Oral GnRH Antagonists in Combination with Estradiol and Norethindrone Acetate for Pain Relief Associated with Endometriosis: A Review of Evidence of a Novel Class of Hormonal Agents

Figures & data

Table 1 Summary of Clinical Trials of Elagolix in the Treatment of Endometriosis Associated Pain

Author/Year	Study Design	Participants	Intervention	Comparator	Duration	Outcomes
						Efficacy			Safety
						Effect on Dysmenorrhea	Effect on NMPP	Effect on Dyspareunia	Hot Flushes	BMD Loss (Lumbar Spine)
Carr et al, 2014^Citation29	Phase 2, randomized, multicenter, double-blind, active-controlled study	Women aged 18–49 years, with laparoscopically confirmed endometriosis and CPSSS of ≥ 6, dysmenorrhea and NMPP components of ≥ 2 prior to randomization	Elagolix 150 mg once daily Elagolix 75 mg twice daily	Depo medroxyprogesterone acetate (DMPA) 104 mg subcutaneously at week 1 and 12	24 weeks of treatment and 24 weeks follow up	Mean change dysmenorrhea component of CPSSS	Mean change NMPP component of CPSSS	Mean change dyspareunia component of CPSSS	Percent patients with ≥1 episode of hot flushes:	Percent change of BMD from baseline at 24 weeks
						Elagolix 150 ng once daily: – 1.5 Elagolix 75 mg twice daily: – 1.3 DMPA: – 1.7	Elagolix 150 ng once daily: – 1.2 Elagolix 75 mg twice daily: – 1.2 DMPA: – 1.05	Elagolix 150 ng once daily: – 1.2 Elagolix 75 mg twice daily: – 1.0 DMPA: – 0.9	Elagolix 150 ng once daily: 71.1% Elagolix 75 mg twice daily: 82.1% DMPA: 75.9%	Elagolix 150 ng once daily: – 0.11% Elagolix 75 mg twice daily: – 1.28% DMPA: – 0.99%
Taylor et et al, 2017 Elaris-I^Citation30	Double blinded, phase 3, RCT	Premenopausal women aged 18–49 years with surgically diagnosed endometriosis and moderate to severe endometriosis pain	Elagolix 150 mg once daily -Elagolix 200 mg/ twice daily	Placebo	6 months	Dysmenorrhea responder rates at 6 months	NMPP responder rates at 6 months:	Change in dyspareunia score (baseline to 3 months)	Proportion of participants with hot flushes	Percent BMD change from baseline
						Placebo: 23.1% Elagolix 150 once daily: 42.1% Elagolix 200 mg twice daily: 75.3%	Placebo: 34.9% Elagolix 150 once daily: 45.7% Elagolix 200 mg twice daily: 62.1%	Placebo: − 0.29 ± 0.04 Elagolix 150 mg once daily: − 0.39 ± 0.05 Elagolix 200 mg twice daily: − 0.49 ± 0.05	Placebo 7% Elagolix 150 mg once daily: 23.7% Elagolix 200 mg twice daily 42.3%	Placebo 0.47% Elagolix 150 mg once daily: – 0.32% Elagolix 200 mg twice daily – 2.61%
