Advertisement

Development of relugolix combination therapy as a medical treatment option for women with uterine fibroids or endometriosis

Open AccessPublished:November 21, 2022DOI:https://doi.org/10.1016/j.xfre.2022.11.010
      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.

      Key Words

      Uterine fibroids (UF) and endometriosis (EM) are diseases with systemic implications and potentially devastating outcomes affecting approximately 7 in 10 women by menopause onset and 1 in 10 (190 million) women of reproductive age globally (
      • Zondervan K.T.
      • Becker C.M.
      • Missmer S.A.
      ,
      • Donnez J.
      • Dolmans M.-M.
      Uterine fibroid management: from the present to the future.
      ,
      • Al-Hendy A.
      • Myers E.R.
      • Stewart E.
      Uterine fibroids: burden and unmet medical need.
      ).
      Approximately 1 in 3 women with UF will request treatment, with heavy menstrual bleeding (HMB) being the most common and debilitating symptom resulting in 18%–30% of gynecological visits in the United States, followed by pain (
      • Donnez J.
      • Dolmans M.-M.
      Uterine fibroid management: from the present to the future.
      ,
      • Al-Hendy A.
      • Myers E.R.
      • Stewart E.
      Uterine fibroids: burden and unmet medical need.
      ). The HMB is often associated with anemia that can cause fatigue and may be life-threatening, leading to hospitalization and sometimes blood transfusion (
      • Nelson A.L.
      • Ritchie J.J.
      Severe anemia from heavy menstrual bleeding requires heightened attention.
      ). The EM symptoms can be broad and are characterized mainly by menstrual pain (dysmenorrhea), nonmenstrual pelvic pain (NMPP), deep pain with intercourse (dyspareunia), lower back pain, painful urination (dysuria), and gastrointestinal symptoms, including painful defecation (dyschezia), constipation, and/or diarrhea, among others (
      • Zondervan K.T.
      • Becker C.M.
      • Missmer S.A.
      ).
      Delay from symptom onset to diagnosis ranges from 4 to 11 years in women with EM worldwide. Women are most likely to be diagnosed with EM when seeking treatment for infertility, representing 20% to 50% of cases (
      • Dmowski W.P.
      • Lesniewicz R.
      • Rana N.
      • Pepping P.
      • Noursalehi M.
      Changing trends in the diagnosis of endometriosis: a comparative study of women with pelvic endometriosis presenting with chronic pelvic pain or infertility.
      ). The UF accounts for an additional 10% of infertility cases, and both conditions, UF and EM, are associated with serious pregnancy-related complications, including miscarriages, preterm delivery, and cesarian delivery.
      Together, UF and EM are considered the leading cause of gynecological hospitalization and hysterectomy in the US. Treatment guidelines support nonsurgical options for the management of symptoms associated with UF and EM that preserve the uterus and avoid repeated surgeries, irrespective of the desire for future pregnancy. Therefore, medical treatment options that are effective and well tolerated may provide women with UF and EM with an alternative to surgical procedures.
      Oral contraceptives, nonsteroid anti-inflammatory drugs, and opioids are often used to treat symptoms of UF and EM. However, evidence demonstrating the effectiveness of these treatments for symptomatic relief of UF and EM is lacking. Women with EM often go through more than one of these medications in an attempt to manage their symptoms.
      The GnRH receptor agonists have been used successfully for the short-term management of symptoms associated with UF and EM; however, their use has several disadvantages (
      ACOG
      Management of symptomatic uterine leiomyomas: ACOG practice bulletin, Number 228.
      ). First, these agents initially stimulate the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and the production of estradiol (E2), thereby worsening the symptoms of UF and EM before the suppression of FSH and LH secretion through desensitization and down-regulation of the pituitary GnRH receptor, thereby reducing systemic E2 concentrations. Second, GnRH agonists are peptides requiring intramuscular or subcutaneous injection. Importantly, GnRH agonists are approved as monotherapy, with a limited treatment duration of up to 6 months because of the risk for bone mineral density (BMD) loss and up to 12 months in combination with NETA.
      Relugolix is an orally active, nonpeptide, GnRH receptor antagonist that competitively and reversibly binds to GnRH receptors in the anterior pituitary, preventing the release of FSH and LH into the systemic circulation (
      • MacLean D.B.
      • Shi H.
      • Suri A.
      • Faessel H.
      • Saad F.
      Safety and testosterone-lowering effects of the investigational, oral, GnRH antagonist, TAK-385 in healthy male volunteers: results of a phase 1 inpatient/outpatient study.
      ,
      • Miwa K.
      • Hitaka T.
      • Imada T.
      • Sasaki S.
      • Yoshimatsu M.
      • Kusaka M.
      • et al.
      Discovery of 1-{4-[1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d] pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
      ,
      • Nakata D.
      • Masaki T.
      • Tanaka A.
      • Yoshimatsu M.
      • Akinaga Y.
      • Asada M.
      • et al.
      Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice.
      ). In women, the reduction in FSH concentrations prevents natural follicular development, suppressing ovarian production of E2, and, together with reductions in LH concentrations, prevents ovulation, corpus luteum formation, and the production of progesterone (P) (Fig. 1). The reduction of E2 and P systemic concentrations by relugolix improves UF- and EM-associated symptoms (
      • Markham A.
      Relugolix: first global approval.
      ,
      • Osuga Y.
      • Enya K.
      • Kudou K.
      • Tanimoto M.
      • Hoshiai H.
      Oral gonadotropin-releasing hormone antagonist relugolix compared with leuprorelin injections for uterine leiomyomas: a randomized controlled trial.
      ,
      • Osuga Y.
      • Enya K.
      • Kudou K.
      • Hoshiai H.
      Relugolix, a novel oral gonadotropin-releasing hormone antagonist, in the treatment of pain symptoms associated with uterine fibroids: a randomized, placebo-controlled, phase 3 study in Japanese women.
      ,
      • Osuga Y.
      • Seki Y.
      • Tanimoto M.
      • Kusumoto T.
      • Kudou K.
      • Terakawa N.
      Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose–response manner: a randomized, double-blind, placebo-controlled study.
      ,
      • Harada T.
      • Osuga Y.
      • Suzuki Y.
      • Fujisawa M.
      • Fukui M.
      • Kitawaki J.
      Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study.
      ). Relugolix 40 mg, under the trade name RELUMINA, was the first GnRH antagonist approved for the improvement of UF-associated symptoms (hypermenorrhea, lower abdominal pain, lower back pain, and anemia) in Japan (January 2019) and EM-associated pain (December 2021) (

      RELUMINA Prescribing Information. 2021.

