Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist
Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, Diamond MP, Surrey E, +14 more
New England Journal of Medicine (2017) · n=1,689
Two replicate phase 3 trials established the first orally bioavailable GnRH antagonist for endometriosis pain — and the dose-proportional bone mineral density loss that the label-mandated duration ceilings have to manage.
This paper reports the replicate Elaris EM-I and Elaris EM-II phase 3 trials behind the FDA approval of elagolix (Orilissa, AbbVie) as the first orally bioavailable gonadotropin-releasing-hormone antagonist for moderate-to-severe endometriosis-associated pain. The two double-blind randomised placebo-controlled 6-month trials shared an identical protocol and ran in parallel: Elaris EM-I enrolled 872 women across 151 sites in the United States and Canada, and Elaris EM-II enrolled 817 women across 187 sites in 13 countries, for a pooled sample size of 1,689. All participants had surgically diagnosed endometriosis and moderate-to-severe endometriosis-associated pain at baseline, and were randomised 1:1:1 to oral elagolix 150 mg once daily, elagolix 200 mg twice daily, or matching placebo.
The two co-primary endpoints at month 3 were the proportion of women achieving a clinical response with respect to dysmenorrhoea and the proportion achieving a clinical response with respect to non-menstrual pelvic pain, with response defined as a clinically meaningful reduction on the daily-electronic-diary pain composite together with stable or reduced rescue-analgesic use. Both elagolix doses were superior to placebo on both endpoints in both trials. In Elaris EM-I, the dysmenorrhoea response rate was 46.4% on 150 mg daily and 75.8% on 200 mg twice daily versus 19.6% on placebo, and the non-menstrual pelvic-pain response rate was 50.4% and 54.5% versus 36.5%. In Elaris EM-II, the corresponding rates were 43.4% and 72.4% versus 22.7% for dysmenorrhoea, and 49.8% and 57.8% versus 36.5% for non-menstrual pelvic pain. P-values were below 0.001 for all comparisons except the lower-dose non-menstrual-pelvic-pain comparison in Elaris EM-II, which reached P = 0.003.
The pre-specified safety dossier captured the hypoestrogenic adverse-event profile predicted by the partial-suppression pharmacology of elagolix. Lumbar-spine bone-mineral-density decline from baseline at month 6 was approximately 0.3% on 150 mg daily and approximately 2.6% on 200 mg twice daily, with placebo trending neutrally — a dose-proportional signal consistent with the depth of estrogen suppression each dose achieves. Hot flushes were reported in roughly 24% on 150 mg daily and roughly 42% to 46% on 200 mg twice daily across the two trials, versus 7% to 10% on placebo. Lipid elevations occurred at higher rates in the elagolix groups. The trial program supported FDA approval of Orilissa on 24 July 2018, with labelled treatment durations capped at 24 months for 150 mg daily and 6 months for 200 mg twice daily — both ceilings driven directly by the dose-proportional BMD trajectory characterised in these trials.
The 6-month trial duration is short relative to the chronic-disease nature of endometriosis and the up-to-24-month labelled treatment ceiling for the lower dose; the long-term efficacy and safety questions are addressed in subsequent extension trials and in the Schlaff et al. 2020 Elaris UF program, which extended the elagolix platform into uterine fibroids under the Oriahnn fixed-dose-combination product with estradiol-norethindrone add-back, rather than in the present paper. Bone-mineral-density loss is dose-proportional and label-limiting — the 200 mg twice-daily ceiling at 6 months and the 150 mg once-daily ceiling at 24 months trace directly to the BMD trajectory in these trials, and the longer-term BMD-recovery question after treatment cessation is incompletely characterised here. The Orilissa label includes warnings around dose-dependent hepatic transaminase elevations, suicidal ideation and mood-related adverse events, and bone-loss monitoring; a formal boxed warning is carried by the Oriahnn fixed-dose-combination product rather than by Orilissa monotherapy, primarily on the basis of the thromboembolic-event signal associated with the estradiol-norethindrone add-back. The trial population excluded women trying to conceive — endometriosis-associated infertility is a major clinical question that this trial design was not powered to address, and the elagolix labelling reflects that exclusion. AbbVie sponsorship is disclosed transparently and the primary-endpoint analysis is regulatory-grade. The placebo-arm response rate is high on the non-menstrual pelvic-pain endpoint (36.5% in both trials) versus the dysmenorrhoea endpoint (19.6% to 22.7%), reflecting the well-documented placebo responsiveness of cyclical pelvic pain in this disease. The class-level framing — partial-suppression-without-add-back at 150 mg daily versus full-suppression-with-add-back as the engineering approach taken by relugolix in the Myfembree fixed-dose combination — is covered on the GnRH-antagonist class page.
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