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Drug Evaluation

An evaluation of relugolix/estradiol/norethindrone acetate for the treatment of heavy menstrual bleeding associated with uterine fibroids in premenopausal women

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Pages 421-429 | Received 05 Oct 2021, Accepted 14 Jan 2022, Published online: 24 Jan 2022

References

  • Baird DD, Patchel SA, Saldana TM, et al. Uterine fibroid incidence and growth in an ultrasound-based, prospective study of young African Americans. Am J Obstet Gynecol. 2020;223(3):402 e1–402 e18.
  • Ali M, Chaudhry ZT, Al-Hendy A. Successes and failures of uterine leiomyoma drug discovery. Expert Opin Drug Discov. 2018;13(2):169–177.
  • Machado-Lopez A, Simon C, Mas A. Molecular and cellular insights into the development of uterine fibroids. Int J Mol Sci. 2021;22(16):8483.
  • Bariani MV, Rangaswamy R, Siblini H, et al. The role of endocrine-disrupting chemicals in uterine fibroid pathogenesis. Curr Opin Endocrinol Diabetes Obes. 2020;27(6):380–387.
  • Ali M, A RS, Hendy AA. Elagolix in the treatment of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. Expert Rev Clin Pharmacol. 2021;14(4):427–437.
  • Ali M, Shahin SM, Sabri NA, et al. Activation of beta-catenin signaling and its crosstalk with estrogen and histone deacetylases in human uterine fibroids. J Clin Endocrinol Metab. 2020;105(4):e1517–e1535.
  • El Sabeh M, Afrin S, Singh B, et al. uterine stem cells and benign gynecological disorders: role in pathobiology and therapeutic implications. Stem Cell Rev Rep. 2021;17(3):803–820.
  • Markham A. Relugolix: first global approval. Drugs. 2019;79(6):675–679.
  • Archer DF, Stewart EA, Jain RI, et al. Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: results from a phase 2a proof-of-concept study. Fertil Steril. 2017;108(1):152–160. e4.
  • Carr BR, Stewart EA, Archer DF, et al. Elagolix alone or with add-back therapy in women with heavy menstrual bleeding and uterine leiomyomas: a randomized controlled trial. Obstet Gynecol. 2018;132(5):1252–1264.
  • Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382(4):328–340.
  • Simon JA, Al-Hendy A, Archer DF, et al. Elagolix Treatment for Up to 12 months in women with heavy menstrual bleeding and uterine leiomyomas. Obstet Gynecol. 2020;135(6):1313–1326.
  • Slomski A. Elagolix reduces fibroid-related heavy menstrual bleeding long-term. Jama. 2020;324(8):733.
  • Neri M, Melis GB, Giancane E, et al. Clinical Utility of elagolix as an oral treatment for women with uterine fibroids: a short report on the emerging efficacy data. Int J Womens Health. 2019;11:535–546.
  • Angioni S, D’Alterio MN, Daniilidis A. Highlights on medical treatment of uterine fibroids. Curr Pharm Des. 2021;27(36):3821-3832.
  • Farris M, Bastianelli C, Rosato E, et al. Uterine fibroids: an update on current and emerging medical treatment options. Ther Clin Risk Manag. 2019;15:157–178.
  • Lynch SE, Mayer DC. Oriahnn: new drug approved for treating heavy menstrual bleeding in women with uterine fibroids. Ann Pharmacother. 2022;56(1):93–101.
  • Stewart EA, Archer DF, Owens CD, et al. Reduction of heavy menstrual bleeding in women not designated as responders to elagolix plus add back therapy for uterine fibroids. J Womens Health (Larchmt). 2021. Epub ahead of print. PMID: 34582715
  • Pfizer, Myovant Sciences and Pfizer Receive FDA Approval for MYFEMBREE®, the First Once-Daily Treatment for Heavy Menstrual Bleeding Associated With Uterine Fibroids. [cited 2022 Jan. Available from: https://www.pfizer.com/news/press-release/press-release-detail/myovant-sciences-and-pfizer-receive-fda-approval-myfembreer 2021.