      ). However, because of the associated hypoestrogenic effects, the approved duration of use is limited to 6 months.
      Figure thumbnail gr1
      Figure 1Mechanism of action of relugolix combination therapy (relugolix 40 mg with E2/NETA 1 mg/0.5 mg). GnRH = gonadotropin-releasing hormone; FSH = follicle-stimulating hormone; LH = luteinizing hormone; E2 = estradiol; NETA = norethindrone acetate; P = progesterone; BMD = bone mineral density; UF = uterine fibroids; EM = endometriosis.
      In April 2016, Myovant Sciences (Myovant) obtained the rights to develop and commercialize relugolix worldwide, except for certain Asian countries, for all diseases and conditions.
      An extensive clinical program demonstrated the efficacy and safety of relugolix and supported approval of ORGOVYX in the United States, UK, and EU as a new option for testosterone suppression in men with prostate cancer (

      ORGOVYX (relugolix) Prescribing Information. ORGOVYX (relugolix) Prescribing Information, FDA. 2020.

      ).
      In women, Myovant pursued the development of relugolix-CT, relugolix 40 mg with E2 (1 mg) and NETA (0.5 mg), as one pill once a day. This approach was based on the idea of achieving an optimal E2 concentration to minimize hypoestrogenic effects associated with relugolix monotherapy, including vasomotor symptoms (eg, hot flashes) and BMD loss, potentially allowing effective long-term management of symptoms associated with UF or EM, improvement of quality of life, and delay/prevention of surgeries in these patients (
      • Friedman A.J.
      • Lobel S.M.
      • Rein M.S.
      • Barbieri R.L.
      Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis.
      ,
      • Barbieri R.L.
      Hormone treatment of endometriosis: the estrogen threshold hypothesis.
      ).
      This review summarizes the milestones of the relugolix-CT development program in women’s health and the resulting key scientific data that supported the approvals of MYFEMBREE for the management of HMB associated with UF and pain associated with EM in the United States and RYEQO for management of symptoms associated with UF in EU and UK (

      MYFEMBREE Prescribing Information. 2022.

      ,
      RYEQO (40 mg relugolix, 1 mg estradiol and 0.5 mg norethisterone acetate).
      ) (Fig. 2) (
      • Giudice L.C.
      • As-Sanie S.
      • Arjona Ferreira J.C.
      • Becker C.M.
      • Abrao M.S.
      • Lessey B.A.
      • et al.
      Relugolix combination therapy in patients with endometriosis pain: two replicate design randomized, double-blind, placebo-controlled phase 3 studies (SPIRIT 1 and SPIRIT 2).
      ).
      Figure thumbnail gr2
      Figure 2Phase 2 and 3 studies to evaluate relugolix combination therapy (international) and monotherapy (Japan) in women with symptoms associated with UF or EM. UF = uterine fibroids; EM = endometriosis; RWS = randomized withdrawal study; LTE = long-term extension. Source: https://clinicaltrials.gov/. Accessed on 30 Aug 2022 (
      • Giudice L.C.
      • As-Sanie S.
      • Arjona Ferreira J.C.
      • Becker C.M.
      • Abrao M.S.
      • Lessey B.A.
      • et al.
      Relugolix combination therapy in patients with endometriosis pain: two replicate design randomized, double-blind, placebo-controlled phase 3 studies (SPIRIT 1 and SPIRIT 2).
      ).

      Clinical pharmacokinetics of relugolix and relugolix combination therapy

      After oral administration, relugolix is rapidly absorbed, reaching an initial peak concentration by 15 minutes postdose, followed by multiple subsequent peaks up to 12 hours postdose; the majority of relugolix is absorbed within 6 hours postdose. The multiple postdose peaks are hypothesized to reflect the variable expression of permeability-glycoprotein (P-gp), an intestinal efflux transporter along the gastrointestinal tract, including other factors such as gastric emptying time. Thereafter, plasma concentrations decline in a multi-phasic manner with a terminal phase elimination half-life of 61.5 hours.
      The absorption of relugolix after oral administration is primarily mediated by P-gp, for which relugolix is a substrate. The intestinal P-gp-mediated efflux of relugolix is thought to limit its oral bioavailability (absolute bioavailability of 11.6%) and governs absorption-mediated drug interactions; therefore, intestinal P-gp is the primary driver of systemic exposure to relugolix. The primary route of elimination of relugolix is metabolism through multiple biotransformation pathways, including CYP3A and CYP2C8, with contributions from renal and biliary excretion of unchanged drug.
      Co-administration of a 40 mg dose of relugolix with erythromycin, an oral P-gp and moderate CYP3A inhibitor, resulted in a 3.5-fold higher total exposure to relugolix, which is clinically meaningful and considered to be primarily based on the inhibition of intestinal P-gp efflux by erythromycin. Given that the mechanism for P-gp inhibition is a competitive and reversible process and most of the absorption of relugolix is complete by 6 hours postdose, it is recommended to administer relugolix first followed by administration of the oral P-gp inhibitor at least 6 hours afterward, when concomitant use of relugolix and an oral P-gp inhibitor cannot be avoided.
      Co-administration of relugolix with voriconazole, a strong CYP3A inhibitor devoid of P-gp inhibition, did not increase the exposure to relugolix in a clinically meaningful manner. However, for relugolix-CT, because both E2 and norethindrone (NET; the active form of NETA) undergo oxidative metabolism by CYP enzymes, including CYP3A4, inhibitors of CYP3A may increase the plasma concentrations of E2 or NET. Combined P-gp and strong CYP3A inducers, such as rifampin, decrease the exposure to relugolix, E2, and/or NET. Therefore, co-administration of relugolix-CT with strong CYP3A4 and P-gp inducers may result in a decrease in the therapeutic effects of relugolix-CT.
      Based on a population pharmacokinetic (PopPK) model developed using relugolix concentration data from across the clinical development program, age did not have a statistically significant effect on the pharmacokinetic parameter estimates for relugolix. Multivariate covariate simulations using the final PopPK model indicated that the effect of the race (Black vs. nonBlack, Asian vs. nonAsian) and body weight on the exposure to relugolix is minimal. In dedicated clinical pharmacology studies, moderate or severe renal impairment and mild or moderate hepatic impairment did not have a clinically meaningful effect on the exposure to relugolix. The effect of end-stage renal disease with or without hemodialysis or severe hepatic impairment has not been evaluated for relugolix. The use of E2 in patients with hepatic disease is contraindicated, and as a result, the administration of relugolix-CT to patients with known hepatic impairment or disease is also contraindicated.
      The physicochemical and pharmacokinetic characteristics of relugolix are provided in Table 1.
      Table 1Pharmacological characteristics of relugolix.
      Generic nameRelugolix
      Other codesTAK-385 and T-1331285 (Takeda codes), RVT-601 (Roivant Sciences code), MVT-601 (Myovant code)
      Chemical name (IUPAC)N-(4-{1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3- (6-methoxypyridazin-3-yl)- 2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidin-6-yl}phenyl)-N'-methoxyurea
      Molecular formulaC29H27F2N7O5S
      Molecular weight623.63
      RouteOral
      Physical propertiesWhite to off-white to light yellow, slightly hygroscopic solid, and practically insoluble in water. In aqueous solutions, it is soluble in 0.1N HCl, sparingly soluble at pH 3.0, slightly soluble at pH 5.0, and practically insoluble at pH 7.0–12.9. In organic solvents, it is freely soluble in dimethyl sulfoxide, soluble in benzyl alcohol, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, acetonitrile, and ethanol.
      Structure
      Mechanism of actionGonadotropin-releasing hormone (GnRH) receptor antagonist
      Absolute bioavailability mean (%CV)11.6 (62%)
      AUC0-inf (ng·hr/mL), mean (SD)
      After single dose administration of relugolix combination therapy.
      198.1 (111.6)
      Cmax (ng/mL), mean (SD)
      After single dose administration of relugolix combination therapy.
      26.0 (18.2)
      Tmax (hr), median (min, max)
      After single dose administration of relugolix combination therapy.
      2.00 (0.25, 5.00)
      DistributionPlasma protein binding is 68% to 71%
      MetabolismCYP3A and, to a lesser extent by CYP2C8 in vitro
      ExcretionApproximately 81% was recovered in feces (4.2% as unchanged) and 4.1% in urine (2.2% as unchanged)
      Terminal phase elimination half-life (t1/2), mean (SD)61.5 (13.2) hr
      AUC = area under the concentration-time curve; AUC0-inf = AUC from time 0 extrapolated to infinity; Cmax = maximum observed concentration; Tmax = time to maximum observed concentration.
      After single dose administration of relugolix combination therapy.