Taylor et et al, 2017 Elaris-II^Citation30	Double blinded, phase 3, RCT	Premenopausal women aged 18–49 years with surgically diagnosed endometriosis and moderate to severe endometriosis pain	Elagolix 150 mg once daily Elagolix 200 mg/ twice daily	Placebo	6 months	Dysmenorrhea responder rates at 6 months	NMPP responder rates at 6 months:	Change in dyspareunia score (baseline to 3 months)	Proportion of participants with hot flushes	Percent BMD change from baseline
						Placebo: 25.4% Elagolix 150 once daily: 46.2% Elagolix 200 mg twice daily: 76.9%	Placebo: 40.6% Elagolix 150 once daily: 51.6% Elagolix 200 mg twice daily: 62.2%	Placebo: − 0.30 ± 0.04 Elagolix 150 mg once daily − 0.39 ± 0.05 Elagolix 200 mg twice daily: − 0.60 ± 0.05	Placebo: 10.3% Elagolix 150 mg once daily: 22.6% Elagolix 200 mg twice daily. 47.6%	Percent BMD change from baseline Placebo: 0.56% Elagolix 150 mg once daily: – 0.72% Elagolix 200 mg twice daily. – 2.49%
Surry et al, 2018 Elaris-III^Citation31	Double blinded, randomized, phase 3, extension clinical trial	Women who completed 6 months of elagolix treatment continued to take the same medication dose for additional 6 months	Elagolix 150 mg once daily	Elagolix 200 mg/ twice daily	Continuous 12 months of treatment	Dysmenorrhea responder rates at 12 months:	NMPP responder rates at 12 months:	Dyspareunia responder rate at 12 months:	Proportion of participants with hot flushes	Percent BMD change from baseline
						Elagolix 150 mg/day: 52.1% Elagolix 200 mg twice daily: 78.2%	Elagolix 150 mg once daily: 67.5% Elagolix 200 mg twice daily: 69.1%	Elagolix 150 mg once daily 34.2% Elagolix 200 mg twice daily: 60.0%	Elagolix 150 mg once daily 29.5% Elagolix 200 mg twice daily: 52.2%	Elagolix 150 mg once daily – 0.63% Elagolix 200 mg twice daily: – 3.6%
Surry et al, 2018 Elaris-IV^Citation31	Double blinded, randomized, phase 3, extension clinical trial	Women who completed 6 months of elagolix treatment continued to take the same medication dose for additional 6 months	Elagolix 150 mg once daily	Elagolix 200 mg/ twice daily	Continuous 12 months of treatment	Dysmenorrhea responder rates at 12 months:	NMPP responder rates at 12 months:	Dyspareunia responder rate at 12 months:	Proportion of participants with hot flushes	Percent BMD change from baseline
						Elagolix 150 mg/day: 50.8% Elagolix 200 mg twice daily: 75.9%	Elagolix 150 mg once daily: 66.4% Elagolix 200 mg twice daily: 67.2%	Elagolix 150 mg once daily 45.9% Elagolix 200 mg twice daily: 58.1%	Elagolix 150 mg once daily 25.4% Elagolix 200 mg twice daily: 55.0%	Elagolix 150 mg once daily – 1.1% Elagolix 200 mg twice daily: – 3.91%

