OBJECTIVE:To assess the effects of relugolix combination therapy (CT) on ovarian function in healthy, ovulatory, premenopausal women. DESIGN:This was an open-label, single-cohort, pharmacodynamic, safety, and tolerability study consisting of five study periods: a pretreatment period to confirm ovulatory status, three 28-day treatment periods, and a posttreatment period to assess the duration of time required to return to ovulation after treatment discontinuation. Ovarian function was assessed by transvaginal ultrasonography and serum hormone concentrations. SUBJECTS:Healthy, premenopausal female participants, 18-35 years of age. EXPOSURE:Relugolix CT (relugolix 40 mg, with estradiol 1 mg and norethindrone acetate 0.5 mg) was taken orally once daily for 84 days. MAIN OUTCOME MEASURES:The primary endpoint was the proportion of women in whom ovulation was inhibited during the 84-day treatment period. Secondary endpoints included proportion of women in whom ovulation was inhibited within each treatment period, number of women who fulfilled the Landgren criterion; characterization of follicular diameter, hormone concentrations, and endometrial thickness; time to return to ovulation after treatment discontinuation; proportion of women who returned to ovulation within 36 days after treatment discontinuation; safety and tolerability. RESULTS:Seventy women were enrolled in the study, 67 of whom completed treatment. Treatment with relugolix CT inhibited ovulation in 100% of women who completed treatment (95% confidence interval, 94.6-100.0). Systemic concentrations of luteinizing hormone and follicle-stimulating hormone were suppressed and maintained at low concentrations during treatment, with an absence of a preovulatory luteinizing hormone surge. Median estradiol concentrations across all women were consistently maintained between 36.8 and 39.1 pg/mL (range, 12.1-121.1 pg/mL) during treatment. All individual progesterone concentrations during treatment remained below 1.57 ng/mL (5 nmol/L). After treatment discontinuation, all women ovulated or initiated menses. The mean time to return to ovulation was 23.5 days. Treatment was generally well tolerated with no safety or tolerability issues identified. CONCLUSION:Relugolix CT inhibits ovulation, which, in the context of this study, was achieved within the first cycle after treatment initiation. The rapid and predictable return of ovarian activity and ovulation after treatment discontinuation is advantageous for patients who wish to conceive thereafter.

WHAT IS THIS SUMMARY ABOUT?:This is a summary of two research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. These studies compared how well a medicine called relugolix combination therapy and placebo worked in reducing heavy menstrual bleeding (periods) in women with uterine fibroids (published in a separate article referenced in the section: Where can readers find more information on these studies?). Researchers also looked at whether women with moderate to severe pain from uterine fibroids saw improvement in their worst pain symptoms after 24 weeks of treatment (results described in the present summary). WHAT ARE THE KEY TAKEAWAYS?:Women with moderate to severe pain from uterine fibroids (menstrual or nonmenstrual pain) took either relugolix combination therapy or placebo (once daily by mouth) for 24 weeks. During the last 5 weeks of treatment, 65% of women taking relugolix combination therapy and 19% of women taking placebo reported having minimal or no menstrual pain. Similarly, 45% of women taking relugolix combination therapy and 22% of women taking placebo reported having minimal or no non-menstrual pain. During the same time period, 71% of the women taking relugolix combination therapy and 40% of women taking placebo reported their worst pain was reduced by about one third compared with the start of the study. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?:Women with moderate to severe pain from uterine fibroids taking relugolix combination therapy were more likely to have minimal or no pain from uterine fibroids after treatment compared with women taking placebo.Clinical Trial Registration: NCT03049735 (LIBERTY 1), NCT03103087 (LIBERTY 2) (ClinicalTrials.gov).

