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Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy Ayman Al‑Hendy, M.D., Ph.D., Andrea S

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Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy Ayman Al‑Hendy, M.D., Ph.D., Andrea S The new england journal of medicine Original Article Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy Ayman Al-Hendy, M.D., Ph.D., Andrea S. Lukes, M.D., Alfred N. Poindexter III, M.D., Roberta Venturella, M.D., Ph.D., Claudio Villarroel, M.D., Hilary O.D. Critchley, M.D., Yulan Li, Ph.D., Laura McKain, M.D., Juan C. Arjona Ferreira, M.D., Andria G.M. Langenberg, M.D., Rachel B. Wagman, M.D., and Elizabeth A. Stewart, M.D.​​ ABSTRACT BACKGROUND From the Department of Obstetrics and Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treat- Gynecology, University of Chicago, Chi- ment with the combination of relugolix (an oral gonadotropin-releasing hormone- cago (A.A.-H.); Carolina Women’s Re- search and Wellness Center, Durham, receptor antagonist), estradiol, and norethindrone acetate, administered once NC (A.S.L.); Advances in Health, Hous- daily, may have efficacy in women with uterine fibroids and heavy bleeding while ton (A.N.P.); the Department of Clinical avoiding hypoestrogenic effects. and Experimental Medicine, Unit of Ob- stetrics and Gynecology, Magna Graecia METHODS University of Catanzaro, Catanzaro, Italy (R.V.); the Institute for Mother and Child We conducted two replicate international, double-blind, 24-week, phase 3 trials Research, Faculty of Medicine, University involving women with fibroid-associated heavy menstrual bleeding. Participants of Chile, Santiago, Chile (C.V.); the Medi- were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix cal Research Council Centre for Repro- ductive Health, University of Edinburgh, combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of noreth- Edinburgh, United Kingdom (H.O.D.C.); indrone acetate), or delayed relugolix combination therapy (40 mg of relugolix Myovant Sciences, Brisbane, CA (Y.L., monotherapy, followed by relugolix combination therapy, each for 12 weeks). The L.M., J.C.A.F., A.G.M.L., R.B.W.); and the Department of Obstetrics and Gynecol- primary efficacy end point in each trial was the percentage of participants with a ogy, Mayo Clinic and Mayo Clinic Alix response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume School of Medicine, Rochester, MN from baseline) in the relugolix combination therapy group, as compared with the (E.A.S). Address reprint requests to Dr. Al-Hendy at the Department of Obstet- placebo group. Key secondary end points were amenorrhea, volume of menstrual rics and Gynecology, University of Chicago, blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid 5841 S. Maryland Ave., Chicago, IL 60637, volume, and uterine volume. Safety and bone mineral density were assessed. or at aalhendy@ bsd . uchicago . edu. RESULTS N Engl J Med 2021;384:630-42. DOI: 10.1056/NEJMoa2008283 A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A Copyright © 2021 Massachusetts Medical Society. total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as com- pared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS Once-daily relugolix combination therapy resulted in a significant reduction in men- strual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIB- ERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.) 630 n engl j med 384;7 nejm.org February 18, 2021 The New England Journal of Medicine Downloaded from nejm.org at CCSS CAJA COSTARRICENSE DE SEGURO SOCIAL BINASSS on March 10, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. Relugolix Treatment for Uterine Fibroid Symptoms terine fibroids are common; the receptor antagonist that is suitable for daily use. cumulative incidence by 50 years of age is It competitively binds to pituitary GnRH recep- approximately 70% among White women tors, blocking the binding and signaling of en- U 1,2 23 and 80% among Black women. Approximately dogenous GnRH and thus leading to reversible, 25% of women with uterine fibroids have symp- dose-dependent decreases in gonadotropin con- toms,3,4 most often heavy menstrual bleeding, centrations and subsequent suppression of ovar- which is often associated with anemia.5-7 Uterine ian estradiol and progesterone production. In pre- fibroid–associated pain is the second most de- vious phase 3 trials involving Japanese women bilitating problem.8-10 with symptomatic fibroids, relugolix at a dose of Although contraceptives are first-line medical 40 mg led to improvements similar to those treatments for uterine