      Pharmacodynamics of relugolix

      Relugolix is an antagonist of the human GnRH receptor that competitively binds to the GnRH receptor with subnanomolar binding affinity. In a phase 1 study, in which single 1- to 80-mg doses of relugolix were administered to healthy premenopausal women, rapid (within hours), dose-dependent (with respect to degree and duration) decreases in circulating concentrations of the pituitary (LH, FSH), and ovarian (E2 and P) hormones were observed. At 24 hours postdose, mean E2 concentrations for the 40- and 80-mg doses of relugolix were similar (30.2 pg/mL and 30.3 pg/mL, respectively), suggesting that doses higher than 40 mg are unlikely to provide further suppression of E2 concentrations with once daily administration. The rapid decrease in pituitary and ovarian hormone concentrations after dosing is consistent with the rapid absorption of relugolix and its mechanism of action as a GnRH receptor antagonist. Notably, relugolix trough concentrations at steady state, the lowest concentration during once daily administration, are 7.5 times the half maximal inhibitory concentration (IC50; 0.32 nM) and approximately equivalent to the IC90 value (2.6 nM) for the GnRH receptor. On multiple-dose administration of relugolix, initial decreases in pituitary and ovarian hormone concentrations are consistently maintained during once daily administration through the 24-hour dosing interval, reflecting a sustained suppression of the hypothalamus-pituitary-gonadal axis. Specifically for E2, mean concentrations on day 14 measured at various postdose time points were consistently low (range: 3.9 to 4.7 pg/mL), demonstrating that after administration of a 40-mg dose of relugolix E2 concentrations are maintained low and stable over the entire 24-hour dosing interval. Collectively, these data demonstrated that decreases in pituitary and ovarian hormone concentrations were achieved at all doses, but doses higher than 40 mg would not achieve greater reductions. Therefore, 10-, 20-, and 40-mg once daily doses were selected for further evaluation in the phase 2 studies in women with UF and EM.

      Relugolix monotherapy in women’s health

      In 2 dose-finding phase 2 studies in women with symptoms associated with UF or EM, respectively, 10-, 20-, or 40-mg doses of relugolix were associated with dose-dependent decreases in menstrual blood loss (MBL) volume in women with UF and pelvic pain in women with EM (
      • Osuga Y.
      • Seki Y.
      • Tanimoto M.
      • Kusumoto T.
      • Kudou K.
      • Terakawa N.
      Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose–response manner: a randomized, double-blind, placebo-controlled study.
      ,

      ClinicalTrials.gov. Available from: https://clinicaltrials.gov. Accessed August 30, 2022.

      ) (Fig. 3). In both studies, relugolix had a safety and tolerability profile characterized by dose-dependent decreases in BMD and greater frequency and severity of vasomotor symptoms (eg, hot flashes). The median E2 serum concentration in the relugolix 40-mg group was reduced to < 10 pg/mL and maintained at that level during the 12-week treatment (

      ClinicalTrials.gov. Available from: https://clinicaltrials.gov. Accessed August 30, 2022.

      ). At the 40-mg dose, relugolix demonstrated significant efficacy compared with placebo in women with UF (

      ClinicalTrials.gov. Available from: https://clinicaltrials.gov. Accessed August 30, 2022.

      ) and significant efficacy relative to placebo and comparable with that observed with leuprorelin in women with EM (
      • Osuga Y.
      • Seki Y.
      • Tanimoto M.
      • Kusumoto T.
      • Kudou K.
      • Terakawa N.
      Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose–response manner: a randomized, double-blind, placebo-controlled study.
      ). In both studies, efficacy with the 40-mg dose was better than that observed with the 20-mg dose. The 40-mg dose was associated with vasomotor symptoms in 39% of women with UF and 52% of women with EM (vs. 3.5% and 8.2% for placebo, respectively). Based on these results, the 40-mg QD dose of relugolix was selected to be evaluated in phase 3 studies.
      Figure thumbnail gr3
      Figure 3Relugolix monotherapy in women with uterine fibroids. (A) Percent of women achieving a pictorial blood assessment chart tcore of < 10 from week 6 to week 12 of treatment with placebo or relugolix (10, 20, or 40 mg); all relugolix groups statistically significant vs. placebo, P< .001. (B) Mean change from baseline in the visual analog scale score for pelvic pain for 28 days before the end of the treatment period; relugolix groups statistically significant vs placebo, 10 mg, 20 mg (P<.05) and 40 mg (P<.0001). (From Hoshiai et al. (

      ClinicalTrials.gov. Available from: https://clinicaltrials.gov. Accessed August 30, 2022.

