Introduction Acute medication overuse can be a risk factor for chronification. Atogepant is an oral, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist. Objectives To evaluate change from baseline in monthly migraine days (MMDs) and acute medication use among participants of the PROGRESS trial with and without acute medication overuse. Methods PROGRESS (NCT03855137) was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial in adults with CM. Participants were randomized 1:1:1 to receive placebo, atogepant 30 mg twice daily (BID), or atogepant 60 mg once daily (QD) for 12 weeks, and categorized by acute medication overuse at baseline. Results From 778 participants randomized to treatment, and 755 participants in the modified intent-to-treat population, 500 (66.2%) had acute medication overuse—placebo: n=169 (68.7%); atogepant 30 mg BID: n=161 (63.6%); atogepant 60 mg QD: n=170 (66.4%). A ≥50% reduction in mean MMDs across the 12-week treatment period was achieved by a greater proportion of acute medication overuse participants treated with atogepant 30 mg BID (44.7%) and atogepant 60 mg QD (41.8%) compared with placebo (24.9%). Conclusion Regardless of acute medication overuse at baseline, atogepant demonstrated efficacy and was associated with a greater reduction in acute medication use days in people with CM.

To evaluate the efficacy and safety of elagolix as compared to placebo in the management of endometriosis-associated pain using a dataset of >1600 women. The efficacy of elagolix was also evaluated in pre-specified subgroups of women with different baseline characteristics. Data were pooled from two 6-month (M), placebo-controlled, phase 3 studies (Elaris Endometriosis [EM]-I and II) evaluating two doses of elagolix (150mg once daily [QD] and 200mg twice daily [BID]). Participants were 18-49 year old women with surgically diagnosed endometriosis and moderate/severe endometriosis-associated pain. Efficacy endpoints included the proportion of responders (controlled for rescue analgesic use) at M3 and M6 based on daily dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) scores recorded in an electronic diary. The proportion of pain responders at M3 was analyzed for different baseline (BL) characteristic subgroups (age, years: <25, 25-35,>35; Body Mass Index [BMI] kg/m2: <25, 25-30, >30; time since diagnosis, years: <2, 2-<5, ≥5; BL DYS score: 0.05 for DYS and NMPP; BL NMPP: p>0.05 for DYS and p=0.025 for NMPP). The most common AEs for elagolix-treated women were hot flush, headache, and nausea (Table). Decreases in BMD were observed with elagolix treatment at month 6, however no women had a BMD Z-score ≤ -2.0. Elagolix provided reductions in DYS and NMPP that were superior compared to placebo across numerous subgroups of women with different BL characteristics. Safety from this dataset of >1600 women was consistent with dose-dependent hypoestrogenic effects and the published safety from Elaris EM-I and II (Taylor et al., 2017).TableEfficacy and Safety of Elagolix vs. Placebo from an Integrated Analysis of Elaris EM-I and IIPlaceboElagolix 150mg QDElagolix 200mg BIDBaseline CharacteristicsN=734N=475N=477Age, years, mean (SD)32.4 (6.6)32.3 (6.4)32.3 (6.6)Race, white, n (%)645 (87.9%)419 (88.2%)422 (88.5%)BMI, kg/m2, mean (SD)a27.7 (6.3)27.6 (6.6)27.4 (6.6)Months since surgical diagnosis, mean (SD)45.1 (34.8)41.6 (33.0)45.7 (34.6)DYS score, mean (SD)2.2 (0.5)2.2 (0.5)2.1 (0.5)NMPP score, mean (SD)1.6 (0.5)1.7 (0.5)1.6 (0.5)Baseline Rescue Analgesic UseN=734N=475N=477None, mean, (SD)61 (8.3%)55 (11.6%)38 (8.0%)NSAID only, mean (SD)237 (32.3%)142 (29.9%)149 (31.2%)Opioid only, mean (SD)127 (17.3%)78 (16.4%)81 (17.0%)NSAID and Opioid, mean (SD)309 (42.1%)200 (42.1%)209 (43.8%)Efficacy at Month 3, n(%):N=726N=469N=469DYS respondersDYS: 153 (21.1%)DYS: 211 (45.0%)***DYS: 348 (74.2%)***NMPP respondersNMPP: 265 (36.5%)NMPP: 235 (50.1%)***NMPP: 263 (56.1%)***Efficacy at Month 6, n(%):N=727N=468N=468DYS respondersDYS: 176 (24.2%)DYS: 206 (44.0%)***DYS: 356 (76.1%)***NMPP respondersNMPP: 274 (37.7%)NMPP: 227 (48.5%)***NMPP: 291 (62.2%)***Safety during treatment period, n (%)N=734N=475N=477Any adverse event (AE)537 (73.2%)380 (80.0%)*399 (83.6%)***Any serious AE24 (3.3%)14 (2.9%)12 (2.5%)Any AE leading to discontinuation44 (6.0%)26 (5.5%)46 (9.6%)Hot Flush63 (8.6%)110 (23.2%)214 (44.9%)Headache88 (12.0%)80 (16.8%)95 (19.9%)Nausea92 (12.5%)51 (10.7%)76 (15.9%)Lumbar spine BMD, mean (SD) % change from baseline to month 60.5 (2.4) [N=553]-0.5 (2.3) [N=360]-2.5 (3.1) [N=365]BMI = body mass index, DYS = dysmenorrhea; NMPP = non-menstrual pelvic pain; NSAID = nonsteroidal anti-inflammatory drugs. Statistical significance vs. placebo is indicated for P<0.05 (*) and P<0.001 (***).a.Placebo N=731, elagolix 150mg QD N=472, elagolix 200mg BID N=473 Open table in a new tab