fibroid symptoms,11 the observed with leuprolide acetate with regard to quality of evidence for their use is low.7,12 Inject- heavy menstrual bleeding, anemia, and pain24 able long-acting gonadotropin-releasing hormone and to a significant reduction in pain as com- (GnRH) agonists (e.g., leuprolide acetate) are ef- pared with placebo.25 To achieve efficacy, mini- fective; however, hypoestrogenic sequelae limit mize hypoestrogenic side effects, and preserve their duration of use or lead to the administra- bone mineral density, relugolix combination ther- tion of additional hormonal therapy to mitigate apy (consisting of 40 mg of relugolix, 1 mg of side effects.5,13 The GnRH antagonist elagolix, estradiol, and 0.5 mg of norethindrone acetate) administered with estradiol and norethindrone was developed as a once-daily treatment for acetate, reduces heavy menstrual bleeding in maintaining estradiol levels within the physio- women with uterine fibroids14 and is approved logic range of the early follicular phase of the for the treatment of uterine fibroids for 24 menstrual cycle,26,27 with the addition of a pro- months.15 However, elagolix involves twice-daily gestin to mitigate the unopposed estrogen ac- administration because of its short half-life,16 tion that could lead to endometrial hyperplasia.28 and its use has been associated with a loss of We report the results of two replicate interna- bone mineral density at 1 year and with adverse tional, double-blind, randomized, placebo-con- effects on blood pressure and levels of lipids and trolled, phase 3 trials (LIBERTY 1 and LIBERTY 2) liver enzymes.15 in which we assessed the efficacy and safety The selective progesterone-receptor modula- of once-daily relugolix combination therapy in tor ulipristal acetate has been approved to treat women with fibroid-associated heavy menstrual uterine fibroids in some countries12,17; however, bleeding. We also evaluated a delayed relugolix it has been linked to rare cases of serious liver combination therapy regimen, which consisted injury, and the European Commission, on the of relugolix monotherapy for 12 weeks followed basis of guidance from the European Medicines by 12 weeks of relugolix combination therapy, in Agency, has recommended that ulipristal acetate an additional group of participants to assess the for the treatment of uterine fibroids be used only benefit and safety of the addition of estradiol in premenopausal women in whom surgical pro- and norethindrone acetate. cedures (including uterine fibroid embolization) 18 are not appropriate or have not worked. Surgery Methods remains a common treatment option, although uterine-sparing procedures are associated with a Participants substantial incidence of reoperation,19 and hyster- In these two trials, we enrolled women in Africa, ectomy (both with and without ovarian conserva- Europe, North America, and South America. tion) has long-term sequelae, including increased LIBERTY 1 (trial L1) was conducted at 80 sites, mortality and risk of cardiovascular disease.20-22 and LIBERTY 2 (trial L2) at 99 sites. Premeno- With an estimated $34 billion in health care pausal women 18 to 50 years of age who had a costs associated with fibroids in the United diagnosis of fibroids as confirmed on ultraso- States alone,22 there is a major need for a non- nography and who had heavy menstrual bleed- surgical long-term treatment option,7 particu- ing, as assessed by the alkaline hematin meth- larly one that addresses women’s usual prefer- od,29 were eligible. The alkaline hematin method ence for uterine-sparing alternatives regardless directly measures the volume of menstrual blood of their reproductive plans.4 loss by comparing hematin from menstrual Relugolix is an orally active nonpeptide GnRH- products against calibration curves created from n engl j med 384;7 nejm.org February 18, 2021 631 The New England Journal of Medicine Downloaded from nejm.org at CCSS CAJA COSTARRICENSE DE SEGURO SOCIAL BINASSS on March 10, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. The new england journal of medicine a simultaneous venous blood sample.29 Heavy ses, and vouch for fidelity of the trial to the menstrual bleeding was defined as a volume of protocol, available at NEJM.org. The first draft menstrual blood loss of 80 ml or more per cycle of the manuscript was written by the penultimate for two cycles or a volume of 160 ml or more author. The other authors critically reviewed during one cycle. and provided feedback on the first draft and Patients were excluded from the trials if they subsequent versions.
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