      ). Reprinted by permission of the BMC Women’s Health) and (From Osuga et al. (
      • Osuga Y.
      • Seki Y.
      • Tanimoto M.
      • Kusumoto T.
      • Kudou K.
      • Terakawa N.
      Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose–response manner: a randomized, double-blind, placebo-controlled study.
      ). Reprinted by permission of the publisher.).
      Takeda continued development with phase 3 studies in Japan and obtained approval for relugolix for the treatment of UF- and EM-associated symptoms (
      • Markham A.
      Relugolix: first global approval.
      ,
      • Osuga Y.
      • Enya K.
      • Kudou K.
      • Tanimoto M.
      • Hoshiai H.
      Oral gonadotropin-releasing hormone antagonist relugolix compared with leuprorelin injections for uterine leiomyomas: a randomized controlled trial.
      ,
      • Osuga Y.
      • Enya K.
      • Kudou K.
      • Hoshiai H.
      Relugolix, a novel oral gonadotropin-releasing hormone antagonist, in the treatment of pain symptoms associated with uterine fibroids: a randomized, placebo-controlled, phase 3 study in Japanese women.
      ,
      • Harada T.
      • Osuga Y.
      • Suzuki Y.
      • Fujisawa M.
      • Fukui M.
      • Kitawaki J.
      Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study.
      ).
      Although the decreases in systemic E2 concentrations by relugolix resulted in symptomatic relief in patients with UF and EM, they were also associated with hypoestrogenic symptoms. Reported adverse events associated with relugolix monotherapy were consistent with the class effects associated with suppression of ovarian hormone production by GnRH receptor agonists and antagonists, including hot flashes and BMD loss. To enable the potential for a long-term treatment option with relugolix, Myovant pursued a different approach for development that mitigated these negative effects of a hypoestrogenic state.