To evaluate the impact of elagolix, a novel oral gonadotropin-releasing hormone antagonist, on the health-related quality of life assessed by the EQ-5D-5L survey among patients with moderate-to-severe endometriosis-associated pain Premenopausal women with surgically-confirmed endometriosis and moderate-to-severe endometriosis-associated pain were randomized to placebo, elagolix 150mg once daily (QD) or elagolix 200mg twice daily (BID) in a 6-month, phase III placebo-controlled randomized trial. EQ-5D-5L was administered at baseline and months 1, 3 and 6 of treatment. Changes from baseline in EQ-5D-5L visual analog scale (VAS) and index scores (where “1” represents perfect health and “0” represents death) were compared between each elagolix dose and placebo using analysis of covariance while controlling for baseline scores A total of 815 patients were randomized and dosed (n=360, 226 and 229 in placebo, elagolix 150mg QD and elagolix 200mg BID; respectively). Baseline mean VAS scores were not significantly different between treatment groups (66.79, 65.19 and 68.0 for placebo, elagolix 150mg QD and elagolix 200mg BID; respectively). Least square (LS) mean change from baseline at month 3 was significantly higher (i.e. better) for each elagolix dose compared to placebo (5.09, 9.65 and 12.3 for placebo, elagolix 150mg QD and elagolix 200mg BID respectively; each p<0.01). Similar results were observed at month 6 (each p<0.05). Mean index scores were similar at baseline (0.73, 0.72 and 0.75 for placebo, elagolix 150mg QD and elagolix 200mg BID; respectively). LS mean changes from baseline were higher (i.e. better) for each elagolix dose compared to placebo at month 3 (0.06, 0.09 and 0.1 for placebo, elagolix 150mg QD and elagolix 200mg BID respectively; each p<0.01) . Similarly, each elagolix dose had higher LS mean changes at month 6 (p<0.05 for elagolix 200mg BID only) Both doses of elagolix significantly improved health-related quality of life measured by EQ-5D-5L among endometriosis patients

To evaluate self-reported improvements in endometriosis-associated pelvic pain (dysmenorrhea and non-menstrual pelvic pain), dyspareunia (DYSP), and quality of life (QoL) in women treated with elagolix for at least 12-months (M). Elaris EM-III and Elaris EM-IV were two extension studies of the 6M, pivotal, elagolix phase 3 studies. The extension studies evaluated two elagolix doses (150mg once daily [QD] and 200mg twice daily [BID]) for an additional 6M (overall treatment period of 12M). The data presented are from women who received elagolix in both the pivotal and extension studies. Study participants (treated: Elaris EM-III, n=287; Elaris EM-IV, n=282) were women, age 18-49, with surgically diagnosed endometriosis and moderate/severe endometriosis-associated pain at baseline during the pivotal trial. Endometriosis-associated pelvic pain was measured using a daily electronic Numeric Rating Scale (NRS; 0-10, which included both bleeding and non-bleeding days). The Patient Global Impression of Change (PGIC) was assessed monthly. The effects on DYSP were recorded in a daily electronic pain impact diary. QoL was evaluated with the 30-item Endometriosis Health Profile (EHP-30). The baseline values for these analyses were assessed prior to dosing in the pivotal studies. The improvements in endometriosis-associated pelvic pain (NRS pain scores and PGIC), reported in the pivotal study were maintained over 12M of elagolix treatment (table).1 The DYSP responder rate after 12M was higher with elagolix 200mg BID than with elagolix 150mg QD, which reflects a dose-dependent effect that was similar to the effect on DYSP reported in the pivotal studies.1 Changes from baseline