STUDY QUESTION What is the efficacy and safety of long-term treatment (up to 2 years) with relugolix combination therapy (CT) in women with moderate to severe endometriosis-associated pain? SUMMARY ANSWER For up to 2 years, treatment with relugolix CT improved menstrual and non-menstrual pain, dyspareunia, and function in women with endometriosis; after an initial decline of <1%, the mean bone mineral density (BMD) remained stable with continued treatment. WHAT IS KNOWN ALREADY Endometriosis is a chronic condition characterized by symptoms of dysmenorrhea, non-menstrual pelvic pain (NMPP), and dyspareunia, which have a substantial impact on the lives of affected women, their partners, and families. SPIRIT 1 and 2 were phase 3, randomized, double-blind, placebo-controlled studies of once-daily relugolix CT (relugolix 40 mg, oestradiol 1 mg, norethisterone acetate 0.5 mg) in premenopausal women (age 18-50 years) with endometriosis and moderate-to-severe dysmenorrhea and NMPP. These trials demonstrated a significant improvement of dysmenorrhea, NMPP, and dyspareunia in women treated with relugolix CT, with minimal decline (<1%) in BMD versus placebo at 24 weeks. STUDY DESIGN, SIZE, DURATION Patients participating in this open-label, single-arm, long-term extension (LTE) study of the 24-week SPIRIT pivotal studies (SPIRIT 1 and 2) received up to an additional 80 weeks of once-daily oral relugolix CT treatment between May 2018 and January 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS Premenopausal women with confirmed endometriosis and moderate to severe dysmenorrhea and NMPP who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials; ) and who met all entry criteria were eligible to enrol. Two-year results were analysed by treatment group based on original randomization in pivotal studies: relugolix CT, delayed relugolix CT (relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT), or placebo -> relugolix CT (placebo for 24 weeks followed by relugolix CT). The primary endpoints of the LTE study were the proportion of dysmenorrhea and NMPP responders at Week 52 and Week 104/end-of-treatment (EOT). A responder was a participant who achieved a predefined, clinically meaningful reduction from baseline in Numerical Rating Scale (NRS) scores (0 = no pain, 10 = worst pain imaginable) for the specific pain type with no increase in analgesic use. The predefined clinically meaningful threshold for dysmenorrhea was 2.8 points and for NMPP was 2.1 points. Secondary efficacy endpoints included change from baseline in Endometriosis Health Profile-30 (EHP-30) pain domain scores, a measure of the effects of endometriosis-associated pain on daily activities (function), NRS scores for dysmenorrhea, NMPP, dyspareunia, and overall pelvic pain, and analgesic/opioid use. Safety endpoints included adverse events and changes in BMD. MAIN RESULTS AND THE ROLE OF CHANCE Of 1261 randomized patients, 1044 completed the pivotal studies, 802 enrolled in the LTE, 681 completed 52 weeks of treatment, and 501 completed 104 weeks of treatment. Demographics and baseline characteristics of the extension population were consistent with those of the original randomized population. Among patients randomized to relugolix CT at pivotal study baseline who continued in the LTE (N = 277), sustained improvements in endometriosis-associated pain were demonstrated through 104 weeks. The proportion of responders at Week 104/EOT for dysmenorrhea and NMPP was 84.8% and 75.8%, respectively. Decreases in dyspareunia and improvement in function assessed by EHP-30 pain domain were also sustained over 2 years. At Week 104/EOT, 91% of patients were opioid-free and 75% of patients were analgesic-free. Relugolix CT over 104 weeks was well tolerated with a safety profile consistent with that observed over the first 24 weeks. After initial least squares mean BMD loss <1% at Week 24, BMD plateaued at Week 36 and was sustained for the duration of 104 weeks of treatment. Efficacy and safety results were generally consistent in women in the placebo -> relugolix CT and delayed relugolix CT groups. LIMITATIONS, REASONS FOR CAUTION The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Of the 802 patients who were enrolled in this LTE study, 681 patients (84.9%) and 501 patients (62.5%) of patients completed 52 and 104 weeks of treatment, respectively. In addition, there currently are no comparative data to other hormonal medications. Finally, a third (37.4%) of the study population terminated participation early. WIDER IMPLICATIONS OF THE FINDINGS In conclusion, relugolix CT offers an additional option to help address an important unmet clinical need for effective, safe, and well-tolerated medical treatments for endometriosis that can be used longer-term, reducing the need for opioids and improving quality of life. The findings from this study may help support the care of women with endometriosis seeking longer-term effective medical management of their symptoms. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Myovant Sciences GmbH (now Sumitomo Pharma Switzerland GmbH). C.M.B. reports fees from Myovant, grants from Bayer Healthcare, fees from ObsEva, and Chair of ESHRE Endometriosis Guideline Group (all funds went to the University of Oxford); N.P.J. reports personal fees from Myovant Sciences, during the conduct of the study, personal fees from Guerbet, personal fees from Organon, personal fees from Roche Diagnostics; S.A.-S. reports personal fees from Myovant Sciences, personal fees from Bayer, personal fees from Abbvie, personal fees from UpToDate; J.S.P., and R.B.W. are employees and shareholders of Myovant Sciences; J.C.A.F. and S.J.I. are shareholders of Myovant Sciences (but at time of publicaion are no longer employess of Myovant Sciences); M.S.A. and K.W. have no conflicts to declare; V.M. is a consultant to Myovant; L.C.G. reports personal fees from Myovant Sciences, Inc and Bayer. The authors did not receive compensation for manuscript writing, review, and revision. TRIAL REGISTRATION NUMBER NCT03654274.

Relugolix is a gonadotropin-releasing hormone receptor antagonist. Relugolix 40-mg monotherapy is associated with vasomotor symptoms and long-term bone mineral density loss due to hypoestrogenism. This study assessed whether the addition of estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg to relugolix 40 mg (relugolix combination therapy) provides systemic E2 concentrations in the 20–50 pg/mL range to minimize these undesirable effects. This was a randomized, open-label, parallel-group study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of relugolix 40 mg alone or in combination with E2 1 mg and NETA 0.5 mg in healthy premenopausal women. Eligible women were randomized 1:1 to receive relugolix alone or relugolix plus E2/NETA for 6 weeks. Study assessments included pharmacokinetic parameters of E2, estrone, and relugolix in both treatment groups, and norethindrone in the relugolix plus E2/NETA treatment group at weeks 3 and 6. Median E2 24 h average concentrations with the relugolix plus E2/NETA group (N = 23) were 31.5 pg/mL, 26 pg/mL higher compared with the relugolix-alone group (6.2 pg/mL) (N = 25). There were 86.4

