Linzagolix versus leuprorelin in Japanese women with uterine leiomyomas: a phase 3, randomized, active-controlled, non-inferiority trial.
Linzagolix showed comparable efficacy to leuprorelin for reducing menstrual bleeding in women with uterine leiomyomas, with a quicker onset of action.
Where it sits
this study against the rest of the goserelin corpusSummary and findings
This study evaluated the efficacy of linzagolix compared to leuprorelin for heavy menstrual bleeding in premenopausal women with uterine leiomyomas. A total of 287 patients were randomized to receive either linzagolix 200 mg daily or leuprorelin 1.88 mg every 4 weeks for 24 weeks. Results indicated that linzagolix was non-inferior to leuprorelin in reducing menstrual bleeding.
Abstract
<h4>Study question</h4>How 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?<h4>Summary answer</h4>Reductions in menstrual bleeding with linzagolix were rapidly achieved, non-inferior to leuprorelin at Weeks 6-12, and maintained over 24 weeks of treatment.<h4>What is known already</h4>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.<h4>Study design, size, duration</h4>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.<h4>Participants/materials, setting, methods</h4>Eligible 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%).<h4>Main results and the role of chance</h4>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.<h4>Limitations, reasons for caution</h4>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.<h4>Wider implications of the findings</h4>This 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.<h4>Study funding/competing interest(s)</h4>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.<h4>Trial registration number</h4>NCT05440383.<h4>Trial registration date</h4>27 June 2022.<h4>Date of first patient’s enrolment</h4>11 October 2022.
Background
This paper addresses the comparative efficacy of linzagolix, a GnRH receptor antagonist, versus leuprorelin, a GnRH agonist, for treating heavy menstrual bleeding in women with uterine leiomyomas. Prior knowledge indicates that GnRH agonists can lead to adverse effects such as bone mineral density loss and symptom flare-ups. This study is significant as it explores a potential alternative that may mitigate these limitations.
Methods
This was a phase 3, multicentre, randomized, double-blind, parallel-group, non-inferiority trial conducted in Japan. A total of 287 premenopausal women aged ≥20 years with uterine leiomyomas and heavy menstrual bleeding were randomized 1:1 to receive either oral linzagolix 200 mg daily or subcutaneous leuprorelin 1.88 mg every 4 weeks for 24 weeks. The primary endpoint was the proportion of patients with a total PBAC score <10 from Weeks 6 to 12.
Results
From Weeks 6 to 12, the proportion of patients with a total PBAC score <10 was 89.9% in the linzagolix group and 90.8% in the leuprorelin group, with a difference of -0.9% (-8.6, 6.9). The median time to achieve a total PBAC score <10 was significantly shorter in the linzagolix group at 6.0 days compared to 20.0 days for leuprorelin (P=0.023). Improvements in pain and myoma/uterine volumes were also observed earlier in the linzagolix group.
Interpretation
The findings suggest that linzagolix is non-inferior to leuprorelin in reducing menstrual bleeding, with a statistically significant earlier onset of action. However, the small difference in the primary endpoint raises questions about clinical significance. The study's funding by Kissei Pharmaceutical Co., Ltd. may introduce bias, and the results should be interpreted with caution until further studies are conducted.
Key findings
- 89.9% of patients in the linzagolix group had a total PBAC score <10 from Weeks 6 to 12, 95% CI 83.7, 94.4.
- 90.8% of patients in the leuprorelin group had a total PBAC score <10 from Weeks 6 to 12, 95% CI 84.7, 95.0.
- Median time to a total PBAC score <10 was 6.0 days for linzagolix versus 20.0 days for leuprorelin, P=0.023.
- The incidence of adverse events was 97.2% in the linzagolix group and 96.5% in the leuprorelin group.
- The most common adverse event in the linzagolix group was hot flush (53.8%) and breakthrough bleeding in the leuprorelin group (55.6%).
Limitations
- Further studies needed to evaluate longer-term safety and efficacy.
- Industry-funded study may introduce bias.
- Short follow-up period of 24 weeks.