2.3.1 Endometriosis
Elagolix 150 mg once daily and 200 mg twice daily improved dysmenorrhea symptoms and nonmenstrual pelvic pain in women with endometriosis and moderate to severe endometriosis-associated pain in the ELARIS EM-I and ELARIS EM-II trials [
11]. Compared with placebo recipients, significantly greater proportions of elagolix 150 mg once daily and 200 mg twice daily recipients had clinical responses for dysmenorrhea (46.4 and 75.8% vs. 19.6%;
p < 0.001 for both comparisons) and nonmenstrual pelvic pain (50.4 and 54.5% vs. 36.5%;
p < 0.001 for both comparisons) at 3 months (primary endpoints) in ELARIS EM-I (Violet PETAL; NCT01620528) [
11]. Clinical response rates for dysmenorrhea and nonmenstrual pelvic pain were sustained, remaining significantly higher with both elagolix doses versus placebo at 6 months (
p ≤ 0.008 for all comparisons). Both elagolix doses were associated with significantly greater reductions in endometriosis-associated pain from baseline to month 3 than placebo (
p < 0.001) and elagolix 200 mg twice daily (but not 150 mg once daily) reduced the use of rescue analgesics relative to placebo at both 3 months and 6 months (
p < 0.001) [
11]. Of the 872 women randomized in ELARIS EM-I [
11], 149 elagolix 150 mg once daily recipients and 138 elagolix 200 mg twice daily recipients entered the double-blind ELARIS EM-III extension study (NCT01760954) [
12]. After an additional 6 months of elagolix therapy at the same dose in ELARIS EM-III (i.e. after 12 continuous treatment months), elagolix 150 mg once daily and 200 mg twice daily recipients had response rates of 52.1 and 78.2%, respectively, for dysmenorrhea, 67.5 and 69.1% for nonmenstrual pelvic pain, and 45.2 and 60.0% for dyspareunia [
12].
Clinical response rates were significantly higher in elagolix recipients than placebo recipients with respect to dysmenorrhea (43.4 and 72.4% vs. 22.7%;
p < 0.001 for both comparisons) and nonmenstrual pelvic pain (49.8 and 57.8% vs. 36.5%;
p = 0.003 and
p < 0.001, respectively) at 3 months (primary endpoints) in ELARIS EM-II (Solstice; NCT01931670) [
11]. These significant differences in clinical response rates were maintained at 6 months (
p ≤ 0.01 for all comparisons). Both elagolix doses significantly improved change from baseline in endometriosis-associated pain at 3 months (
p < 0.001 vs. placebo) and elagolix 200 mg twice daily (but not 150 mg once daily) reduced the use of rescue analgesics relative to placebo at both 3 months and 6 months (
p < 0.001 vs. placebo) [
11]. Of the 817 women randomized in ELARIS EM-II [
11], 142 elagolix 150 mg once daily recipients and 140 elagolix 200 mg twice daily recipients proceeded to enter the double-blind ELARIS EM-IV extension study (NCT02143713) [
12]. At 12 months (following an additional 6 months of elagolix therapy at the same dose in ELARIS EM-IV), elagolix 150 mg once daily and 200 mg twice daily recipients had response rates of 50.8 and 75.9% for dysmenorrhea, 66.4 and 67.2% for nonmenstrual pelvic pain, and 45.9 and 58.1% for dyspareunia [
12].
ELARIS EM-I and EM-II were randomized, double-blind, multicentre, phase III trials that enrolled premenopausal women aged 18–49 years with a surgical diagnosis of endometriosis within the previous 10 years and moderate to severe endometriosis-associated pain [including a Composite Pelvic Signs and Symptoms Score (CPSSS) of ≥ 6 with scores of ≥ 2 for dysmenorrhea and nonmenstrual pelvic pain at screening] [
11]. The phase II trials discussed below enrolled women aged 18–45 [
13] or 18–49 years [
14‐
16] with laparoscopically-confirmed endometriosis and a CPSSS of ≥ 6 (with scores of ≥ 2 for dysmenorrhea and ≥ 1 [
13,
16] or ≥ 2 [
14,
15] for nonmenstrual pelvic pain) [
13‐
16].
Relative to placebo, elagolix was associated with significantly greater reductions in dysmenorrhea (
p < 0.0001), non-menstrual pelvic pain (
p = 0.0066) and dyspareunia scores (
p = 0.007) from baseline to week 8 (primary outcomes) in the multicentre, phase II Daisy PETAL trial (NCT00973973) [
15]. In this trial, 137 women were randomized to elagolix 150 mg once daily or placebo for an 8-week double-blind period and a subsequent 16-week open-label period [
15].