      Relugolix combination therapy in women’s health

      In parallel with the phase 3 program of relugolix monotherapy in Japan, the development of relugolix-CT was envisioned to demonstrate significant symptom relief in women with UF or EM while maintaining E2 concentrations within a range that minimizes the effects of hypoestrogenism associated with relugolix monotherapy, leading to BMD loss and vasomotor symptoms.
      On administration of relugolix 40 mg alone or relugolix-CT once daily for 6 weeks in healthy premenopausal women, median 24-hour average E2 concentrations were 26 pg/mL higher for relugolix-CT compared with relugolix alone (31.5 pg/mL and 6.2 pg/mL, respectively). The E2 concentrations with relugolix-CT reflect the combined effect of suppression of endogenous E2 production by relugolix and exogenous administration of 1 mg of E2 as a component of relugolix-CT. They are consistent with those observed in the early follicular phase of a natural menstrual cycle and fall within the hypothesized range (ie, 20 to 50 pg/mL) required to minimize BMD loss, enabling the potential for long-term treatment of symptoms of UF (
      • Friedman A.J.
      • Lobel S.M.
      • Rein M.S.
      • Barbieri R.L.
      Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis.
      ) or EM (
      • Barbieri R.L.
      Hormone treatment of endometriosis: the estrogen threshold hypothesis.
      ). An open-label, single-cohort study in healthy premenopausal women was conducted to assess the effects of relugolix-CT on ovarian function over an 84-day treatment period and the return of ovulation after discontinuation of treatment. Relugolix-CT inhibited ovulation in 100% of the 67 women who completed the study treatment, with a Hoogland-Skouby Score < 5 during the entire 84-day treatment period. The systemic LH and FSH concentrations were consistently maintained low without preovulatory LH surges during treatment. The addition of a 1 mg dose of E2 as a component of relugolix-CT resulted in median E2 concentrations across all women consistently maintained between 36.8 to 39.1 pg/mL during treatment. All women ovulated or returned to menses after discontinuation of treatment, with a mean time to return to ovulation of 23.5 days (
      • Hoshiai H.
      • Seki Y.
      • Kusumoto T.
      • Kudou K.
      • Tanimoto M.
      Relugolix for oral treatment of uterine leiomyomas: a dose-finding, randomized, controlled trial.
      ). In summary, relugolix-CT was associated with a rapid onset of action, effectively suppressed ovarian function in women of reproductive age, with a rapid return of ovulation within the first cycle after discontinuation of treatment in most women. Relugolix-CT provided systemic E2 concentrations within a therapeutic range that is expected to effectively manage symptoms associated with UF and EM while minimizing the risk for BMD loss and vasomotor symptoms.
      To demonstrate the safety and efficacy of once daily oral relugolix-CT for the management of UF- or EM-associated symptoms, 2 comprehensive phase 3 clinical programs were designed. The LIBERTY and SPIRIT programs included each 2 replicate, randomized, double-blind, placebo-controlled, multinational, phase 3 studies, with similar designs in premenopausal women 18 to 50 years of age with HMB (defined as MBL volume of > 80 ml) associated with UF or moderate to severe pain associated with EM, respectively (Fig. 4). These patients were randomly allocated (1:1:1) to placebo or relugolix-CT for 24 weeks or to delayed combination therapy (12 weeks relugolix 40 mg monotherapy followed by 12 weeks relugolix-CT therapy).
      Figure thumbnail gr4
      Figure 4Replicate, double-blind, randomized, placebo-controlled, multinational, phase 3 studies to evaluate relugolix-CT in women with HMB associated with uterine fibroids (LIBERTY) or endometriosis-associated pain (SPIRIT). Relugolix-CT = relugolix combination therapy; HMB = heavy menstrual bleeding.
      In LIBERTY 1 (L1) and 2 (L2) studies, respectively, 388 and 382 premenopausal women with UF-associated HMB were randomized (
      • Duijkers I.
      • Migoya E.M.
      • Arjona Ferreira J.C.
      • Klipping C.
      Characterization of pituitary and ovarian hormone concentrations during treatment with relugolix combination therapy.
      ). The proportion of patients with MBL volume of < 80 mL and at least a 50% reduction from baseline in MBL volume over the last 35 days of treatment, the primary endpoint in these studies, was significantly higher (P<.001) in the relugolix-CT group (73% in L1 and 71% in L2) relative to the placebo group (19% in L1 and 15% in L2) (Fig. 5). Seven key secondary endpoints were evaluated in both trials (Table 2), of which 6 endpoints (MBL measures, including amenorrhea, pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume but not fibroid volume) were significantly improved with relugolix-CT compared with placebo in both studies. The mean percent decrease in MBL volume from baseline, a key secondary endpoint, was 84.3% in the relugolix-CT group in both trials compared with 23.2% and 15.1% in the placebo group (P<.001 each) in L1 and L2, respectively. In a secondary analysis of L1 and L2 pooled data, relugolix-CT significantly reduced moderate to severe UF-associated pain in 45.2% of the women compared with 13.9% of women treated with placebo (nominal P<.001) with a significant effect on both menstrual (65.0% relugolix-CT vs. 19.3% placebo; nominal P<.001) and nonmenstrual pain (44.6% relugolix-CT vs. 21.6% placebo; nominal P=.004) (
      • Al-Hendy A.
      • Lukes A.S.
      • Poindexter A.N.
      • Venturella R.
      • Villarroel C.
      • Critchley H.O.D.
      • et al.
      Treatment of uterine fibroid symptoms with relugolix combination therapy [Supplementary Appendix].
      ). Overall, relugolix-CT was well tolerated, with an incidence of adverse events similar to those observed with a placebo. Vasomotor symptoms, including hot flashes, were the most frequently reported adverse events in the relugolix-CT group (10.6%) and at a higher incidence than in the placebo group (6.6%) in pooled data from both trials (Table 3).
      Figure thumbnail gr5
      Figure 5Primary endpoint for LIBERTY 1 and 2 studies. The proportion of women responding with MBL volume < 80 mL and ≥ 50% reduction from baseline to week 24 (last 35 days of treatment) in MBL volume. MBL volume measured by alkaline hematin method. Error bars show an upper limit of 95% confidence interval; analysis was conducted using Cochran–Mantel–Haenszel test statistic for proportions stratified by mean MBL at baseline mean and geographic region. MBL = menstrual blood loss; Relugolix-CT = Relugolix Combination Therapy. (From Al-Hendy et al. (
      • Duijkers I.
      • Migoya E.M.
      • Arjona Ferreira J.C.
      • Klipping C.
      Characterization of pituitary and ovarian hormone concentrations during treatment with relugolix combination therapy.
      ). Reprinted by permission of the publisher.).
      Table 2LIBERTY 1 and 2 key secondary efficacy endpoints.
      Key secondary efficacy endpointsPlaceboRelugolix-CTDifference (95% CI)P value
      LS mean (SE)%LS mean (SE)%
      Amenorrhea over last 35 d of treatment periodL165247 (37 to 56)<.001
      L235047 (38 to 57)<.001
      Menstrual blood loss volume (% change from baseline at wk24)L1–23.2 (4.6)–84.3 (4.7)−61.1 (−73.5 to −48.6)<.001
      L2–15.1 (5.5)–84.3 (5.5)−69.2 (−84.1 to −54.3)<.001
      Bleeding and Pelvic Discomfort scale score (change from baseline at wk24)L1−16.1 (2.8)−45.0 (2.9)−28.9 (−36.3 to −21.5)<.001
      L2−18.3 (2.9)−51.7 (2.9)33.4 (−41.2 to −25.5)<.001
      Participants with anemia at baseline and an increase in hemoglobin level of >2 g/dl at wk 24
      Calculated in the subgroup of participants with anemia (hemoglobin level ≤10.5 g per deciliter) at baseline with hemoglobin data reported at week 24, it was tested as the fourth in trial L1 and fifth in trial L2.
      L1225028 (4 to 53).038
      L256156 (37 to 75)<.001
      Maximum NRS score ≤1 over last 35 days of treatment period among participants in pain-evaluation subgroup
      Calculated in the subgroup of participants with pain ratings that could be evaluated (maximum NRS score of ≥4 at baseline, with ≥28 days [80% of the last 35 days of the treatment period] of pain scores recorded in an electronic diary); it was tested as the fifth in trial L1 and fourth in trial L2.
      L1104333 (18 to 48)<.001
      L2174730 (16 to 44)<.001
      Volume of primary uterine fibroid (% change from baseline at wk24)
      P-value did not meet the cutoff for statistical significance according to the Hochberg procedure.
      L1−0.3 (5.4)−12.4 (5.6)−12.1 (−26.3 to 2.0).092
      L2−7.4 (5.9)−17.4 (5.9)−10.0 (−25.8 to 5.8).215
      Uterine volume (% change from baseline at wk24)L12.2 (3.0)−12.9 (3.1)−15.1 (−23.0 to −7.3)<.001
      L2−1.5 (3.4)−13.8 (3.4)−12.2 (−21.3 to −3.2).008
      Data are n (%) or least squares mean (SE) unless otherwise stated. Changes from baseline at week 24 with adjustment for multiplicity.
      L1 = LIBERTY 1; L2 = LIBERTY 2; LS = least squares; SE = standard error; CI = confidence interval; NRS = Numerical Rating Scale. The first 4 (L1) and the first 3 and fifth (L2) end points were tested sequentially in the order listed, and the remaining ones were tested using the Hochberg step-up procedure.
      Adapted from N Engl J Med, Al-Hendy A, Lukes AS, Poindexter AN, Venturella R, Villarroel C, Critchley HOD, et al., Treatment of uterine fibroid symptoms with relugolix combination therapy, 384:630–42. Copyright © (2021) Massachusetts Medical Society. Reprinted with permission. (
      • Duijkers I.
      • Migoya E.M.
      • Arjona Ferreira J.C.
      • Klipping C.
      Characterization of pituitary and ovarian hormone concentrations during treatment with relugolix combination therapy.
      )
      Calculated in the subgroup of participants with anemia (hemoglobin level ≤10.5 g per deciliter) at baseline with hemoglobin data reported at week 24, it was tested as the fourth in trial L1 and fifth in trial L2.
      Calculated in the subgroup of participants with pain ratings that could be evaluated (maximum NRS score of ≥4 at baseline, with ≥28 days [80% of the last 35 days of the treatment period] of pain scores recorded in an electronic diary); it was tested as the fifth in trial L1 and fourth in trial L2.
      § P-value did not meet the cutoff for statistical significance according to the Hochberg procedure.
      Table 3Adverse reactions occurring in 3% or more of women treated with relugolix-CT and at a greater incidence than placebo in studies LIBERTY 1 and 2.
      Adverse ReactionRelugolix-CT (N = 254) %Placebo (N = 256) %
      Vasomotor symptoms
      Includes hot flashes, hyperhidrosis, or night sweats
      10.66.6
      Abnormal uterine bleeding
      Includes menorrhagia, metrorrhagia, vaginal hemorrhage, polymenorrhea, and irregular menstruation
      6.31.2
      Alopecia3.50.8
      Libido decreased
      Includes decreased libido and loss of libido. Relugolix-CT = relugolix combination therapy.
      3.10.4
      From: MYFEMBREE Prescribing Information (

      MYFEMBREE Prescribing Information. 2022.