WHAT IS THIS SUMMARY ABOUT?:This is a summary of research studies (known as clinical trials) called SPIRIT 1 and SPIRIT 2. The SPIRIT 1 and SPIRIT 2 studies compared how well a medicine called relugolix combination therapy worked in relieving pain in women with moderate to severe endometriosis compared to a placebo, a pill with no active medication. Endometriosis occurs when tissue similar to what normally lines the uterus grows in other places, such as the ovaries, fallopian tubes, and bowels. WHAT WERE THE RESULTS?:Researchers looked at 1261 adult women with moderate to severe endometriosis. Randomly, 420 (33%) of these women were assigned to relugolix combination therapy, 420 (33%) were assigned to delayed relugolix combination therapy (relugolix alone first and then relugolix combination therapy for the remainder of the study), and 421 (33%) were assigned to placebo. The SPIRIT 1 and SPIRIT 2 studies showed that more women taking relugolix combination therapy (75% from SPIRIT 1 and 75% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain during menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (27% from SPIRIT 1 and 30% from SPIRIT 2). The SPIRIT 1 and SPIRIT 2 studies also showed that more women taking relugolix combination therapy (59% from SPIRIT 1 and 66% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain between menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (40% from SPIRIT 1 and 43% from SPIRIT 2). Women taking relugolix combination therapy had less pelvic or groin pain during and between menstrual periods within 4 weeks of starting the medicine. The most common side effects were headaches, the common cold, and hot flushes or feeling hot among women taking relugolix combination therapy, delayed relugolix combination therapy, and placebo. Relugolix combination therapy was considered safe for those with no major medical problems. Women taking relugolix combination therapy had little to no loss of bone mineral density (a way of knowing how strong bones are) after 24 weeks of treatment. WHAT DO THE RESULTS OF THESE STUDIES TELL US?:Women with moderate to severe endometriosis taking relugolix combination therapy had much less pain from endometriosis than women taking placebo. Clinical Trial Registration: NCT03204318 (SPIRIT-1); NCT03204331 (SPIRIT-2) (ClinicalTrials.gov).

BACKGROUND:In the pivotal LIBERTY 1 and 2 trials and long-term extension study, once-daily relugolix combination therapy (40 mg relugolix, 1 mg estradiol, 0.5 mg norethindrone acetate) reduced menstrual blood loss volume and pain among women with uterine fibroids. Relugolix combination therapy was well tolerated with preservation of bone mineral density through 52 weeks. OBJECTIVE:This study aimed to report the 2-year relugolix combination therapy efficacy and safety results of the phase 3 LIBERTY randomized withdrawal study. STUDY DESIGN:Women with uterine fibroid-associated heavy menstrual bleeding who completed the 24-week LIBERTY 1 or 2 trials, followed by the 28-week long-term extension study (up to 52 weeks total treatment), and who met the responder criteria (menstrual blood loss volume <80 mL and ≥50% reduction from pivotal study baseline at week 48 [week 24 of long-term extension]) were randomized in a 1:1 ratio to either blinded treatment with relugolix combination therapy or placebo for 52 weeks (total treatment period, 104 weeks). For women who had a relapse of heavy menstrual bleeding during the study (menstrual blood loss volume ≥80 mL), open-label relugolix combination therapy was offered. The primary endpoint was the proportion of women who maintained menstrual blood loss volume <80 mL through week 76 (week 24 of randomized withdrawal study). Secondary endpoints included time to menstrual blood loss volume ≥80 mL, proportion of women who maintained a menstrual blood loss volume of <80 mL through week 104 (over the 52-week randomized treatment period), the proportion of women who achieved or maintained amenorrhea at week 76 at the end of treatment, and the change in Uterine Fibroid Symptom-Quality of Life Bleeding and Pelvic Discomfort Scale and symptom severity scores. Analyses were performed for the modified intent-to-treat population, including all randomized women who received ≥1 dose of the study drug. RESULTS:Of the 229 randomized women (relugolix combination therapy, n=115; placebo, n=114), 228 received the study drug and 175 (76.7%) completed the randomized withdrawal study. Through week 76, 78.4% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 15.1% in the placebo group (difference, 63.4%; 95% confidence interval, 52.9%-73.9%; P<.0001). At week 104, 69.8% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 11.8% in the placebo group (difference, 58.0%; 95% confidence interval, 47.0%-69.1%; P<.0001). Through week 104, 88.3% of women on placebo relapsed with heavy menstrual bleeding (median time to relapse, 5.9 weeks). Among the 89 women in the placebo group who relapsed and received open-label rescue treatment, 87 women responded to relugolix combination therapy with a menstrual blood loss volume <80 mL. The proportion of women who achieved or maintained amenorrhea were 57.4% vs 13.3% at week 76 (difference, 44.1%; 95% confidence interval, 33.10%-55.1%; P<.0001) and 58.3% vs 10.6% at week 104 (difference, 47.6%; 95% confidence interval, 37.0%-58.3%; nominal P<.0001) for relugolix combination therapy and the placebo group, respectively. Relugolix combination therapy was generally well tolerated; no new safety signals were identified, and the adverse event profile over the second year was consistent with that reported through the first year of treatment. Bone mineral density remained stable in women who received relugolix combination therapy from week 52 to week 104. In women continuously treated with relugolix combination therapy up to 2 years, bone mineral density was generally preserved. CONCLUSION:After 2 years of treatment with relugolix combination therapy, there was evidence of durability of the effect in maintaining low menstrual blood loss volume in women with symptomatic uterine fibroids. Most women had return of heavy menstrual bleeding and associated symptoms after treatment cessation, which improved upon retreatment with relugolix combination therapy. Relugolix combination therapy was well tolerated, the adverse event profile remained consistent, and the mean bone mineral density was generally preserved through 2 years of treatment.