Elagolix significantly improved reductions from baseline in monthly mean pelvic pain relative to placebo (
p < 0.05 for elagolix 150 and 250 mg once daily vs. placebo at week 4 and elagolix 250 mg vs. placebo at week 8; no differences at week 12) in the randomized, double-blind, multinational, phase II Tulip PETAL trial (NCT00797225) [
13]. In this 24-week trial, women (
n = 174) received elagolix 150 mg once daily, elagolix 250 mg once daily, intramuscular monthly leuprorelin acetate or placebo; patients assigned to leuprorelin or placebo were re-randomized to elagolix at week 12 [
13].
Compared with placebo, elagolix 150 and 250 mg once daily did not significantly improve reductions in monthly mean endometriosis-associated pain from baseline to week 12 (primary efficacy measure) in the randomized, double-blind, multicentre, phase II Lilac PETAL trial (NCT00619866) [
16]. Participants (
n = 155) received elagolix for 24 weeks or placebo for 12 weeks with re-randomization to an elagolix dose for the remaining 12 weeks [
16].
Elagolix 150 mg once daily and 75 mg twice daily were associated with least-squares mean (LSM) changes in total CPSSS of −5.5 and −5.2 from baseline to week 24 in the randomized, double-blind, multicentre phase II PETAL trial (NCT00437658), while subcutaneous depot medroxyprogesterone acetate (injected at weeks 1 and 12) was associated with a LSM change of −5.3 [
14]. Women in PETAL received 24 weeks of double-blind treatment (
n = 84 per treatment arm) [
14].
2.3.2 Uterine Leiomyoma
Elagolix 300 mg twice daily in combination with low-dose hormone add-back therapy reduced heavy menstrual bleeding. Significantly more elagolix than placebo recipients achieved a clinical response at month 6 (68.5 vs. 8.7%;
p < 0.001) in the randomized, double-blind, multicentre phase III ELARIS UF-I trial (NCT02654054; M12-815) [
17].
Similarly, elagolix 300 mg twice daily in combination with low-dose hormone add-back therapy reduced heavy menstrual bleeding in a significantly higher proportion of patients than placebo (76.2 vs. 10.1% achieving a clinical response at month 6;
p < 0.001) in the randomized, double-blind, multicentre phase III ELARIS UF-II trial (NCT02691494; M12-817) [
18].
Clinical responses with elagolix therapy were durable. Elagolix 300 mg twice daily in combination with low-dose hormone add-back therapy reduced heavy menstrual bleeding for up to 12 months in the randomized, double-blind, multicentre phase III ELARIS UF-EXTEND extension study (NCT02925494; M12-816), with 87.9% of women achieving a clinical response at month 12 [
19]. In ELARIS UF-EXTEND, patients who had received elagolix 300 mg twice daily with or without hormone add-back therapy in ELARIS UF-I or –II received an additional 6 months of the same treatment, while patients who had initially received placebo were randomized to either of the two active treatment groups [
19].
Significantly higher proportions of patients receiving elagolix monotherapy, elagolix in combination with low-dose hormone add-back therapy and elagolix in combination with standard-dose hormone add-back therapy achieved clinical responses than patients receiving placebo (92, 85 and 79% vs. 27% at month 6; all
p < 0.001 vs. placebo) in the randomized, double-blind, multinational phase IIb (NCT01817530; M12-813) [cohort 1 results;
n = 259] [
20]. Mean endometrial thickness decreased by 0.52, 1.33 and 0.56 mm from baseline to month 6 in the respective elagolix groups, while increasing by 2.1 mm with placebo (cohort 1;
p ≤ 0.05 for elagolix plus low-dose hormone therapy vs. placebo) [
21]. Compared with the placebo group, elagolix groups had significantly greater mean reductions in symptom severity and improvements in health-related quality of life from baseline to month 6 (cohort 1;
p ≤ 0.001 for all comparisons) [
22]. Efficacy results in cohort 2 were consistent with those in cohort 1 [
20‐
22]. In each cohort, patients were assigned to elagolix, elagolix in combination with low- or standard -dose hormone add-back therapy, or placebo [
21]. Elagolix was administered at 300 mg twice daily in cohort 1 and 600 mg once daily in cohort 2 [
21].