Abbreviations: NMPP, non-menstrual pelvic pain; CPSSS, Composite Pelvic Symptoms and Signs Score; DMPA, depot medroxyprogesterone acetate; BMD: bone mineral density.

Table 2 Clinical Trials of Relugolix Without Hormonal Add-Back in Endometriosis Related Pain

Author/Year	Study Design	Participants	Intervention	Comparator	Duration	Outcomes
						Efficacy				Safety
						Effect on Overall Pelvic Pain	Effect on Dysmenorrhea	Effect on Dyspareunia	Effect on NMPP	Hot Flushes	BMD Loss
Osuga et al, 2021^Citation34	Phase 2, multicenter, double blinded, parallel group, placebo controlled RCT	Japanese women diagnosed with endometriosis (surgically or imaging of chocolate cysts). With moderate/ severe dysmenorrhea and pelvic pain	Relugolix 10 mg/ day Relugolix 20 mg/day Relugolix 40 mg/dy	Placebo Leuprolin 3.74 mg / 4 weeks	12 weeks	Change in pelvic pain from baseline (VAS, 1–100 mm)	Change in dysmenorrhea from baseline (VAS, 1–100 mm)	Change in dyspareunia from baseline. (VAS, 1–100 mm)	Change in NMPP from baseline. (VAS, 1–100 mm)	Proportion of participants with hot flushes	Percent BMD change from baseline
						Placebo: −3.8 (95% CI: −5.9, – 1.6) Relugolix 10 mg/day: −6.2 (95% CI: −8.0, – 4.4) Relugolix 20 mg/day: – 8.1 (95% CI: −10.7, – 5.4) Relugolix 40 mg/day: – 10.4 (95% CI: −12.6, – 8.3) Leuprolin: – 10.6 (95% CI: −12.9, – 8.63)	Placebo: – 5.0 Relugolix 10 mg/day: – 15.0 Relugolix 20 mg/day: – 20.0 Relugolix 40 mg/day: – 28.0 Leuprolin: – 30.0	Placebo: – 4.0 Relugolix 10 mg/day: – 1.0 Relugolix 20 mg/day: – 1.0 Relugolix 40 mg/day: – 1.0 Leuprolin: – 6.0		Placebo 8.2% Relugolix 10 mg/day: 8.7% Relugolix 20 mg/day: 19% Relugolix 40 mg/day: 52.4% Leuprolin: 41.3%	Placebo – 1% (1.7) Relugolix 10 mg/day: – 1% (1.9) Relugolix 20 mg/day: – 1.3% (2.1) Relugolix 40 mg/day: – 2.2% (2.2) Leuprolin: – 2.2% (1.7)
Osuga et al, 2021^Citation35	Phase 2, randomized, open-label, parallel-group extension study	Japanese women who completed treatment with relugolix in previous phase-2 study.	Relugolix 10 mg/ day Relugolix 20 mg/day Relugolix 40 mg/dy	Placebo Leuprolin 3.74 mg / 4 weeks	Additional 12 weeks as an extension study	Change in pelvic pain from baseline (VAS, 1–100 mm)	Change in dysmenorrhea from baseline (VAS, 1–100 mm)	Change in dyspareunia from baseline. (VAS, 1–100 mm)	Change in NMPP from baseline. (VAS, 1–100 mm)	Proportion of participants with hot flushes	Percent BMD change from baseline
						Placebo – 3.2 (12.6) Relugolix 10 mg/day: – 6.8 (10.56) Relugolix 20 mg/day: – 9.0 (11.84) Relugolix 40 mg/day – 11.9 (11.23) Leuprolin: – 12.7 (12.57)	Placebo: – 5.8 (17.13) Relugolix 10 mg/day: – 15.4 (18.05) Relugolix 20 mg/day: – 19.8 (20.43) Relugolix 40 mg/day – 29,5 (17.54) Leuprolin: – 27.2 (19.86),	Placebo: – 1.1 (12.66) Relugolix 10 mg/day: – 3.5 (10.85) Relugolix 20 mg/day: – 3.6 (11.55) Relugolix 40 mg/day – 0.9 (12.04) Leuprolin: – 4.6 (15.09)		Placebo: 8.2% Relugolix 10 mg/day: 11.7% Relugolix 20 mg/day: 23% Relugolix 40 mg/day: 53.4% Leuprolin: 46.3%	Placebo: – 1.99% Relugolix 10 mg/day: – 2.34% Relugolix 20 mg/day: – 2.94% Relugolix 40 mg/day: – 2.91% Leuprolin: – 2.16%
Harada et al, 2021^Citation36	Phase 3, multicenter, active controlled, double blinded RCT	Japanese women diagnosed with endometriosis (surgically, imaging of chocolate cysts, or clinical signs), with moderate/ severe dysmenorrhea and pelvic pain	Relugolix 40 mg as oral daily dose	Leuprolin 3.74 mg / 4 weeks Subcutaneous injection	24 weeks	Change in pelvic pain from baseline (VAS, 1–100 mm)	Change in dysmenorrhea from baseline (VAS, 1–100 mm)	Change in dyspareunia from baseline. (VAS, 1–100 mm)	Change in NMPP from baseline. (VAS, 1–100 mm)	Proportion of participants with hot flushes	Percent BMD change from baseline
						Relugolix 40 mg/ day: – 52.6 ± 1.3 Leuprolin: – 57.5 ± 1.4	Relugolix 40 mg/ day: – 61.6 ± 0.5 Leuprolin: – 63.9 ± 0.6	Relugolix 40 mg/ day: – 13.2 ± 3.3 Leuprolin: – 15.4 ± 3.7	Relugolix 40 mg/ day: – 19.7 ± 1.2 Leuprolin: – 23.2 ±1.2	Relugolix 40 mg/ day: 42.7% Leuprolin: 48.8%	Relugolix 40 mg/ day: – 4.80% Leuprolin: – 4.84%

Abbreviations: VAS, visual analogue scale (0–100 mm); BMD, bone mineral density.