What is this summary about? This is a summary of research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. The LIBERTY 1 and LIBERTY 2 studies looked at how well a medication called relugolix combination therapy worked to reduce heavy bleeding at the time of menstruation compared with placebo. The studies also looked at what side effects were reported in women with uterine fibroids and heavy menstrual bleeding. What were the results? Researchers looked at 388 adult women in the LIBERTY 1 study and 382 adult women in the LIBERTY 2 study. All women had heavy menstrual bleeding with uterine fibroids before the start of the LIBERTY 1 and LIBERTY 2 studies. The women were given one of three treatments during the studies: relugolix combination therapy or placebo for 24 weeks, or delayed relugolix combination therapy (relugolix alone for the first 12 weeks, then relugolix combination therapy for the last 12 weeks of the studies). More women taking relugolix combination therapy in the LIBERTY 1 study (73%) and LIBERTY 2 study (71%) had menstrual blood loss of less than one-third of a cup (80 mL) and had reduction of at least 50% less blood loss during their last menstrual period after 24 weeks of taking the medicine compared with placebo (LIBERTY 1: 19% and LIBERTY 2: 15%). The women taking relugolix combination therapy also had less pain than those taking placebo. Side effects were similar across treatment groups. Headaches and hot flushes were the most common side effects. What do the results mean? More women with uterine fibroids taking relugolix combination therapy for 24 weeks were likely to have fewer uterine fibroid symptoms than women receiving placebo. Clinical Trial Registration: NCT03049735 (LIBERTY 1); NCT03103087 (LIBERTY 2)

Relugolix combination therapy (Rel-CT [once-daily relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg]) is being developed to treat heavy menstrual bleeding associated with uterine fibroids (UF), and endometriosis-associated pain (EM). In the Phase 3 LIBERTY 1/2 trials and long-term extension (LTE) study for UF, Rel-CT maintained BMD through 52 weeks. In the SPIRIT 1/2 trials and LTE study for EM, Rel-CT minimized BMD loss through 24 weeks, after which BMD plateaued up to 52 weeks. Since the mean age of women in the UF studies was higher than that in the EM studies, a pooled population assessment was undertaken to determine if a single BMD profile with a full range of ages could be developed for Rel-CT. A 52-week observational study in a group of contemporaneous age-matched women with UF or EM (Natural History Study [NHS], N=714) was used to benchmark BMD data from the pivotal and LTE studies. Percent change in BMD from baseline with 95% CI was summarized by treatment group and anatomical location using descriptive statistics: mean, 95% CI (Table). There were 2019 women included in pooled data from the 24-week LIBERTY and SPIRIT studies and associated 28-week LTE studies. Percent change from baseline in pooled BMD was consistent with trends in the separate UF and EM populations. Specifically, at the lumbar spine at Week 12, there was a –0.56% change in BMD with Rel-CT that was not clinically significant and likely reflected adjustment from endogenous to exogenous estradiol in the context of Rel-CT. This timepoint marked the beginning of a plateau. At Week 52, the change from baseline was –0.66% in women treated with Rel-CT compared with 0.19% in women in the NHS (Table). Women initially treated with relugolix monotherapy experienced a larger change in BMD from baseline to Week 12 (–1.84%) that plateaued after transition to Rel-CT with change from baseline to Week 52 of –1.31%.TablePercent change from baseline in lumbar spine BMDNHS (mean, 95% CI)N=714Pooled SPIRIT and LIBERTYRel-CT (mean, 95% CI)N=672Delayed Rel-CT* (mean, 95% CI)N=675Week 12––0.56% (–0.76, –0.36)–1.84% (–2.03, –1.64)Week 240.26% (0.07, 0.44)–0.57% (–0.78, –0.36)–2.00% (–2.23, –1.77)Week 36––0.61% (–0.88, –0.34)–1.67% (–1.94, –1.40)Week 520.19% (–0.04, 0.42)–0.66% (–0.97, –0.35)–1.31% (–1.62, –1.01)*Relugolix monotherapy for 12 weeks then Rel-CT for 40 weeks. Open table in a new tab *Relugolix monotherapy for 12 weeks then Rel-CT for 40 weeks. In premenopausal women with UF or EM, treatment with Rel-CT lead to an initial insignificant decline in BMD followed by a plateau through the 52 weeks of the study.

