Linzagolix 200mg tablets

Abstract STUDY QUESTION Was the efficacy of linzagolix, observed at 6 months in women with endometriosis-associated pain, maintained when administered for an additional 6 months? SUMMARY ANSWER Efficacy from this extension study complements the results of the main trial, by showing that linzagolix is effective at reducing endometriosis-associated pain for a majority of women. WHAT IS KNOWN ALREADY In the pivotal EDELWEISS 3 randomized controlled trial, the efficacy and safety of 24 weeks of once-daily oral linzagolix (a GnRH antagonist) were reported in women with endometriosis-related pain. Risks of bone mineral density (BMD) loss and vasomotor symptoms were minimized in both groups. STUDY DESIGN, SIZE, DURATION EDELWEISS 3 was a prospective, randomized, double-blind study. Subjects completing the 6-month treatment period in EDELWEISS 3 were invited to participate in the present extension study: EDELWEISS 6. Only subjects who had completed the full 6-month treatment course in the main study and who met the inclusion criteria were eligible for entry into the extension study. Among 486 patients who completed the 6-month study, 353 participated in the extension study from March 2020 to February 2023. The current extension study started at Month 6 of the main EDELWEISS 3 phase-3 trial. Upon the end of treatment in the extension study (6-month treatment period from Month 6 to Month 12), subjects entered a post-treatment follow-up period of 6 months. The current report describes outcomes from the extension treatment period (up to 12 months) and subsequent follow-up of 6 months with no investigational medicinal product. The co-primary endpoints were the reduction in dysmenorrhea and non-menstrual pelvic pain at Month 12. PARTICIPANTS/MATERIALS, SETTING, METHODS Premenopausal women with moderate-to-severe endometriosis who previously completed the full 6-month treatment period in the main study and met the inclusion criteria were eligible for the extension study. All subjects (n = 353), whether given placebo or not in the main study, received either 75 mg linzagolix alone or 200 mg combined with hormonal add-back therapy (ABT) once daily for the additional 6 months, i.e. those who were given a placebo during the main study were randomized to either group and those who had received active treatment continued with the same treatment (placebo/75 mg linzagolix [n = 57], placebo/200 mg linzagolix plus ABT [n = 57], 75 mg linzagolix [n = 118], and 200 mg linzagolix plus ABT [n = 121]). Pain was measured daily on a verbal rating scale and recorded in an electronic diary. The trial was performed in clinics and university hospitals in the USA and Europe. MAIN RESULTS AND THE ROLE OF CHANCE By Month 12, of the 353 women who were treated and analyzed, the proportion of subjects with a significant reduction in dysmenorrhea and stable or decreased use of analgesics was 55.9% in the 75 mg linzagolix group and 91.0% in the 200 mg+ABT linzagolix group. The proportion of subjects with a significant reduction in non-menstrual pelvic pain and stable or decreased use of analgesics was 59.5% in the 75 mg linzagolix group and 67.6% in the 200 mg+ABT linzagolix group. A steady reduction in mean daily dyschezia, dyspareunia, and overall pelvic pain scores was observed in both linzagolix groups from baseline to Month 12, with a more marked reduction in the 200 mg+ABT linzagolix group. Quality of life was assessed using the EHP-30 questionnaire. At Month 12, clear improvements (total score reductions) were observed in both linzagolix groups, with greater improvements in five out of five dimensions in the 200 mg+ABT linzagolix group. Changes in body mass index were minimal, with no clinically meaningful modifications from Month 6 to Month 12. Adverse events including hot flushes were encountered in fewer than 1% of subjects. During the off-treatment follow-up period of 6 months, some of the improvements were maintained for several months. LIMITATIONS, REASONS FOR CAUTION Efficacy was originally compared between the linzagolix and placebo groups from the main study, however, it would have been useful to have results from comparative studies with estro-progestogens or progestogens, to ascertain whether a GnRH antagonist has significant benefits over traditional first-line medications. WIDER IMPLICATIONS OF THE FINDINGS Linzagolix, when administered orally once daily at a dose of 200 mg in combination with ABT, offers an additional option for effective, safe, and well-tolerated medical treatments for endometriosis that can be proposed in cases of estro-progestogen or progestogen inefficacy, as it can be used for a longer term, improving quality of life and reducing the need for analgesics and opioids. The risks of bone mineral loss and vasomotor symptoms were minimized due to the ABT. The 75 mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT and may offer an option for some women, although further research is needed to confirm this finding. STUDY FUNDING, COMPETING INTEREST(S) Funding for the EDELWEISS 6 study was provided by Geneva, Switzerland. Analysis of data was partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK), and Kissei (Japan). Grant 5/4/150/5 was awarded to M.-M.D. by the Fonds National de la Recherche Scientifique (FNRS). J.D. was a member of the scientific advisory board of ObsEva and Preglem until 2023 and reports consulting fees from ObsEva, Gedeon Richter, and Theramex. C.M.B. declares consulting fees (paid to University of Oxford) from Myovant for an advisory board and from Theramex; payment or honoraria (paid to University of Oxford) for talks at different meetings from [Theramex and Gedeon Richter]; support for attending meetings and/or travel (paid to University of Oxford) from [Gedeon Richter]; being a member of the independent data monitoring board for the EDELWEIS 3 trial and member of the advisory board for Myovant for Spirit 1 and 2 trials (funds for both were paid to University of Oxford); being Chair of the ESHRE Endometriosis Guideline Committee (unpaid) and a member of the Medical Advisory Board Endometriosis UK (unpaid). F.P. has received fees and honoraria for lectures from Theramex. A.W.H. declares consultancy fees (paid to institution) from Roche Diagnostics, Gesynta, and Theramex; lecture fees from Gedeon Richter and Theramex; grant funding from the EU, UKRI, NIHR, CSO, Wellbeing of Women and Roche Diagnostics; UK Patent 2217921-2; participation on a Data Safety Monitoring Board for PANDA DMC; and roles as Trustee and Medical Advisor to Endometriosis UK, and Specialty Advisor to the Scottish Government’s Chief Medical Officer for Obstetrics and Gynaecology. S.B. has received consulting fees and honoraria for lectures from Theramex. S.P.R. reports consulting fees and honoraria for lectures from Gedeon Richter and Theramex. F.C.H. reports consulting fees and honoraria for lectures, presentations, or educational events from Theramex and Gedeon Richter; and honoraria for participation in a data safety monitoring board for Organon. HT has received grants from Abbvie, reports consulting fees from ObsEva and Gedeon Richter and stock options from DotLab; declares a patent on endometriosis biomarkers, owned by Yale University (US10 982 282). M.P. was a principal investigator in the ObsEva-sponsored EDELWEISS trials and has received fees and honoraria from Theramex. E.B. and S.H. are employees of Theramex. M.-M.D. has received fees for lectures from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER NCT04335591 (ClinicalTrials.gov).

