Elagolix is a gonadotropin releasing hormone (GnRH) antagonist. It competitively inhibits GnRH receptors in the pituitary gland, resulting in suppression of gonadotropin secretion. Decreased serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) lead to attenuated production of estradiol and progesterone in ovarian tissue. Lower levels of circulating estrogen inhibits the growth of both uterine and ectopic endometrial tissue and can thereby reduce endometriosis-associated pain.
Elagolix is hepatically metabolized. It is a major substrate (and weak-moderate inducer) of CYP3A4 and a minor substrate of CYP2D6/CYP2C8 and the UGTs. Elagolix is also a substrate of P-gp and OATP1B1 transporters.
Elagolix has a half-life of 4-6 hours and is eliminated fecally. Individuals with some organic anion transporter polypeptide (OATP) 1B1 polymorphisms experience decreased elagolix metabolic efficiency and increased serum drug levels. Renal impairment does not affect elagolix exposure, but hepatic impairment significantly increases peak serum elagolix concentrations.
Elagolix was developed in the late 2000’s for the treatment of endometriosis and uterine fibroids. In July 2018, it was approved by the FDA for the treatment of moderate-severe pain associated with endometriosis.
History and Foundational Studies
2008: Novel GnRH antagonist 10b (elagolix) is synthesized, characterized, and tested in macaques by Neurocrine Biosciences.
2009: Phase I clinical trial (double-blind RCT, 55 participants) of elagolix in healthy premenoupausal women. Drug administration appears to be safe and results in pituitary-gonadal suppression and decreased circulating estradiol, FSH, and LH.
2008-2009 (published 2013): Phase II clinical trial (155 women, double-blind, RCT) of elagolix for endometriosis pain. Efficacy did not reach statistical significance over placebo in primary endpoint, but dysmenorrhea and other nonmenstrual pelvic pain symptoms improved on elagolix.
2012-2014 (Published 2017)– Phase III clinical trials, Elaris Endometriosis I (EM I)-I & Elaris Endometriosis II (EM II), double-blind RCTs with 1285 total participants, demonstrate elagolix efficacy in endometriosis. Dysmenorrhea symptoms improved in significantly more women (46-72%) in the treatment group compared to those who received placebo (23%).
2011-2014 (Published 2017): Phase II randomized, double-blind clinical trial of elagolix in 271 women with heavy menstrual bleeding associated with uterine fibroids. Treatment-branch participants experienced mean blood volume reductions between 72 and 98%.
2012-2014 (Published 2018) – Phase III extension studies of EM-I/EM-II, Elaris Endometriosis (EM III) & Elaris Endometriosis IV (EM IV) demonstrate sustained improvement in endometriosis pain associated with elagolix therapy, with no additional safety concerns arising in the treatment arm.