Background: Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 can induce oocyte maturation during in vitro fertilization treatment, including in women who are at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported. Design:Two randomized, placebo-controlled, parallel-group, dose-finding trials Setting:Clinical trials unit. Objective: To determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (phase-2a trial). Patients: Healthy women aged 18-35 years, either without (phase-1; n = 24), or with ovarian stimulation (phase-2a; n = 75). Interventions: Phase-1: single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 mu g) or placebo, (n = 6 per dose). Phase-2a: single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 mu g; n = 16-17 per dose), triptorelin 0.2 mg (n = 5; active comparator), or placebo (n = 5). Main Outcome Measures: Phase-1: safety/tolerability; pharmacokinetics; and pharmacodynamics (luteinizing hormone [LH] and hormones); and time to ovulation assessed by transvaginal ultrasound. Results: In both the trials, MVT-602 was safe and well tolerated across the entire dose range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours. In the phase-2a trial, LH concentrations increased dose dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3 mu g MVT-602 and remained >15 IU/L for 33 hours. Time to ovulation after drug administration was 3.3-3.9 days (MVT-602), 3.4 days (triptorelin), and 5.5 days (placebo). Ovulation occurred within 5 days of administration in 100% (3 mu g), 88% (1 mu g), 82% (0.3 mu g), and 75% (0.1 mu g),ofwomen after MVT-602, 100% after triptorelin and 60% after placebo. Conclusions: MVT-602 induces LH concentrations of similar amplitude and duration as the physiological midcycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR.

OBJECTIVE: To assess the effect of once-daily relugolix combination therapy (relugolix-CT: relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) compared with placebo on moderate-to-severe pain in women with uterine leiomyomas and heavy menstrual bleeding. METHODS: Two replicate, multinational, double-blind, 24-week, randomized, phase 3 studies (LIBERTY 1 and 2) were conducted in premenopausal women with uterine leiomyoma–associated heavy menstrual bleeding (80 mL or greater per cycle for two cycles or 160 mL or greater during one cycle). A predefined secondary objective was to determine the effect of relugolix-CT on moderate-to-severe uterine leiomyoma–associated pain in the pain subpopulation (women with maximum pain scores of 4 or higher on the 0–10 numerical rating scale at baseline, with pain score reporting compliance of 80% (ie, 28 days or more over the last 35 days of treatment). This key secondary endpoint was defined as the proportion of women achieving minimal-to-no uterine leiomyoma–associated pain (maximum numerical rating scale score 1 or lower) at week 24; menstrual and nonmenstrual pain were evaluated in prespecified secondary analyses. Treatment comparisons were performed in the pooled LIBERTY 1 and 2 pain subpopulation using the Cochran-Mantel-Haenszel test stratified by baseline menstrual blood loss volume. RESULTS: Across both trials, 509 women were randomized to relugolix-CT or placebo (April 2017–December 2018). Of these, 277 (54.4%) met pain subpopulation requirements. With relugolix-CT, 45.2% (95% CI 36.4–54.3) of women achieved minimal-to-no pain compared with 13.9% (95% CI 8.8–20.5) with placebo (nominal P<.001). The proportions of women with minimal-to-no pain during menstrual days and during nonmenstrual days were significantly higher with relugolix-CT (65.0% [95% CI 55.6–73.5] and 44.6% [95% CI 32.3–57.5], respectively) compared with placebo (19.3% [95% CI 13.2–26.7], nominal P<.001, and 21.6% [95% CI 12.9–32.7], nominal P=.004, respectively). CONCLUSION: Over 24 weeks, relugolix-CT significantly reduced moderate-to-severe uterine leiomyoma–associated pain with a more pronounced effect on menstrual pain. These data support that relugolix-CT had clinically meaningful effects on women's experience of uterine leiomyoma–associated pain. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: LIBERTY 1, NCT03049735; LIBERTY 2, NCT03103087. FUNDING SOURCE: Myovant Sciences GmbH.