Abstract licence: CC BY 4.0

Abstract STUDY QUESTION 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? 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, METHODS 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%). 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 FINDINGS 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. 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.

Abstract licence: CC BY 4.0

Abstract Estrogens play a critical role in the pathogenesis of endometriosis and it is logical to assume that lowering estradiol levels with oral gonadotropin-releasing hormone (GnRH) antagonists may prove effective, especially in women who fail to respond to progestogens. Indeed, due to progesterone resistance, oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis, but are ineffective in 33% of women. Oral GnRH antagonists have therefore been evaluated for management of premenopausal women with endometriosis-associated pelvic pain. The first publication on these drugs reported the efficacy of elagolix. The present paper is a narrative review of linzagolix, which is an orally administered GnRH receptor antagonist with low pharmacokinetic/pharmacodynamic variability. It binds to and blocks the GnRH receptor in the pituitary gland, resulting in a dose-dependent drop in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production. This reduction in LH and FSH levels in turn leads to a dose-dependent decline in estrogen. Phase 2 and 3 trials are reviewed and discussed here. There is a place for GnRH antagonists in the management of symptomatic endometriosis, and linzagolix with or without add-back therapy (ABT) is one option that can be used at low doses, avoiding the need for ABT, which is contraindicated in some patients.

Abstract licence: CC BY-NC 3.0

Non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonists exhibit remarkable potency and specificity in inhibiting GnRH receptor activity. The orally administered versions of these drugs, notably elagolix and relugolix, have obtained official clearance in various countries for treating moderate-to-severe endometriosis-related pain. Concurrently, linzagolix and opigolix (ASP1707) continue to advance through late-stage clinical trials. The primary objective of this review is to comprehensively evaluate the clinical efficacy and safety profile of oral GnRH antagonists, specifically elagolix, relugolix, linzagolix, and opigolix, for the management of endometriosis-associated pain. Specifically, this study summarizes and analyzes their effectiveness in alleviating dysmenorrhea and non-menstrual pelvic pain, evaluates the dose-dependent impacts on bone mineral density and adverse effects such as hot flushes, and explores the role of add-back therapy in improving treatment safety and patient adherence. Research has demonstrated that oral GnRH antagonists effectively alleviate endometriosis-related pain while enhancing patients’ quality of life. Furthermore, when combined with add-back therapy, these medications enhance treatment safety and contribute to greater patient compliance. Compared to alternative hormonal treatments, oral GnRH antagonists emerge as a particularly promising approach for managing endometriosis.

Abstract licence: CC BY-NC