Clinical development of the oral gonadotropin-releasing hormone antagonist elagolix

Because uterine fibroids growth and bleeding symptoms are mostly progesterone-dependent, all clinical phase II and III studies were focused on higher elagolix doses that inhibit ovulation. These doses require hormonal add-back therapy for chronic treatment. All phase II and III studies were conducted by AbbVie Inc. (North Chicago, IL). The safety and efficacy of elagolix vs. placebo and elagolix with low-dose add-back therapy was evaluated in a proof-of-concept (phase IIa), dose-ranging, multiple-cohort study in premenopausal women with fibroids and HMB,(menstrual blood loss [MBL], >80 mL per cycle) ( 9 ). Women (n = 271) were treated for 3 months with elagolix alone (100 mg 2 times per day, 200 mg 2 times per day, 300 mg 2 times per day, 400 mg once daily, or 600 mg once daily [all but the 600 mg once daily arm were placebo-controlled]) or elagolix plus add-back therapy (200 mg 2 times per day plus continuous low-dose E2 0.5 mg/norethindrone acetate [NETA] 0.1 mg or elagolix 300 mg 2 times per day plus E2 1 mg continuously and cyclic progesterone 200 mg). The main outcome efficacy and safety measures were the mean percentage change in MBL and AEs, respectively. The mean age was 41.8 years; 73.8% were black; the mean baseline MBL was 267 mL. The MBL percentage change from baseline to the last month was significantly greater with elagolix alone and was dose-dependent (range, −72% to −98% vs. placebo [range, −8% to −41%]); the mean percentage changes with add-back regimens were −80% to −85%. Hot flush was the most common AE. The study concluded that elagolix significantly reduced HMB in women with fibroids and low-dose add-back regimens substantially reduced flushing with marginal effects on efficacy. The selected treatment regimens were further evaluated in a large (n = 571) phase IIb study of a 6-month treatment duration ( 10 ). This placebo-controlled study evaluated the efficacy and safety of elagolix in cohorts 1 (300 mg 2 times per day) and 2 (600 mg once daily) with 4 arms per cohort: placebo; elagolix alone; elagolix with 0.5 mg E2/0.1 mg NETA; and elagolix with 1.0 mg E2/0.5 mg NETA. The composite primary end point was the percentage of women who had <80 mL of MBL and ≥50% reduction in MBL from baseline to the last 28 days of treatment. Safety assessments included changes in the BMD. The results of this study showed that elagolix with and without add-back therapy significantly reduced MBL (responder rates, elagolix groups, >73%, and placebo, 27%) in women with uterine fibroids. Add-back therapy reduced the hypoestrogenic effects, including a decrease in the BMD. The phase III program consisted of 2 identical, double-blind, randomized, placebo-controlled, 6-month phase III trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) ( 11 ) followed by a 6-month extension study (UF-EXTEND) (total duration of 12 months) ( 12 ). The UF-1 (n = 412) and UF-2 (n = 378) trials evaluated the efficacy and safety of elagolix 300 mg 2 times per day with hormonal add-back therapy (E2 1 mg and NETA 0.5 mg once daily) in women with fibroid-associated bleeding during treatment for 6 months ( 11 ). The primary end point was MBL of <80 mL during the final month of treatment and at least a 50% reduction in MBL from baseline to the final month. The key secondary efficacy end points included changes in additional bleeding parameters, increases in the hemoglobin levels, and impact on symptoms using the Uterine Fibroid Symptom and Quality of Life questionnaire. Approximately 68% of the women who were enrolled in these studies were black, which is consistent with the uterine fibroid epidemiology. In the elagolix alone groups, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2 ( Fig. 5 ). In addition, in the elagolix plus add-back groups a greater percentage of women showed an increase in hemoglobin levels more than 2 g/100 mL (from a baseline level of 10.5 g/100 mL or less) compared to placebo. These treatments were associated with significant improvements in scores on the Uterine Fibroid Symptom and Quality of Life questionnaire. Hot flushes (the most common AE) were significantly more common with elagolix plus add-back therapy (20.4% and 19.6%, respectively, in UF-1 and UF-2) and elagolix alone (64.4% and 43%) than with placebo (8.8% and 4%). The hypoestrogenic effects of elagolix, especially decreases in the BMD, were attenuated with add-back therapy. Figure 5 Reduction in heavy menstrual bleeding in women with uterine fibroids. The percentages of women who met the criteria for the primary end point (a menstrual blood loss volume of 50% reduction in the menstrual blood loss volume from baseline to the final month) in the 2 trials. A significantly greater percentage of women who received elagolix with add-back therapy met the criteria for the primary end point than women who received placebo. The final month was defined as the last 28 days before and including the last treatment period visit date. CI = confidence interval. (From Schlaff et al. [ 11 ]. Reprinted by permission of the publisher.) Reduction in heavy menstrual bleeding in women with uterine fibroids. The percentages of women who met the criteria for the primary end point (a menstrual blood loss volume of 50% reduction in the menstrual blood loss volume from baseline to the final month) in the 2 trials. A significantly greater percentage of women who received elagolix with add-back therapy met the criteria for the primary end point than women who received placebo. The final month was defined as the last 28 days before and including the last treatment period visit date. CI = confidence interval. (From Schlaff et al. [ 11 ]. Reprinted by permission of the publisher.) A total of 433 women were enrolled in the UF-EXTEND study, and 218 received up to 12 months of elagolix with add-back treatment ( 12 ). The safety and efficacy end points were similar to the placebo-controlled phase III studies. The percentage of women who met the primary end point in this elagolix with add-back group was 87.9% (95% confidence interval, 83.4–92.3) ( Fig. 6 ). The most frequently reported AEs with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). The mean percentage decreases in the BMD from baseline to extension month 6 were significantly lower with elagolix plus add-back therapy than with elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with add-back therapy. Figure 6 Reduction in heavy menstrual bleeding in women with uterine fibroids during long-term treatment. Percentage of women who met (A) the primary end point and (B) mean change from baseline in menstrual blood loss in women treated with up to 12 months of elagolix with add-back therapy. Data are % or mean with error bars indicating 95% confidence interval. Baseline was before first dosing in the Elaris Uterine Fibroids 1 (UF-1) and 2 (UF-2) studies. ∗The mean changes from baseline in menstrual blood loss for UF-1 and UF-2 are presented as least squares means. (From Simon et al. [ 12 ]. Reprinted by permission of the publisher.) Reduction in heavy menstrual bleeding in women with uterine fibroids during long-term treatment. Percentage of women who met (A) the primary end point and (B) mean change from baseline in menstrual blood loss in women treated with up to 12 months of elagolix with add-back therapy. Data are % or mean with error bars indicating 95% confidence interval. Baseline was before first dosing in the Elaris Uterine Fibroids 1 (UF-1) and 2 (UF-2) studies. ∗The mean changes from baseline in menstrual blood loss for UF-1 and UF-2 are presented as least squares means. (From Simon et al. [ 12 ]. Reprinted by permission of the publisher.)