Abstract Study question To assess the long-term efficacy and safety of once-daily Relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain over two years. Summary answer Relugolix-CT previously demonstrated sustained improvement of endometriosis-associated pain and was generally well tolerated over 52 weeks. Research is ongoing: two-year results will be reported. What is known already SPIRIT 1&2 were international, Phase 3, replicate, randomized, double-blind, placebo-controlled studies of Relugolix-CT (relugolix 40mg, estradiol 1mg, norethisterone acetate 0.5mg) in premenopausal women with moderate-to-severe endometriosis-associated pain, which were followed by the open-label, 80-week, long-term extension. 52-week results showed sustained improvement in dysmenorrhea and non-menstrual pelvic pain (NMPP) with 84.8% and 73.3% of responders, respectively. Efficacy was evidenced by reductions in dysmenorrhea (82.8%,) NMPP (62.9%,) proportion of women using opioids, and improvements in function. Relugolix-CT was generally well tolerated. Bone mineral density (BMD) assessment showed minimal initial decline (<1%) from baseline followed by stabilization from Week 24 to 52. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1&2) were eligible to enroll in an 80-week open-label, single-arm, long-term extension study of safety and efficacy, representing up to 104 weeks of treatment in total. All women enrolled in the long-term extension study received once-daily oral Relugolix-CT. Analyses were performed based on the initial randomized treatment groups in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Participants/materials, setting, methods Primary endpoints are proportion of dysmenorrhea and NMPP responders at Weeks 52 and 104 based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable) and analgesic use. Responders are women who achieved a predefined, clinically meaningful reduction from baseline in NRS score and no increase in analgesic use. Secondary efficacy endpoints include change in Endometriosis Health Profile-30 pain domain scores, use of opioids/analgesics. Safety endpoints include adverse events and BMD (percent change). Main results and the role of chance Of 1251 randomized patients in SPIRIT 1&2, 1044 (83.4%) completed the pivotal studies; 802 (76.8%) enrolled in the long-term extension, and 681 (84.9%) completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the long-term extension population were consistent with those of the pivotal study population. The study remains ongoing at the time of writing. Efficacy and safety data with Relugolix-CT for up to Week 104, will be presented at the scientific session of the 2022 congress. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Wider implications of the findings Through 52 weeks of treatment, Relugolix-CT demonstrated sustained improvement of dysmenorrhea, NMPP, function, and reduced need for opiates in women with endometriosis-associated pain. No new safety concerns were identified, and treatment was associated with BMD loss <1%. Data from 104 weeks of treatment will be presented at the 2022 congress. Trial registration number NCT03654274

Background Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. Methods In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4.0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2.5 or higher, or a mean score of 1.25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received >= 1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. Findings 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47.6% [95% CI 39.3-56.0]; p<0.0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44.9% [95% CI 36.2-53.5]; p<0.0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18.9% [9.5-28.2]; p<0.0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23.4% [95% CI 13.9-32.8]; p<0.0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0.70% versus 0.21% in SPIRIT 1 and -0.78% versus 0.02% in SPIRIT 2, and in the delayed relugolix combination group was -2.0% in SPIRIT 1 and -1.9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. Interpretation Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.

Treatment of uterine fibroids (UF) and endometriosis (EM) has relied on the surgical skills of gynecologists to improve symptoms and potentially alter the course of these debilitating diseases. Medical management of symptoms for both diseases leverages combined hormonal contraceptives used off label as a first-line treatment, with nonsteroid anti-inflammatory drugs and opioids to manage pain as needed. Gonadotropin-releasing hormone (GnRH) receptor agonists (peptide analogs) have been used as short-term therapy to manage severe symptoms of UF or EM, treat anemia, and reduce fibroid size before surgery. The introduction of oral GnRH receptor antagonists opened the door for the development of new treatment options for UF, EM, and other estrogen-driven diseases. Relugolix is an orally active, nonpeptide, GnRH receptor antagonist that competitively binds to GnRH receptors, preventing the release of follicle-stimulating hormone and luteinizing hormone (LH) into the systemic circulation. In women, the reduction in follicle-stimulating hormone concentrations prevents natural follicular development, suppressing ovarian production of estrogen, and together with reductions in LH concentrations, prevent ovulation, corpus luteum formation, and, thereby, the production of progesterone (P). By reducing circulating concentrations of estradiol (E2) and P, relugolix improves heavy menstrual bleeding and other symptoms associated with UF and moderate to severe pain associated with EM, including dysmenorrhea, nonmenstrual pelvic pain (NMPP) and dyspareunia. However, as monotherapy, the use of relugolix is associated with signs and symptoms of a hypoestrogenic state, including bone mineral density loss and vasomotor symptoms. The clinical development of relugolix incorporated the addition of a 1 mg dose of E2 and a 0.5-mg dose of norethindrone acetate (NETA) to achieve systemic E2 concentrations that remain in a therapeutic range while mitigating the risk for bone mineral density loss and vasomotor symptoms, enabling the longer-term treatment and reducing the impact of symptoms on quality of life, and potentially delaying or preventing the need for surgery. Relugolix 40 mg in combination with estradiol (E2) 1 mg and NETA 0.5 mg as a single fixed-dose combination tablet (relugolix combination therapy [relugolix-CT]) approved in the United States as MYFEMBREE is the first and only once daily oral GnRH antagonist combination therapy indicated for the management of heavy menstrual bleeding associated with UF and moderate to severe pain associated with EM. In the European Union (EU) and the United Kingdom (UK), relugolix-CT is approved as RYEQO for the management of symptoms associated with UF. In Japan, relugolix 40 mg, as monotherapy, was the first GnRH receptor antagonist approved to improve symptoms associated with UF or pain associated with EM under the brand name RELUMINA. In men, relugolix suppresses testosterone production. Relugolix 120 mg (ORGOVYX) was developed by Myovant Sciences and is approved in the United States, EU, and UK as the first and only oral androgen-deprivation therapy for the treatment of advanced prostate cancer. This review is focused on the development of relugolix and relugolix-CT in women's health indications.