      ).
      Includes hot flashes, hyperhidrosis, or night sweats
      Includes menorrhagia, metrorrhagia, vaginal hemorrhage, polymenorrhea, and irregular menstruation
      Includes decreased libido and loss of libido. Relugolix-CT = relugolix combination therapy.
      In the phase 3 SPIRIT 1 (S1) and 2 (S2) studies, respectively, 638 and 623 women with moderate to severe EM-associated pain were randomized. Patients were considered responders if they achieved a mean reduction in Numerical Rating Scale scores of ≥ 2.8 points for dysmenorrhea or ≥ 2.1 points for NMPP with no increase in the use of analgesic medications recorded in a daily eDiary at week 24 or at the end of the treatment pain-assessment period. Significantly higher (P<.0001) proportion of patients (75%) in the relugolix-CT group in both studies met the dysmenorrhea responder criteria compared with the placebo group (27% in S1 and 30% in S2) (Fig. 6) (
      • Stewart E.A.
      • Lukes A.S.
      • Venturella R.
      • Arjona Ferreira J.-C.
      • Li Y.
      • Hunsche E.
      • et al.
      Relugolix combination therapy for uterine leiomyoma–associated pain in the LIBERTY randomized trials.
      ). Similarly, a significantly greater proportion of patients (P<.0001) met the NMPP responder criteria in the relugolix-CT groups (59% in S1 and 66% in S2) compared with the placebo groups (40% in S1 and 43% in S2). All secondary endpoints were met in S1, and 6 of 7 key secondary endpoints were met in S2 (Table 4). Relugolix-CT significantly reduced the effect of pain on daily function, assessed by the Endometriosis Health Profile questionnaire (EHP-30) pain domain at week 24 relative to placebo. The mean dysmenorrhea Numerical Rating Scale score rapidly decreased from severe pain at baseline to mild pain by week 8, and this improvement was sustained through week 24, with a decrease from baseline of 73% and 75%, in S1 and S2, respectively. The NMPP also decreased with relugolix-CT, approximately 50%, from moderate pain at baseline to mild pain over 24 weeks in both trials. Relugolix-CT achieved significant improvement in dyspareunia with a mean reduction of 40% and 46% from baseline in S1 and S2, respectively. Significantly higher proportions of women in the relugolix-CT groups were analgesic-free and/or opioid-free at week 24 compared with those in the placebo group. The most common adverse events were headache, nasopharyngitis, and vasomotor symptoms, including hot flashes, as most frequent in both trials (Table 5).
      Figure thumbnail gr6
      Figure 6Co-Primary Endpoints for SPIRIT 1 and 2 Studies: Dysmenorrhea and Nonmenstrual Pelvic Pain. Error bars show an upper limit of 95% confidence intervals. ∗No increase in analgesic use. Relugolix-CT = relugolix combination therapy; NRS = Numerical Rating Scale. (From Giudice et al. (
      • Stewart E.A.
      • Lukes A.S.
      • Venturella R.
      • Arjona Ferreira J.-C.
      • Li Y.
      • Hunsche E.
      • et al.
      Relugolix combination therapy for uterine leiomyoma–associated pain in the LIBERTY randomized trials.
      ). Reprinted by permission of the Lancet.)
      Table 4SPIRIT 1 and 2 co-primary and key secondary efficacy endpoints.
      PlaceboRelugolix-CTDifference (95% CI)P value
      LS mean (SE)%LS mean (SE)%
      Dysmenorrhea respondersS1277548 (39 to 56)<.0001
      S2307544.9 (36.2 to 53.5)<.0001
      Nonmenstrual pelvic pain respondersS1405918.9 (9.5 to 28.2)<.0001
      S2436623.4 (14.0 to 32.8)<.0001
      Change in EHP-30 pain domain∗S1–18.7 (1.8)–33.8 (1.8)–15·1 (–19.7 to –10.5)<.0001
      S2–19.9 (1.7)–32.2 (1.7)–12.3 (–16.7 to –7.9)<.0001
      Change in dysmenorrhea NRSS1–1.8 (0.2)–5.1 (0.2)–3.3 (–3.8 to –2.8)<.0001
      S2–2.0 (0.2)–5.1 (0.2)–3.2 (–3.7, too –2.7)<.0001
      Change in nonmenstrual pelvic pain NRSS1–2.0 (0.2)–2.9 (0.2)–0·9 (–1.4 to –0.4).0002
      S2–2.0 (0.2)–2.7 (0.2)–0·7 (–1.2 to –0.3).0012
      Change in overall pelvic pain NRSS1–1.9 (0.2)–3.1 (0.2)–1·1 (–1.6 to –0.7)<.0001
      S2–2.0 (0.2)–2.9 (0.2)–0.9 (–1.4 to –0.5)<.0001
      Patients not using opioids during treatmentS176869.4 (2.0 to 16.8).0005
      S2668215.9 (7.5 to 24.2)<.0001
      Change in dyspareunia NRSS1–1.7 (0.2)–2.4 (0.2)–0.7 (–1.3 to –0.1).0149
      S21.9 (0.2)–2.4 (0.2)–0.5 (–1.0 to 0.0).0371
      Patients not using analgesics for endometriosis-associated pain during treatmentS1315625.5 (16.4 to 34.6)<.0001
      S2245430.8 (21.9 to 39.8)<.0001
      Change in daily analgesic useS1–0.4 (0.1)–0.5 (0.1)–0.1 (–0.3 to 0.1).4094
      S2–0.4 (0.1)–0.5 (0.1)–0·1 (–0.3 to 0.0).1141
      Data are n (%) or least squares mean (SE) unless otherwise stated. Changes from baseline at week 24. Relugolix-CT = relugolix combination therapy; S1 = SPIRIT 1; S2 = SPIRIT 2; LS = least squares; SE = standard error; CI = confidence interval; NRS = Numerical Rating Scale. EHP-30 = Endometriosis Health Profile∗ 30-item questionnaire to evaluate the effect of pain on normal daily activity, including the ability to stand, sit, walk, exercise, sleep, participate in social events and jobs, and the effect on appetite. SPIRIT2 and SPIRIT 1, data from a post-hoc exploratory analysis.
      Adapted from The Lancet, Giudice LC, As-Sanie S, Arjona Ferreira JC, Becker CM, Abrao MS, Lessey BA, et al, Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: 2 replicate phase 3, randomized, double-blind, studies (SPIRIT 1 and 2), 2022;399:2267–79. Creative Commons License (CC BY 4.0). (
      • Stewart E.A.
      • Lukes A.S.
      • Venturella R.
      • Arjona Ferreira J.-C.
      • Li Y.
      • Hunsche E.
      • et al.
      Relugolix combination therapy for uterine leiomyoma–associated pain in the LIBERTY randomized trials.
      )
      Table 5Adverse reactions occurring in 3% or more of women treated with relugolix-CT and at a greater incidence than placebo in studies SPIRIT 1 and 2.
      Adverse ReactionRelugolix-CT (N = 418) %Placebo (N = 416) %
       Headache33.026.4
      Vasomotor symptoms
      Includes hot flashes, hyperhidrosis, night sweats, and flushing.
      13.27.2
       Nasopharyngitis10.07.0
       Mood disorders
      Includes affect lability, affective disorder, anxiety, depressed mood, depression, emotional distress, generalized anxiety disorder, irritability, mixed anxiety and depressive disorder, mood altered, mood swings, and suicidal ideation
      9.17.2
      Abnormal uterine bleeding
      Includes menorrhagia, metrorrhagia, vaginal hemorrhage, uterine hemorrhage, polymenorrhea, and menstruation irregular
      6.74.6
       Nausea6.04.1
       Toothache5.52.4
       Back pain4.82.9
      Decreased sexual desire and arousal
      Includes libido decreased, libido disorder, and female sexual arousal disorder. Relugolix-CT = relugolix combination therapy.
      4.31.2
       Bone density decreased3.82.2
       Urinary tract infection3.62.6
      Arthralgia3.62.2
      Influenza3.32.4
      Fatigue3.12.4
      Dizziness3.11.2
      From: MYFEMBREE Prescribing Information (

      MYFEMBREE Prescribing Information. 2022.