This review was based on a PubMed search for human studies with elagolix conducted to date with focus on advanced phase II and III studies.

Elagolix is the first novel, nonpeptide, orally active GnRH antagonist that has been approved by the Food and Drug Administration in the United States for the management of moderate to severe endometriosis-associated pain and HMB associated with uterine fibroids. Elagolix competitively inhibits GnRH receptors in the pituitary gland and leads to a rapid and dose-dependent reduction in circulating gonadotropins and ovarian sex hormones, including E2. In women with endometriosis-associated pelvic pain, both higher (200 mg 2 times per day) and lower (150 mg once daily) doses of elagolix were effective in improving dysmenorrhea and NMPP during a 6-month period in the placebo-controlled phase III trials and sustained pain reduction during long-term extension studies. The regulatory approval of elagolix (Orilissa) offers a new medical treatment option for the management of moderate and severe pain associated with endometriosis. The recommended treatment duration with Orilissa in women with normal liver function or mild hepatic impairment is up to 24 months for 150 mg once daily and up to 6 months for 200 mg 2 times per day ( 5 ). Elagolix (300 mg 2 times per day) with add-back therapy (E2 1 mg and NETA 0.5 mg once daily; Oriannh) was also effective in reducing HMB in women with uterine fibroids. The phase III studies showed that up to 12 months of elagolix plus add-back therapy provides sustained reductions in MBL in women with uterine fibroids. Add-back therapy attenuated the hypoestrogenic effects of elagolix alone with marginal effects on efficacy. This treatment offers an alternative to surgical approaches. The use of Oriannh should be limited to 24 months because of to the risk of continued bone loss, which may not be reversible.