In women with endometriosis-associated pain, once-daily relugolix combination therapy (Rel-CT) was associated with maintenance of efficacy on dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) through 104 weeks (wks) of treatment (Becker, ESHRE 2022). Here, the time course of when women first reported minimal/no pain for either DYS or NMPP was examined.

Study Objective To evaluate long-term safety and efficacy of relugolix combination therapy (Relugolix-CT) to treat endometriosis-associated pain. Design SPIRIT Extension was a Phase 3, open-label, single-arm, 80-week study. Setting 170 clinical research centers globally. Patients or Participants Premenopausal women (age 18–50 years) with endometriosis, moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP) at baseline who completed the 24-week pivotal studies (SPIRIT 1/2) and were eligible to participate were enrolled. Interventions Once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg). Measurements and Main Results Co-primary endpoints: proportion of dysmenorrhea/NMPP responders at Week 52, using Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable). Dysmenorrhea/NMPP responder: women who achieved a clinically meaningful reduction from baseline in NRS score (2.8/2.1, respectively) without increased analgesic use. Secondary endpoints: change in Endometriosis Health Profile-30 (EHP-30) pain domain scores, analgesic/opioid use. Safety endpoints: adverse events, bone mineral density (BMD) evaluation. Of 1,261 women randomized in SPIRIT 1/2, 802 enrolled in the extension; 681 completed 52 weeks of treatment. Data are reported for women who received Relugolix-CT through 52 weeks. The proportion of responders for dysmenorrhea was 84.8% and 73.3% for NMPP. NRS least squares (LS) mean scores for dysmenorrhea, NMPP and dyspareunia decreased from 7.4 (severe), 6.0 (moderate) and 5.9 (moderate) at pivotal baseline to 1.3 (mild), 2.2 (mild) and 2.4 (mild) at Week 52, equating to 82.8%, 62.9% and 60.1% reductions. Daily functioning (EHP-30 pain domain score) improved (–38.1 point); most women (85.6%) were opioid-free at Week 52. No disproportionate increase in adverse event incidence and no new safety signals were identified. Lumbar spine BMD was preserved, with LS mean change from baseline to Week 52 of –0.81% (95% CI: –1.26, –0.36). Conclusion Relugolix-CT was well tolerated and demonstrated sustained improvement of endometriosis-associated pain and maintenance of BMD through 52 weeks. To evaluate long-term safety and efficacy of relugolix combination therapy (Relugolix-CT) to treat endometriosis-associated pain. SPIRIT Extension was a Phase 3, open-label, single-arm, 80-week study. 170 clinical research centers globally. Premenopausal women (age 18–50 years) with endometriosis, moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP) at baseline who completed the 24-week pivotal studies (SPIRIT 1/2) and were eligible to participate were enrolled. Once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg). Co-primary endpoints: proportion of dysmenorrhea/NMPP responders at Week 52, using Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable). Dysmenorrhea/NMPP responder: women who achieved a clinically meaningful reduction from baseline in NRS score (2.8/2.1, respectively) without increased analgesic use. Secondary endpoints: change in Endometriosis Health Profile-30 (EHP-30) pain domain scores, analgesic/opioid use. Safety endpoints: adverse events, bone mineral density (BMD) evaluation. Of 1,261 women randomized in SPIRIT 1/2, 802 enrolled in the extension; 681 completed 52 weeks of treatment. Data are reported for women who received Relugolix-CT through 52 weeks. The proportion of responders for dysmenorrhea was 84.8% and 73.3% for NMPP. NRS least squares (LS) mean scores for dysmenorrhea, NMPP and dyspareunia decreased from 7.4 (severe), 6.0 (moderate) and 5.9 (moderate) at pivotal baseline to 1.3 (mild), 2.2 (mild) and 2.4 (mild) at Week 52, equating to 82.8%, 62.9% and 60.1% reductions. Daily functioning (EHP-30 pain domain score) improved (–38.1 point); most women (85.6%) were opioid-free at Week 52. No disproportionate increase in adverse event incidence and no new safety signals were identified. Lumbar spine BMD was preserved, with LS mean change from baseline to Week 52 of –0.81% (95% CI: –1.26, –0.36). Relugolix-CT was well tolerated and demonstrated sustained improvement of endometriosis-associated pain and maintenance of BMD through 52 weeks.

