Linzagolix 200mg tablets

PURPOSE: Uterine fibroids are the most common pelvic tumors in women, representing the primary indication of hysterectomy. Gonadotropin-releasing hormone (GnRH) antagonists represent a new therapeutic option for premenopausal women. The aim of this review is to evaluate the efficacy and safety of GnRH antagonists in the treatment of uterine fibroids (size reduction and symptom control). METHODS: A review of studies from electronic databases (PubMed and Cochrane Central) published up to December 2023 was performed. Eleven randomized clinical trials with a total of 4164 patients were included in the review, which evaluated GnRH antagonists (Relugolix, Elagolix, Linzagolix and Cetrorelix) against placebo or GnRH agonists in premenopausal women with uterine fibroids and heavy menstrual bleeding. RESULTS: The results of the measures evaluated to determine the efficacy and safety of GnRH antagonists versus placebo are favorable for the variables of control of uterine bleeding (Relative risk (RR) = 5.09; 95% CI 3.19 to 8.14), percentage reduction of fibroid volume (Mean difference (MD) = -27.36; 95% CI -38.89 to -15.83) and lower reduction of bone density (MD -0.35; 95% CI -0.47 to -0.24). The results do not allow us to conclude whether there are differences between the alternatives compared in the control of vasomotor symptoms. CONCLUSIONS: GnRH antagonists represent an effective alternative for uterine fibroids treatment as they allow a superior reduction in menstrual bleeding and uterine fibroid volume compared to the placebo group.

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Background: Elagolix, Linzagolix, and Relugolix, as oral gonadotropin-releasing hormone antagonists, have emerged as promising treatments for endometriosis-associated pain. Objective: To evaluate pain intensity reduction as the primary outcome and assess side effects and quality of life as secondary outcomes through an updated meta-analysis. Materials and Methods: A systematic search was conducted in Cochrane, Scopus, and PubMed/Medline. Study quality was assessed using the Cochrane risk of bias in non-randomized studies of interventions tool. The pooled standard mean difference and p-value were calculated using a random-effects model (DerSimonian-Laird method), and the inconsistency index was applied to evaluate heterogeneity. Results: 7 randomized controlled trials were included. Gonadotropin-releasing hormone antagonists significantly reduced dysmenorrhea, dyspareunia, and non-menstrual chronic pelvic pain when measured with the verbal and numeric rating scales, but not with the modified Biberoglu and Behrman score. Secondary outcomes showed significant improvements in health status (endometriosis health profile and patient global impression of change). However, treatment was associated with increased hot flushes (3.61-fold higher), an 8.96% increase in low-density lipoprotein after 6 months, and a rise in high-density lipoprotein compared with placebo. Bone mineral density in the spine was significantly lower in the treatment group (p < 0.001). Conclusion: This meta-analysis provides updated evidence on Elagolix, Linzagolix, and Relugolix, confirming their effectiveness in managing endometriosis-associated pain, while highlighting important considerations regarding metabolic and bone health.

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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 INTERESTS: 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).

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Abstract: Current medical treatment options for endometriosis associated pains are inadequate. Evidence on effects of nonsteroidal anti-inflammatory drugs is scarce. Around one third of patients are not responsive to oral contraceptives or progestins due to progesterone resistance. Gonadotropin-releasing hormone (GnRH) agonists can only be used for a short duration because of associated side effects. Oral GnRH antagonists, including elagolix, relugolix, and linzagolix allow oral administration, induce dose dependent reduction of estradiol levels, do not cause initial flare up of endometriosis symptoms, and allow the fast return of ovarian function and menstruation after discontinuation. Elagolix at a low dose of 150 mg once daily, or the higher dose of 200 mg twice daily, significantly increased the proportion of women achieving clinically meaningful decline of dysmenorrhea, noncyclic pelvic pain, and dyspareunia. Relugolix at an oral dose of 40 mg/day results in improvement in different forms of endometriosis related pelvic pain, with an efficacy and side effect profile similar to that of GnRH agonists. Adding 1 mg of estradiol and 0.5 mg of norethindrone to 40 mg of relugolix (relugolix combination therapy) allows extension of treatment to 24 weeks with maintained efficacy and an improved side effect profile. Linzagolix, in a dose of 75 mg/day, can be used alone to treat endometriosis associated pain. For severe pelvic pain and dyspareunia, linzagolix can be used in a high dose of 200 mg/day with hormonal add-back therapy to preserve bone health. Plain Language Summary: Oral gonadotropin-releasing hormone (GnRH) antagonists, including elagolix, relugolix, and linzagolix, represent a new addition in the armamentarium against endometriosis associated pain. They are given orally, do not cause an initial flare-up of disease symptoms, allow a return of menses quickly after their withdrawal and produce a balance between ability to relieve endometriosis associated pain and side effects profile. The addition of hormonal agents like estradiol 1 mg and norethindrone acetate 0.5 mg to relugolix (relugolix combination therapy) allowed longer use of the medication for relief of endometriosis associated pain while reducing side effects like bone mineral density loss and hot flushes. Keywords: endometriosis, pain, elagolix, relugolix, linzagolix, estradiol, norethindrone

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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.