  • Elsharoud A, Ali M, Al-Hendy A. Relugolix. GnRH (LHRH) receptor antagonist, Treatment of uterine fibroids, Treatment of endometriosis-related pain, Treatment of prostate cancer. Drugs Future. 2019;44(2):131.
  • Miwa K, Hitaka T, Imada T, 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(14):4998–5012.
  • Barra F, Seca M, Della Corte L, et al., Relugolix for the treatment of uterine fibroids. Drugs Today (Barc). 55(8): 503–512. 2019.
  • MacLean DB, Shi H, Faessel HM, et al. Medical castration using the investigational oral GnRH antagonist TAK-385 (Relugolix): phase 1 study in healthy males. J Clin Endocrinol Metab. 2015;100(12):4579–4587.
  • Nakata D, Masaki T, Tanaka A, 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.
  • EMEA-002428-PIP02-18. Relugolix/estradiol/ norethisterone acetate. European Medicines Agency 2019. Last accessed Oct 2021 https://file.wuxuwang.com/ema/ryeqo-epar-public-assessment-report_en.pdf
  • Emmanuelle NE, Marie-Cécile V, Florence T, et al. Critical role of estrogens on bone homeostasis in both male and female: from physiology to medical implications. Int J Mol Sci. 2021;22(4):1568–1586.
  • Eastell R. Role of oestrogen in the regulation of bone turnover at the menarche. J Endocrinol. 2005;185(2):223–234.
  • Huvinen E, Holopainen E, Heikinheimo O. Norethisterone and its acetate – what’s so special about them? BMJ Sex Reprod Health. 2021;47(2):102.
  • Stanczyk FZ, Archer DF, Bhavnani BR. Ethinyl estradiol and 17beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception. 2013;87(6):706–727.
  • O’Connell MB. Pharmacokinetic and pharmacologic variation between different estrogen products. J Clin Pharmacol. 1995;35(9s):18s–24s.
  • de Lignières B, Silberstein S. Pharmacodynamics of Oestrogens and Progestogens. Cephalalgia. 2000;20(3):200–207.
  • Lee AJ, Cai MX, Thomas PE, et al. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003;144(8):3382–3398.
  • Korhonen T, Turpeinen M, Tolonen A, et al. Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone. J Steroid Biochem Mol Biol. 2008;110(1–2):56–66.
  • Barra F, Scala C, Ferrero S. Current understanding on pharmacokinetics, clinical efficacy and safety of progestins for treating pain associated to endometriosis. Expert Opin Drug Metab Toxicol. 2018;14(4):399–415.
  • Clinicaltrial.gov. Study of Relugolix Alone and Relugolix Combined With Hormonal Add-Back Therapy in Healthy Premenopausal Female Participants. 2021. Last accessed Oct 2021. https://www.clinicaltrials.gov/ct2/show/NCT04978688
  • Lukes A, Johnson B, Jones L, et al. Pharmacokinetics, pharmacodynamics, and safety of relugolix, a potent oral once-daily gonadotropin-releasing hormone (GnRH) receptor antagonist, as monotherapy and in combination with estradiol/norethindrone acetate add-back therapy. Hum Reprod. 2017;32:i267‐i268.
  • Hoshiai H, Seki Y, Kusumoto T, et al. Phase 2 study of relugolix vs placebo in heavy menstrual bleeding associated with uterine fibroids [17H]. Obstetrics Gynecol. 2017;129(5):86S–86S.
  • Osuga Y, Enya K, Kudou K, et al. Oral gonadotropin-releasing hormone antagonist relugolix compared with leuprorelin injections for uterine leiomyomas: a randomized controlled trial. Obstet Gynecol. 2019;133(3):423–433.
  • Osuga Y, Enya K, Kudou K, et al. 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(5):922–929. e2.
  • Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al., Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 384(7): 630–642. 2021.
  • Stewart EA, Lukes AS, Venturella R, et al. Relugolix combination therapy reduced uterine fibroid-associated pain in two phase 3 LIBERTY studies [32B]. 2020;Vol. 135:27S.
