Development of relugolix combination therapy as a medical treatment option for women with uterine fibroids or endometriosis
Juan Camilo Arjona Ferreira, Elizabeth Migoya
Abstract
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. 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. 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 (1Zondervan K.T. Becker C.M. Missmer S.A. Endometriosis. N Engl J Med. 2020; 382: 1244-1256Crossref PubMed Scopus (664) Google Scholar, 2Donnez J. Dolmans M.-M. Uterine fibroid management: from the present to the future.Hum Reprod Update. 2016; 22: 665-686Crossref PubMed Scopus (390) Google Scholar, 3Al-Hendy A. Myers E.R. Stewart E. Uterine fibroids: burden and unmet medical need.Semin Reprod Med. 2017; 35: 473-480Crossref PubMed Scopus (110) Google Scholar). 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 (2Donnez J. Dolmans M.-M. Uterine fibroid management: from the present to the future.Hum Reprod Update. 2016; 22: 665-686Crossref PubMed Scopus (390) Google Scholar, 3Al-Hendy A. Myers E.R. Stewart E. Uterine fibroids: burden and unmet medical need.Semin Reprod Med. 2017; 35: 473-480Crossref PubMed Scopus (110) Google Scholar). The HMB is often associated with anemia that can cause fatigue and may be life-threatening, leading to hospitalization and sometimes blood transfusion (4Nelson A.L. Ritchie J.J. Severe anemia from heavy menstrual bleeding requires heightened attention.Am J Obstet Gynecol. 2015; 213 (97.e1–97.e6)Abstract Full Text Full Text PDF Scopus (38) Google Scholar). 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 (1Zondervan K.T. Becker C.M. Missmer S.A. Endometriosis. N Engl J Med. 2020; 382: 1244-1256Crossref PubMed Scopus (664) Google Scholar). 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 (5Dmowski 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: 238-243Abstract Full Text PDF PubMed Scopus (132) Google Scholar). 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 (6ACOGManagement of symptomatic uterine leiomyomas: ACOG practice bulletin, Number 228.Obstet Gynecol. 2021; 137: e100-e115Crossref PubMed Scopus (59) Google Scholar). 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 (7MacLean 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, CA2013Google Scholar, 8Miwa K. Hitaka T. Imada T. Sasaki S. Yoshimatsu M. Kusaka M. et al.Discovery of as a orally active, antagonist of the hormone Google Scholar, T. A. Yoshimatsu M. M. et of the by TAK-385 a investigational, orally active, hormone (GnRH) in GnRH receptor J PubMed Scopus Google Scholar). In women, the reduction in FSH concentrations prevents natural follicular development, suppressing ovarian production of and, together with reductions in LH concentrations, prevents ovulation, corpus luteum formation, and the production of progesterone The reduction of E2 and systemic concentrations by relugolix improves and symptoms A. first PubMed Scopus Google Scholar, K. K. M. H. Oral hormone antagonist relugolix with for uterine leiomyomas: a Gynecol. PubMed Scopus Google Scholar, K. K. H. a oral hormone antagonist, in the treatment of pain symptoms associated with uterine fibroids: a phase 3 study in Steril. Full Text Full Text PDF PubMed Scopus Google Scholar, M. T. K. N. an oral hormone receptor antagonist, pain in a a Steril. 2021; Full Text Full Text PDF PubMed Scopus (38) Google Scholar, T. M. M. J. an oral hormone receptor antagonist, pain with in a phase Steril. Full Text Full Text PDF PubMed Scopus Google Scholar). Relugolix 40 mg, under the name was the first GnRH antagonist approved for the of symptoms lower pain, lower back pain, and in and pain Scholar). However, because of the associated hypoestrogenic the approved duration of use is limited to 6 In Myovant Sciences the to and relugolix for for diseases and clinical the and of relugolix and of in the United States, and as a new for testosterone suppression in with prostate Scholar). In women, Myovant the development of relugolix 40 mg with E2 and NETA as one once a This was on the of an E2 to hypoestrogenic effects associated with relugolix monotherapy, including vasomotor symptoms and potentially effective management of symptoms associated with UF or EM, of quality of life, and of in these and in women with uterine with hormone the J Obstet Gynecol. 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