Table 3 Summary of Clinical Trials of Relugolix Plus Combination Hormonal Therapy in Endometriosis Related Pain

Study/ Author/Year	Study Design	Participants	Intervention	Comparator	Duration	Outcomes
						Efficacy				Safety
						Effect on Dysmenorrhea	Effect on NMPP	Effect on Dyspareunia	Effect on Analgesic use	Hot Flushes	BMD Loss
SPIRIT-1 Giudice, et al, 2022^Citation37	Phase 3, multicenter, placebo controlled, double blinded RCT (N=638)	Women with surgically confirmed endometriosis with moderate/ severe dysmenorrhea and associated non-menstrual pain	Combination therapy of Relugolix 40 mg + estradiol 1 mg and norethindrone acetate 0.5 mg as oral daily dose	-Placebo -Delayed relugolix regimen: relugolix 40 mg/ day as monotherapy for 12 weeks followed by relugolix combination therapy for another 12 weeks	24 weeks	Responder rate in dysmenorrhea	Responder rate in NMPP	Change in dyspareunia NRS	Proportion of participants not using analgesic	Proportion of participants with hot flushes	BMD loss at lumbar spine
						Placebo: 27% Relugolix combination therapy: 75% Delayed relugolix combination therapy: 72%	Placebo: 40% Relugolix combination therapy: 59% Delayed relugolix combination therapy: 58%	Placebo: – 1.7 0.2) Relugolix combination therapy: – 2.4 (0.2) Delayed relugolix combination therapy: – 2.2 (0.2)	Placebo 31% Relugolix combination therapy: 56% Delayed relugolix combination therapy: 58%	Placebo 10% Relugolix combination therapy: 10% Delayed relugolix combination therapy: 34%	Placebo < 1% Relugolix combination therapy: < 1% Delayed relugolix combination therapy: – 2% (lumbar spine)
SPIRIT-2 Giudice, et al, 2022^Citation37	Phase 3, multicenter, placebo controlled, double blinded RCT (N= 623)	Women with surgically confirmed endometriosis with moderate/ severe dysmenorrhea and associated non-menstrual pain	Combination therapy of Relugolix 40 mg + estradiol 1 mg and norethindrone acetate 0.5 mg as oral daily dose	-Placebo -Delayed relugolix regimen (relugolix 40 mg/ day as monotherapy for 12 weeks followed by relugolix combination therapy for another 12 weeks	24 weeks	Responder rate in dysmenorrhea	Responder rate in NMPP	Change in dyspareunia NRS	Proportion of participants not using analgesics	Proportion of participants with hot flushes	BMD loss at lumbar spine
						Placebo 30% Relugolix combination therapy: 75% Delayed relugolix combination therapy: 73%	Placebo: 43% Relugolix combination therapy: 66% Delayed relugolix combination therapy: 53%	Placebo: – 1.9 (0.2) Relugolix combination therapy: – 2.4 (0.2) Delayed relugolix combination therapy: −2.3 (0.2)	Placebo 24% Relugolix combination therapy: 54% Delayed relugolix combination therapy: 57%	Placebo 3% Relugolix combination therapy: 14% Delayed relugolix combination therapy: 35%	Placebo < 1% Relugolix combination therapy: < 1% Delayed relugolix combination therapy: – 2% (lumbar spine)

Abbreviations: NRS, numerical rating scale (0–10); NMPP, non-menstrual pelvic pain; BMD, bone mineral density.