  • Al-Hendy A, Andrea S, Lukes AP, et al. Liberty: long-term extension study demonstrating one-year efficacy and safety of relugolix combination therapy in women with symptomatic uterine. Fertil Steril. 2021;114(3). https://www.fertstert.org/article/S0015-0282(20)30781-0/fulltext#relatedArticles
  • clinicaltrials.gov. Study of relugolix alone and relugolix combined with hormonal add-back therapy in healthy premenopausal female participants. 2021; Available from: www.clinicaltrials.gov
  • Clinical Trials_clincosm. [cited 2022 Jan. Available from: https://www.clincosm.com/
  • Al-Hendy A, Venturella R, Ferreira JCA, et al. Liberty randomized withdrawal study: 2-year efficacy and safety of relugolix combination therapy in women with heavy menstrual bleeding associated with uterine fibroids. Fertil Steril. 2021;116(3):e2. https://www.fertstert.org/article/S0015-0282(21)00613-0/fulltext.
  • Relugolix, Estradiol, and Norethindrone Acetate. American journal of health-system pharmacy 2021; [cited 2022 Jan. Available from: https://doi.org/https://doi.org/10.1093/ajhp/zxab268
  • Ishizawa C, Hirota Y, Urata Y, et al. Prolapse of a pedunculated uterine leiomyoma through the cervix during GnRH antagonist treatment: case report and literature review. J Obstet Gynaecol Res, 2020.
  • Al-Hendy A, As-Sanie S, Arjona Ferreira JC, et al. Assessment of common adverse events of relugolix combination therapy in premenopausal women treated for symptomatic estrogen-driven conditions: liberty and spirit studies. Fertil Steril. 2021;116(3):e11. https://www.fertstert.org/article/S0015-0282(21)00637-3/fulltext
  • Cardozo ER, Clark AD, Banks NK, et al. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol. 2012;206(3):211 e1–9.
  • (EMA), E.M.A. Ulipristal acetate for uterine fibroids: EMA recommends restricting use. 2020. Oct 2021. https://www.ema.europa.eu/en/medicines/human/referrals/ulipristal-acetate-5mg-medicinal-products
  • Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382(23):2187–2196.
  • Lv J, Lin J. Relugolix as a promising novel oral GnRH antagonist for prostate cancer treatment. Asian J Androl. 2021;23(3):229–230.
  • Donnez J, Taylor HS, Taylor RN, et al. Treatment of endometriosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: a randomized clinical trial. Fertil Steril. 2020;114(1):44–55.
  • Dababou S, Garzon S, Lagana AS, et al. Linzagolix: a new GnRH-antagonist under investigation for the treatment of endometriosis and uterine myomas. Expert Opin Investig Drugs. 2021;30(9):903–911.
  • Eisenhardt S, Fleckenstein J. Traditional Chinese medicine valuably augments therapeutic options in the treatment of climacteric syndrome. Arch Gynecol Obstet. 2016;294(1):193–200.
  • Peng W, Sibbritt DW, Hickman L, et al. A critical review of traditional Chinese medicine use amongst women with menopausal symptoms. Climacteric. 2014;17(6):635–644.
  • Wang YP, Yu Q. The treatment of menopausal symptoms by traditional Chinese medicine in Asian countries. Climacteric. 2021;24(1):64–67.
  • Wang S, Lin H, Cong W. Chinese medicines improve perimenopausal symptoms induced by surgery, chemoradiotherapy, or endocrine treatment for breast cancer. Front Pharmacol. 2019;10:174.
  • Ciebiera M, Ali M, Prince L, et al. The evolving role of natural compounds in the medical treatment of uterine fibroids. J Clin Med. 2020;9(5):1479–1509.
  • Ali M, Al-Hendy A, Yang Q. Vitamin D, a promising natural compound with anti-uterine fibroid characteristics. Fertil Steril. 2019;111(2):268–269.

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