      ).
      Includes hot flashes, hyperhidrosis, night sweats, and flushing.
      Includes affect lability, affective disorder, anxiety, depressed mood, depression, emotional distress, generalized anxiety disorder, irritability, mixed anxiety and depressive disorder, mood altered, mood swings, and suicidal ideation
      Includes menorrhagia, metrorrhagia, vaginal hemorrhage, uterine hemorrhage, polymenorrhea, and menstruation irregular
      § Includes libido decreased, libido disorder, and female sexual arousal disorder. Relugolix-CT = relugolix combination therapy.
      In general, relugolix-CT minimized the incidence of hot flashes associated with relugolix monotherapy. In studies L1 and L2, and S1 and S2, hot flashes were reported in 3% to 10% of the participants in the placebo groups, 6% to 14% of those in the relugolix-CT groups, and 34% to 36 % of those in the delayed relugolix-CT groups (
      • Duijkers I.
      • Migoya E.M.
      • Arjona Ferreira J.C.
      • Klipping C.
      Characterization of pituitary and ovarian hormone concentrations during treatment with relugolix combination therapy.
      ,
      • Stewart E.A.
      • Lukes A.S.
      • Venturella R.
      • Arjona Ferreira J.-C.
      • Li Y.
      • Hunsche E.
      • et al.
      Relugolix combination therapy for uterine leiomyoma–associated pain in the LIBERTY randomized trials.
      ).
      To evaluate the benefit/risk profile and demonstrate the long-term safety of relugolix-CT, changes in BMD were assessed. Overall, least squares mean percentage change in lumbar spine BMD from baseline in the relugolix-CT groups was < 1% in all 4 studies, and in the delayed relugolix-CT group was -1.82% in L1, -2.12% in L2, –2.0% in S1, and –1.9% in S2 at week 24. As expected, lumbar spine and total hip BMD decreased from baseline with relugolix monotherapy at week 12 but stabilized after relugolix-CT initiation (Fig. 7) (
      • Duijkers I.
      • Migoya E.M.
      • Arjona Ferreira J.C.
      • Klipping C.
      Characterization of pituitary and ovarian hormone concentrations during treatment with relugolix combination therapy.
      ,
      • Stewart E.A.
      • Lukes A.S.
      • Venturella R.
      • Arjona Ferreira J.-C.
      • Li Y.
      • Hunsche E.
      • et al.
      Relugolix combination therapy for uterine leiomyoma–associated pain in the LIBERTY randomized trials.
      ).
      Figure thumbnail gr7
      Figure 7LS Mean Percent Change in Lumbar Spine BMD from LIBERTY 1 and 2 (A) and SPIRIT 1 and 2 (B) studies. Error bars show the upper and lower limit of 95% confidence intervals. Delayed relugolix-CT = 12 weeks relugolix monotherapy, then 12 weeks relugolix-CT. BMD = bone mineral density; relugolix-CT = relugolix combination therapy. A (From Al-Hendy et al. (
      • Duijkers I.
      • Migoya E.M.
      • Arjona Ferreira J.C.
      • Klipping C.
      Characterization of pituitary and ovarian hormone concentrations during treatment with relugolix combination therapy.
      ). Reprinted by permission of the publisher.) (
      • Duijkers I.
      • Migoya E.M.
      • Arjona Ferreira J.C.
      • Klipping C.
      Characterization of pituitary and ovarian hormone concentrations during treatment with relugolix combination therapy.
      ). B – (From Giudice et al. (
      • Stewart E.A.
      • Lukes A.S.
      • Venturella R.
      • Arjona Ferreira J.-C.
      • Li Y.
      • Hunsche E.
      • et al.
      Relugolix combination therapy for uterine leiomyoma–associated pain in the LIBERTY randomized trials.
      ). Reprinted by permission of the Lancet.).
      These 4 phase 3 pivotal trials showed that relugolix-CT reduced the UF-associated HMB and EM-associated pain when compared with placebo, without substantive hypoestrogenic effects, over a 24-week period.
      Both programs had extension periods comprising women treated with relugolix-CT for up to 104 weeks (Fig. 4). Eligibility criteria excluded women who had a Z-score < –2.0 or had a ≥ 7% BMD decrease from the pivotal study baseline at lumbar spine, total hip, or femoral neck based on the pivotal study week 24 dual-energy X-ray absorptiometry assessment of BMD. These long-term extension studies demonstrated sustained efficacy with symptom control without new safety signals identified over a longer treatment period. In the LIBERTY program, women who participated and met the responder criteria at one year in the long-term extension study were eligible to enroll in a randomized withdrawal study. The study evaluated efficacy and safety in patients re-randomized 1:1 to continue with blinded treatment with relugolix-CT or switch to placebo for up to additional 52 weeks, totaling 104 weeks. There was evidence of the durability of the effect in maintaining low MBL volume in women who continued with relugolix-CT. The HMB returned in most women who received a placebo. Re-treatment with relugolix-CT in women with HMB relapse was associated with a reduction in MBL volume to < 80 mL. No meaningful changes in BMD or new safety signals were observed with relugolix-CT over the 52-week treatment period.
      In phase 3 pivotal and long-term extension LIBERTY and SPIRIT studies, relugolix-CT provided sustained symptom relief to women with UF and EM, respectively, while maintaining BMD.
      The Food and Drug Administration approved relugolix-CT, as MYFEMBREE, for the management of HMB associated with UF on 26 May 2021 and the management of moderate to severe pain associated with EM on 5 August 2022 in premenopausal women, with a treatment duration up to 24 months (

      MYFEMBREE Prescribing Information. 2022.