Abstract Study question To assess the long-term (52-week) efficacy and safety of relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain. Summary answer Relugolix-CT demonstrated a sustained improvement of endometriosis-associated pain and maintenance of bone mineral density (BMD) over the extension treatment period. It was well tolerated. What is known already Endometriosis is a chronic condition characterized by symptoms of menstrual and non-menstrual pain, and dyspareunia, which have a substantial impact on women’s lives. SPIRIT 1 and 2 were Phase 3, randomized, double-blind, placebo-controlled studies of once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in premenopausal women (age 18–50 years) with surgically diagnosed endometriosis and moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP) at baseline. These trials demonstrated a significant improvement of dysmenorrhea, NMPP and dyspareunia in women treated with Relugolix-CT, with a minimal decline in BMD vs placebo over 24 weeks. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials) were eligible to enroll in an open-label, single-arm, long-term safety and efficacy extension study for an additional 80 weeks. All women received once-daily oral Relugolix-CT. Analyses were done based on original randomization in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40 mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Here, 52-week efficacy and safety outcomes are presented. Participants/materials, setting, methods The primary endpoints were the proportion of dysmenorrhea and NMPP responders at Week 52, based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable). A responder was a woman who achieved a predefined, clinically meaningful reduction from baseline in NRS score with no increase in analgesic use. Secondary efficacy endpoints included change in Endometriosis Health Profile-30 (EHP-30) pain domain scores, and analgesic/opioid use. Safety endpoints included adverse events (AEs) and BMD evaluation. Main results and the role of chance Of 1261 randomized patients, 1044 completed the primary studies; 802 enrolled in the long-term extension and 681 completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the extension population were consistent with those of the original randomized population. Sustained improvement of endometriosis-associated pain was demonstrated with Relugolix-CT through 52 weeks, the proportion of responders for dysmenorrhea was 84.8% and 73.3% for NMPP. NRS least squares (LS) mean scores for dysmenorrhea and NMPP decreased from 7.4 (severe) and 6.0 (moderate) at SPIRIT study baseline to 1.3 (mild) and 2.2 (mild) at Week 52, equating to 82.8% and 62.9% reduction in dysmenorrhea and NMPP, respectively. Mean NRS for dyspareunia decreased from 5.9 (moderate) to 2.4 (mild), demonstrating 60.1% reduction with Relugolix-CT. Daily functioning measured by the EHP-30 pain domain score was improved (–38.1 point) and the majority of women (85.6%) were opioid-free at Week 52. There was no disproportionate increase in the incidence of AEs in the Relugolix-CT group with no new safety signals identified through the 52 weeks. BMD was preserved over the extension period with overall LS mean change from baseline to Week 52 of –0.83% (95% CI: –1.34, –0.32) for lumbar spine in the Relugolix-CT group. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 28 weeks of the extension period. Wider implications of the findings Relugolix-CT demonstrated a sustained improvement of dysmenorrhea, NMPP, and dyspareunia, and reduced pain-related functional limitations and the need for opioids over 52 weeks in women with moderate-to-severe endometriosis-associated pain. Relugolix-CT was generally well tolerated and associated with minimal BMD loss after treatment initiation followed by BMD maintenance over 52 weeks. Trial registration number NCT03654274

In the pivotal LIBERTY 1 and 2 trials and Long-Term Extension (LTE) study, once-daily relugolix combination therapy (Rel-CT: relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) reduced menstrual blood loss (MBL) volume and pain in women with uterine fibroids (UF). Rel-CT was well tolerated, with preservation of bone mineral density (BMD) through 52 weeks. Here we report results of the Phase 3 LIBERTY randomized withdrawal study (RWS), designed to evaluate the efficacy and safety of Rel-CT for up to 2 years. Women with UF-associated heavy menstrual bleeding (HMB) who completed the 24-week LIBERTY 1 or 2 trials and the 28-week LTE study, and who met responder criteria (MBL <80 mL and ≥50% reduction from pivotal study baseline at Week 48 in the LTE study) were randomized 1:1 to blinded treatment with Rel-CT or placebo for up to 52 weeks (total treatment period: 104 weeks). For women who had a relapse of HMB during the study (MBL volume ≥80 mL), treatment with open-label Rel-CT was provided. Primary endpoint was the proportion of women who maintained MBL volume <80 mL at Week 76. Key secondary endpoints included time to MBL volume ≥80 mL, proportion of women who maintained a MBL volume of <80 mL through Week 104 (over the 52-week randomized treatment period), and the proportion of women achieving or maintaining amenorrhea at Week 76/end of treatment. Of the 229 randomized women (Rel-CT: 115, placebo: 114), 228 were treated and 89 (77.4%) and 86 (75.4%) completed the RWS. At Week 76, 78.4% of women on Rel-CT maintained MBL <80 mL vs 15.1% in the placebo group (p<0.0001). Through Week 104, 88.3% of women randomized to placebo at Week 52 relapsed with HMB, with a median time to relapse of 5.9 weeks. Among the 89 women in the placebo group who relapsed and received open-label rescue treatment, 87 women responded to Rel-CT, with an MBL <80 mL. At Week 104, 69.8% of women on Rel-CT maintained MBL <80 mL vs 11.8% in the placebo group (p<0.0001). The proportion of women who achieved or maintained amenorrhea was 57.4% vs 13.3% at Week 76 and 58.3% vs 10.6% at Week 104 for Rel-CT vs the placebo group, respectively (both p<0.0001). Rel-CT was generally well tolerated; no new safety signals were detected, and the adverse event profile was consistent with that reported through 1 year of treatment. BMD remained stable in women who received Rel-CT from Week 52 to Week 104, and cumulative assessment showed that BMD was maintained through 2 years of treatment. After 2 years of treatment with Rel-CT, there was evidence of durability of effect in maintaining low MBL volume in women with symptomatic UF. There was evidence of return of HMB in most women after treatment cessation, which improved upon re-treatment with Rel-CT.