Elagolix significantly improved mean percentage change in MBL from baseline to month 3 relative to placebo (reductions of 72–98% with elagolix vs. reductions of 8–41% with placebo;
p ≤ 0.01 for all doses vs. their respective placebo) in the randomized, dose-ranging, proof-of-concept phase IIa study (NCT01441635; M12-663) [
23]. The highest mean percentage reduction was in women receiving elagolix 300 mg twice daily (98% vs. 41% with placebo;
p ≤ 0.001). In the placebo-controlled treatment groups, patients received elagolix 100, 200 or 300 mg twice daily, or elagolix 400 mg once daily for 3 months (
n = 33, 35, 30 and 32, respectively) [
23].
The trials discussed in this section enrolled premenopausal women aged 18–51 years [
17‐
19,
22] or 20–49 years [
23] with heavy menstrual bleeding associated with uterine fibroids [
17‐
19,
22,
23]. In the phase IIb trial [
20]and the replicate, phase III ELARIS UF-I [
17] and -II [
18] trials, the primary endpoint was the percentage of responders based on menstrual blood loss (MBL) volume reduction at the final month. Clinical response was defined as MBL < 80 mL and ≥ 50% reduction from baseline, as measured using the alkaline hematin method [
17‐
20].
Key clinical trials of elagolix, sponsored by AbbVie
Elagolix ± estradiol/NETA | Moderate to severe endometriosis-associated pain | III | Recruiting | USA; Canada | NCT03343067; M16-383 |
Elagolix ± estradiol/NETA, placebo | Moderate to severe endometriosis-associated pain | III | Recruiting | USA; Canada; Puerto Rico | NCT03213457; M14-702 |
Elagolix, placebo | Moderate to severe endometriosis-associated pain | III | Completed | Multinational | NCT02143713; M12-821; 2013-001047-31 (ELARIS EM-IV) |
Elagolix, placebo | Moderate to severe endometriosis-associated pain | III | Completed | Multinational | NCT01931670; M12-671; 2011-004295-11 (ELARIS EM-II; Solstice) |
Elagolix, placebo | Moderate to severe endometriosis-associated pain | III | Completed | USA; Canada; Puerto Rico | NCT01760954; M12-667 (ELARIS EM-III) |
Elagolix, placebo | Moderate to severe endometriosis-associated pain | III | Completed | USA; Canada; Puerto Rico | NCT01620528; M12-665 (ELARIS EM-I; Violet PETAL) |
Elagolix + estradiol/NETA, placebo | Heavy menstrual bleeding associated with uterine fibroids | IIIb | Recruiting | USA; Puerto Rico | NCT03271489; M16-283 |
Elagolix ± estradiol/NETA | Heavy menstrual bleeding associated with uterine fibroids | III | Active, not recruiting | USA; Canada; Puerto Rico | NCT02925494; M12-816 (ELARIS UF-EXTEND) |
Elagolix ± estradiol/NETA, placebo | Heavy menstrual bleeding associated with uterine fibroids | III | Active, not recruiting | USA; Canada; Puerto Rico | NCT02654054; M12-815 (ELARIS UF-I) |
Elagolix ± estradiol/NETA, placebo | Heavy menstrual bleeding associated with uterine fibroids | III | Active, not recruiting | USA; Canada | NCT02691494; M12-817 (ELARIS UF-II) |
Elagolix, placebo | Endometriosis-associated pain | II | Completed | USA | NCT00973973; NBI-56418-0901 (Daisy PETAL) |
Elagolix, leuprorelin, placebo | Endometriosis-associated pain | II | Completed | Multinational | NCT00797225; NBI-56418-0703; 2007-006474-28 (Tulip PETAL) |
Elagolix, placebo | Endometriosis-associated pain | II | Completed | USA | NCT00619866; NBI-56418-0702 (Lilac PETAL) |
Elagolix, DMPA-SC | Endometriosis-associated pain | II | Completed | USA | NCT00437658; NBI-56418-0603 (PETAL) |
Elagolix, placebo | Endometriosis-associated pain | II | Completed | USA | NCT00109512; NBI-56418-0501 |
Elagolix ± estradiol/NETA, placebo | Heavy menstrual bleeding associated with uterine fibroids | IIb | Completed | Multinational | NCT01817530; M12-813; 2013-000082-37 |
Elagolix ± estradiol/NETA, estradiol or cyclical progesterone, placebo | Heavy menstrual bleeding associated with uterine fibroids | IIa | Completed | USA; Puerto Rico | NCT01441635; M12-663 |