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Uterine fibroids and endometriosis are among the most common conditions encountered in gynaecological practice. Fibroids affect 30-70% of women, with up to half experiencing symptoms that significantly impair quality of life (QoL), including anaemia, pain, and pressure-related symptoms. Additionally, fibroids are the sole cause of infertility in 1-3% of women. Endometriosis is the most common gynaecological cause of chronic pelvic pain syndrome and one of the leading causes of infertility. This condition affects between 2% and 10% of women, leading to symptoms that often have a detrimental impact on QoL. For decades, efforts have been underway to develop pharmacological treatments for oestrogen-dependent conditions that would offer both high efficacy and good tolerability. A significant advancement in the treatment of oestrogen-dependent diseases was the introduction into clinical practice of gonadotropin-releasing hormone (GnRH) antagonists. In recent years, publications have demonstrated the promising therapeutic potential of linzagolix in the management of uterine fibroids and endometriosis. It is an oral, small-molecule, non-peptide GnRH antagonist that induces dose-dependent suppression of ovarian function. The aim of this literature review was to evaluate current evidence on the potential applications of linzagolix for the treatment of uterine fibroids and endometriosis. Linzagolix, with or without add-back therapy, significantly alleviates the symptoms of both uterine fibroids and endometriosis in a dose-dependent manner - the therapeutic effect is rapid and sustained. This drug constitutes a valuable addition to existing methods for treating oestrogen-dependent diseases because it enables treatment personalisation allowing for dose adjustment and the optional use of add-back therapy.

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STUDY QUESTION: Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain? SUMMARY ANSWER: Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months. WHAT IS KNOWN ALREADY?: A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20-60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. STUDY DESIGN, SIZE, DURATION: EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary. MAIN RESULTS AND THE ROLE OF CHANCE: At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P < 0.001), while the rates of responders for non-menstrual pelvic pain were 47.3% and 30.9% (P = 0.007), respectively. The 75 mg linzagolix daily dose demonstrated a clinically meaningful and statistically significant reduction in dysmenorrhea versus placebo at 3 months. The proportion of responders for dysmenorrhea in the 75 mg linzagolix group was 44.0% compared with 23.5% in the placebo group (P < 0.001). Although the 75 mg dose showed a trend toward reduction in non-menstrual pelvic pain at 3 months relative to the placebo, it was not statistically significant (P = 0.279). Significant improvements in dyschezia and overall pelvic pain were observed in both linzagolix groups when compared to placebo. Small improvements in dyspareunia scores were observed in both linzagolix groups but they were not significant. In both groups, hypoestrogenic effects were mild, with low rates of hot flushes and bone density loss of <1%. A daily dose of 200 mg linzagolix with ABT or 75 mg linzagolix alone was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain also at 6 months of therapy. LIMITATIONS, REASONS FOR CAUTION: Efficacy was compared between linzagolix groups and placebo; however, it would be useful to have results from comparative studies with estro-progestogens or progestogens. It will be important to ascertain whether gonadotropin-releasing hormone antagonists have significant benefits over traditional first-line medications. WIDER IMPLICATIONS OF THE FINDINGS: Linzagolix administered orally once daily at a dose of 200 mg in combination with add-back therapy (ABT) demonstrated better efficacy and safety than placebo in the management of moderate-to-severe endometriosis-associated pain. The quality of life was improved and the risks of bone 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, but further research is needed to confirm this. If confirmed, it would offer a viable option for women who do not want to wish to have ABT or for whom it is contraindicated. STUDY FUNDING/COMPETING INTEREST(S): Funding for the EDELWEISS 3 study was provided by ObsEva (Geneva, Switzerland). Analysis of data and manuscript writing were partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK) and Kissei (Japan) and grant 5/4/150/5 was awarded to M.-M.D. by FNRS. J.D. was a member of the scientific advisory board of ObsEva until August 2022, a member of the scientific advisory board of PregLem, and received personal fees from Gedeon Richter, ObsEva and Theramex. J.D. received consulting fees, speakers' fees, and travel support from Gedeon Richter, Obseva and Theramex, which was paid to their institution. C.B. has received fees from Theramex, Gedeon Richter, and Myovant, and travel support from Gedeon Richter-all funds went to the University of Oxford. He was a member of the data monitoring board supervising the current study, and served at an advisory board for endometriosis studies of Myovant. H.T. has received grants from Abbvie and was past president of ASRM. F.C.H. has received fees from Gedeon Richter and Theramex. O.D. received fees for lectures from Gedeon Richter and ObsEva and research grants for clinical studies from Preglem and ObsEva independent from the current study. A.H. has received grants from NIHR, UKRI, CSO, Wellbeing of Women, and Roche Diagnostics; he has received fees from Theramex. A.H.'s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii. M.P. has nothing to declare. F.P. has received fees from Theramex. S.P.R. has been a member of the scientific advisory board of Gedeon Richter and received fees from Gedeon Richter. A.P. and M.B. are employees of Theramex. E.B. was an employee of ObsEva, sponsor chair of the data monitoring board supervising the current study, and has been working as a consultant for Theramex since December 2022; she owns stock options in ObsEva. M.-M.D. has received fees and travel support from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER: NCT03992846. TRIAL REGISTRATION DATE: 20 June 2019. DATE OF FIRST PATIENT’S ENROLLMENT: 13 June 2019.

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