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Long-term safety and efficacy of elagolix, an oral, non-peptide GnRH antagonist for the management of endometriosis-associated pain, was evaluated in two 6-month (M) extension studies (Elaris EM-III and IV) of the pivotal, 6M, phase 3 studies (12M-overall treatment with 150 mg once daily [QD] or 200 mg twice daily [BID]).Women with moderate/severe endometriosis-associated pain, randomized to receive elagolix in the pivotal studies, continued treatment during the extension studies (treated: Elaris EM-III, n=287; Elaris EM-IV, n=282). Baseline was before dosing in pivotal studies. Dysmenorrhea (DYS), non-menstrual pelvic pain (NMPP), and dyspareunia (DYSP) scores were recorded in a daily electronic-diary. Adverse events (AE), bone mineral density (BMD), and endometrium were assessed.DYS, NMPP and DYSP scores across dose groups were significantly decreased compared to placebo at M6 in the pivotal studies (P<.05; exception-DYSP 150 mg), and improvements in scores were maintained after 12M of treatment in Elaris EM-III (Extension-M6 mean percent change from baseline: DYS, 150 mg QD=−49%, 95% CI [−57,−41], 200 mg BID=−82%, 95% CI [−88,−76], NMPP, 150 mg QD=−49, 95% CI [−57,−41], 200 mg BID=−57%, 95% CI [−64,−49]; DYSP, 150 mg QD=−31%, 95% CI [−46,−16], 200 mg BID=−42%, 95% CI [−58,−25]). Hot flush was the most common AE over 12M of treatment (150 mg QD=29.5%; 200 mg BID=52.2%). At extension M6, there was a dose-dependent decrease in BMD from baseline, while mean lumbar spine BMD Z-score was within normal range (−2.0–+2.0). Mean change in endometrial thickness ranged 0.6 to −0.8 mm across doses. Elaris EM-IV results were generally similar.In women with endometriosis-associated pain, long-term elagolix treatment was associated with reductions in DYS, NMPP, and DYSP. No new safety concerns were identified with long-term elagolix use.