Table 4 Summary of EDELWEISS Trial of Linzagolix in Treatment of Endometriosis Associated Pain

Author/year	Study design	Participants	Intervention	Comparator	Duration	Outcomes
						Efficacy			Safety
						Responder Rates for Overall Pelvic Pain at 24 Weeks	Responder Rates for Dysmenorrhea at 24 Weeks	Responder Rates for NMPP at 24 Weeks	Proportion of Participants with hot Flushes at 12 Weeks	BMD Loss % (at Lumbar Spine)
Donnez et al, 2020 EDELWEISS trial^Citation38	Phase 2b, double-blind, randomized, parallel-group, placebo-controlled, dose-ranging trial	Premenopausal women aged 18–49 years with surgically diagnosed endometriosis and moderate to severe endometriosis pain	Linzagolix 50 mg/day Linzagolix 75 mg/ day Linzagolix (titrated dose; start at 75 mg for 12 weeks and adjust dose according to E2 level in next 12 weeks)-Linzagolix 100 mg/day Linzagolix 200 mg/day	Placebo	24 weeks months	Placebo: 34.5% Linzagolix 50 md/day: 52.5% Linzagolix 75 mg/day: 70.8% Linzagolix 75 mg (titrated dose): 66.7% Linzagolix 100 mg/day 66.7% Linzagolix 200 mg/ day: 77.3%	Placebo: 28.5% Linzagolix 50 md/day: 47.5% Linzagolix 75 mg/day: 58.3% Linzagolix 75 mg (titrated dose): 71.1% Linzagolix 100 mg/day 82.1% Linzagolix 200 mg/ day: 84.1%	Placebo: 37.1% Linzagolix 50 md/day: 50% Linzagolix 75 mg/day: 72.9% Linzagolix 75 mg (titrated dose): 64.4% Linzagolix 100 mg/day 64.1% Linzagolix 200 mg/ day: 72.7%	Placebo: Not reported Linzagolix 50 md/day: 10.9% Linzagolix 75 mg/day: 14.3% Linzagolix 75 mg (titrated dose): 19.3% Linzagolix 100 mg/day 26.9% Linzagolix 200 mg/ day:42.1%	Placebo: Not reported Linzagolix 50 md/day: 0.14% Linzagolix 75 mg/day: – 0.8% Linzagolix 75 mg (titrated dose): – 1.0% Linzagolix 100 mg/day – 0.1.37% Linzagolix 200 mg/ day: – 2.6%

Abbreviations: NMPP, non-menstrual pelvic pain; BMD loss, bone mineral density loss.

Carr B, Dmowski WP, O’Brien C, et al. Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density. Reprod Sci. 2014;21(11):1341–1351. doi:10.1177/1933719114549848

 PubMed Web of Science ®Google Scholar

Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an Oral GnRH antagonist. N Engl J Med. 2017;377(1):28–40. doi:10.1056/NEJMoa1700089

 PubMed Web of Science ®Google Scholar

Surrey E, Taylor HS, Giudice L, et al. Long-term outcomes of elagolix in women with endometriosis: results from two extension studies. Obstet Gynecol. 2018;132(1):147–160. doi:10.1097/AOG.0000000000002675

 PubMed Web of Science ®Google Scholar

Osuga Y, Seki Y, Tanimoto M, Kusumoto T, Kudou K, Terakawa N. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: a randomized, double-blind, placebo-controlled study. Fertil Steril. 2021;115(2):397–405. doi:10.1016/j.fertnstert.2020.07.055

 PubMed Web of Science ®Google Scholar

Osuga Y, Seki Y, Tanimoto M, Kusumoto T, Kudou K, Terakawa N. Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, in women with endometriosis-associated pain: phase 2 safety and efficacy 24-week results. BMC Womens Health. 2021;21(1):250. doi:10.1186/s12905-021-01393-3

 PubMed Web of Science ®Google Scholar

Harada T, Osuga Y, Suzuki Y, Fujisawa M, Fukui M, Kitawaki J. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study. Fertil Steril. 2022;117(3):583–592. doi:10.1016/j.fertnstert.2021.11.013

 PubMed Web of Science ®Google Scholar

Giudice LC, As-Sanie S, Arjona Ferreira JC, et al. Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2). Lancet. 2022;399(10343):2267–2279. doi:10.1016/S0140-6736(22)00622-5

 PubMed Web of Science ®Google Scholar

Donnez J, Taylor HS, Taylor RN, et al. Treatment of endometriosis-associated pain with linzagolix, an oral gonadotropin- releasing hormone-antagonist: a randomized clinical trial. Fertil Steril. 2020;114(1):44–55. doi:10.1016/j.fertnstert.2020.02.114

 PubMed Web of Science ®Google Scholar