to 12, the proportion of patients with a total PBAC score <10 was 89.9% (95% CI, 83.7, 94.4) in the linzagolix group, which was non-inferior to 90.8% (84.7, 95.0) in the leuprorelin group (difference, -0.9% [-8.6, 6.9]). Reductions in menstrual bleeding were rapidly achieved with linzagolix; median time to a total PBAC score <10 was significantly shorter in the linzagolix group versus leuprorelin (6.0 vs 20.0 days; P = 0.023). Improvements in pain, haemoglobin, myoma/uterine volumes, and patient-reported outcomes were comparable between groups over 24 weeks, with earlier reductions in pain and myoma/uterine volumes observed in the linzagolix group. Mean plasma oestradiol levels were rapidly reduced to <20 pg/ml by Week 2 in the linzagolix group (without the flare-up effect seen in the leuprorelin group) and were maintained through Week 24. The incidence of AEs was comparable between the linzagolix and leuprorelin groups (97.2% and 96.5%, respectively). The most common AE was hot flush in the linzagolix group (53.8%) and breakthrough bleeding in the leuprorelin group (55.6%), and the incidence of these events was highest during the first 28 days of treatment. Following the end of study treatment, mean plasma oestradiol levels tended to recover earlier in the linzagolix group versus leuprorelin, which coincided with earlier recovery of hot flush AEs, reductions in BMD, and menstruation. LIMITATIONS, REASONS FOR CAUTION: Further studies are warranted to compare linzagolix with other GnRH receptor antagonists, and to evaluate the longer-term safety and efficacy of linzagolix, with or without hormonal add-back therapy, in Japanese women with uterine leiomyomas and HMB. WIDER IMPLICATIONS OF THE

findingsThis phase 3 study met its primary endpoint, and demonstrated the 24-week efficacy, safety, and pharmacodynamic effects of linzagolix in Japanese women with symptomatic uterine leiomyomas. While linzagolix offered comparable efficacy to leuprorelin over 24 weeks of treatment, its earlier onset of action may make linzagolix a favourable treatment option. In particular, rapid reductions in myoma and uterine volumes suggest that linzagolix may be a useful preoperative treatment. Moreover, earlier recovery of oestradiol levels and menstruation following linzagolix may be an important consideration for women planning pregnancy after treatment. Overall, these findings support the use of linzagolix over 24 weeks for the signs and symptoms of uterine leiomyomas. STUDY FUNDING/COMPETING INTEREST(S): Funding for the study and third-party medical writing support was provided by Kissei Pharmaceutical Co., Ltd. The study sponsor participated in the design of the study; the collection, analysis, and interpretation of data; and the development of the manuscript. Y.O. and T.H. report medical writing and clinical trial advisory fees from Kissei Pharmaceutical Co., Ltd. H.T. reports patent applications with Kissei Pharmaceutical Co., Ltd. H.T., A.K., and F.S. are employees of Kissei Pharmaceutical Co., Ltd. TRIAL REGISTRATION NUMBER: NCT05440383. TRIAL REGISTRATION DATE: 27 June 2022. DATE OF FIRST PATIENT’S ENROLMENT: 11 October 2022.