      ). Relugolix-CT was approved for the management of symptoms associated with UF in the EU and UK, as RYEQO, in July and August 2021, respectively (
      RYEQO (40 mg relugolix, 1 mg estradiol and 0.5 mg norethisterone acetate).
      ).
      A study (SERENE, NCT04756037) assessing the contraceptive efficacy and safety of relugolix-CT in women with UF and EM who are at risk for pregnancy is currently ongoing.

      Conclusion

      In summary, the comprehensive development program of relugolix led to the approval of the first and only once daily GnRH receptor antagonist combination product indicated for the management of both HMB associated with UF and moderate to severe pain associated with EM.

      Acknowledgments

      The authors thank Juscilene Menezes, Ph.D., an employee of Myovant Sciences, for the medical writing and editing assistance provided in compliance with Good Publication Practice 3 ethical guidelines. They thank Viatcheslav (Slava) Rakov, MD, an employee of Myovant Sciences, for his critical review of the manuscript.

      References

        • Zondervan K.T.
        • Becker C.M.
        • Missmer S.A.
        Endometriosis. N Engl J Med. 2020; 382: 1244-1256
        • Donnez J.
        • Dolmans M.-M.
        Uterine fibroid management: from the present to the future.
        Hum Reprod Update. 2016; 22: 665-686
        • Al-Hendy A.
        • Myers E.R.
        • Stewart E.
        Uterine fibroids: burden and unmet medical need.
        Semin Reprod Med. 2017; 35: 473-480
        • Nelson A.L.
        • Ritchie J.J.
        Severe anemia from heavy menstrual bleeding requires heightened attention.
        Am J Obstet Gynecol. 2015; 213 (97.e1–97.e6)
        • Dmowski W.P.
        • Lesniewicz R.
        • Rana N.
        • Pepping P.
        • Noursalehi M.
        Changing trends in the diagnosis of endometriosis: a comparative study of women with pelvic endometriosis presenting with chronic pelvic pain or infertility.
        Fertil Steril. 1997; 67: 238-243
        • ACOG
        Management of symptomatic uterine leiomyomas: ACOG practice bulletin, Number 228.
        Obstet Gynecol. 2021; 137: e100-e115
        • MacLean D.B.
        • Shi H.
        • Suri A.
        • Faessel H.
        • Saad F.
        Safety and testosterone-lowering effects of the investigational, oral, GnRH antagonist, TAK-385 in healthy male volunteers: results of a phase 1 inpatient/outpatient study.
        in: SAT 292-325-Breast & Prostate Cancer. (Moscone Center): Endocrine Society, San Francisco, CA2013
        • Miwa K.
        • Hitaka T.
        • Imada T.
        • Sasaki S.
        • Yoshimatsu M.
        • Kusaka M.
        • et al.
        Discovery of 1-{4-[1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d] pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
        J Med Chem. 2011; 54: 4998-5012
        • Nakata D.
        • Masaki T.
        • Tanaka A.
        • Yoshimatsu M.
        • Akinaga Y.
        • Asada M.
        • et al.
        Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice.
        Eur J Pharmacol. 2014; 723: 167-174
        • Markham A.
        Relugolix: first global approval.
        Drugs. 2019; 79: 675-679
        • Osuga Y.
        • Enya K.
        • Kudou K.
        • Tanimoto M.
        • Hoshiai H.
        Oral gonadotropin-releasing hormone antagonist relugolix compared with leuprorelin injections for uterine leiomyomas: a randomized controlled trial.
        Obstet Gynecol. 2019; 133: 423-433
        • Osuga Y.
        • Enya K.
        • Kudou K.
        • Hoshiai H.
        Relugolix, a novel oral gonadotropin-releasing hormone antagonist, in the treatment of pain symptoms associated with uterine fibroids: a randomized, placebo-controlled, phase 3 study in Japanese women.
        Fertil Steril. 2019; 112: 922-929.e2
        • Osuga Y.
        • Seki Y.
        • Tanimoto M.
        • Kusumoto T.
        • Kudou K.
        • Terakawa N.
        Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose–response manner: a randomized, double-blind, placebo-controlled study.
        Fertil Steril. 2021; 115: 397-405
        • Harada T.
        • Osuga Y.
        • Suzuki Y.
        • Fujisawa M.
        • Fukui M.
        • Kitawaki J.
        Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study.
        Fertil Steril. 2022; 117 (S0015028221022147)
      1. RELUMINA Prescribing Information. 2021.

      2. ORGOVYX (relugolix) Prescribing Information. ORGOVYX (relugolix) Prescribing Information, FDA. 2020.

        • Friedman A.J.
        • Lobel S.M.
        • Rein M.S.
        • Barbieri R.L.
        Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis.
        Am J Obstet Gynecol. 1990; 163: 1114-1119
        • Barbieri R.L.
        Hormone treatment of endometriosis: the estrogen threshold hypothesis.
        Am J Obstet Gynecol. 1992; 166: 740-745
      3. MYFEMBREE Prescribing Information. 2022.

      4. RYEQO (40 mg relugolix, 1 mg estradiol and 0.5 mg norethisterone acetate).
        Summary of product characteristics. 2021;
      5. ClinicalTrials.gov. Available from: https://clinicaltrials.gov. Accessed August 30, 2022.

        • Hoshiai H.
        • Seki Y.
        • Kusumoto T.
        • Kudou K.
        • Tanimoto M.
        Relugolix for oral treatment of uterine leiomyomas: a dose-finding, randomized, controlled trial.
        BMC Womens Health. 2021; 21: 375
        • Duijkers I.
        • Migoya E.M.
        • Arjona Ferreira J.C.
        • Klipping C.
        Characterization of pituitary and ovarian hormone concentrations during treatment with relugolix combination therapy.
        Fertil Steril. 2020; 114: e81
        • Al-Hendy A.
        • Lukes A.S.
        • Poindexter A.N.
        • Venturella R.
        • Villarroel C.
        • Critchley H.O.D.
        • et al.
        Treatment of uterine fibroid symptoms with relugolix combination therapy [Supplementary Appendix].
        N Engl J Med. 2021; 384: 630-642
        • Stewart E.A.
        • Lukes A.S.
        • Venturella R.
        • Arjona Ferreira J.-C.
        • Li Y.
        • Hunsche E.
        • et al.
        Relugolix combination therapy for uterine leiomyoma–associated pain in the LIBERTY randomized trials.
        Obstet Gynecol. 2022; 139: 1070-1081
        • Giudice L.C.
        • As-Sanie S.
        • Arjona Ferreira J.C.
        • Becker C.M.
        • Abrao M.S.
        • Lessey B.A.
        • et al.
        Relugolix combination therapy in patients with endometriosis pain: two replicate design randomized, double-blind, placebo-controlled phase 3 studies (SPIRIT 1 and SPIRIT 2).
        Lancet. 2022; 399: 2267-2279