in EHP-30 dimension scores were also maintained over 12M of elagolix treatment.2 No women discontinued due to new incidences of hot flush during the extension treatment period (hot flush new incidence rate: 4-8% across studies/doses). The results of the elagolix extension studies show that the improvements in pain symptoms and QoL observed in the placebo-controlled, 6M, pivotal studies were maintained over 12M of elagolix treatment.Tabled 1Endometriosis-associated pelvic pain, DYSP, and QoL after 12 months of elagolix treatment*Elaris EM-III, ELX/ELX150 mg QDN=149Elaris EM-III, ELX/ELX200 mg BIDN=138Elaris EM-IV, ELX/ELX150 mg QDN=142Elaris EM-IV, ELX/ELX200 mg BIDN=140NRS, mean percent (SD) change from BL-48 (39)-61 (36)-54 (35)-61 (34)PGIC, responders,a n/N [%]77/111 [69]93/102 [91]86/114 [75]89/106 [84]DYSP, responders,b n/N [%]38/84 [45]42/70 [60]39/85 [46]43/74 [58]EHP-30 Dimensions, mean (SD) change from BLPain-31.2 (22.2)-41.6 (21.6)-33.0 (23.7)-38.5 (21.9)Control and Powerlessness-39.6 (26.0)-51.6 (25.8)-36.5 (29.5)-43.5 (28.9)Emotional Well-Being-20.8 (20.6)-31.1 (23.4)-24.1 (22.4)-28.0 (25.6)Social Support-22.6 (30.1)-35.8 (32.1)-24.1 (28.3)-29.4 (31.0)Self-Image-20.2 (29.4)-25.1 (28.9)-20.3 (26.4)-24.9 (30.6)Sexual Intercoursec-24.2 (27.1)-30.6 (33.8)-23.2 (26.3)-33.2 (32.0)BID = twice daily; BL = baseline; DYSP = dyspareunia; EHP-30 = 30-item Endometriosis Health Profile; ELX/ELX = women who were originally randomized to active treatment in the pivotal studies and continued to receive their assigned elagolix doses during the extension studies; M = month; NRS = numeric rating scale; PGIC = Patient Global Impression of Change; QD = once daily; QoL = quality of life* Some women received more than 12-months of treatment due to the timing of their enrollment in the extension studiesa Proportion of women whose response was “very much improved” or “much improved” on the PGIC.b Clinically meaningful response determined in the pivotal studies with a receiver operating characteristics analysis using the Patient Global Impression of Change; responders also required stable or decreased rescue analgesic usec Sexual intercourse is a modular domain of the EHP-30 Open table in a new tab

To evaluate the long-term safety and efficacy of elagolix, an oral, non-peptide gonadotropin-releasing hormone antagonist, for the management endometriosis-associated pain. These were two, extension studies (Elaris EM-III and Elaris EM-IV) of the pivotal, 6-month (M), phase 3 studies. The extension studies evaluated an additional 6M of treatment (overall treatment period of 12M) with two elagolix doses (150mg once daily [QD] and 200mg twice daily [BID]). The data presented are from women who received elagolix in both the pivotal and extension studies (elagolix/elagolix participants). Elagolix/elagolix participants (treated: Elaris EM-III, n=287; Elaris EM-IV, n=282) were 18-49 year old women with surgically diagnosed endometriosis and moderate/severe endometriosis-associated pain. Baseline was assessed prior to dosing in the pivotal studies. The co-primary efficacy endpoints were the proportion of responders (pain reduction and stable/decreased rescue analgesic use) based on the average monthly dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) scores. Safety assessments included new incidences of adverse events (AE) during the extension study, clinical laboratory tests, and changes in bone mineral density (BMD). The reductions in DYS and NMPP following 6M of elagolix treatment reported in the pivotal studies were maintained over 12M of treatment across both extension studies/dose groups. Over 50% of women were responders for DYS and NMPP following 12M of elagolix treatment at both doses (table). The proportion of women with new incidences of hot flush ranged between 4-8%. A dose-dependent decrease from baseline in BMD was observed in the extension at M6 in both studies/dose groups. Elagolix provided sustained reductions in DYS and NMPP in these two long-term extension studies. The safety/tolerability was consistent with hypoestrogenic effects and no new safety concerns were identified with long-term elagolix use.Tabled 1Primary efficacy and safety of elagolix over 12-months of treatmentEfficacyElaris EM-III, ELX/ELX 150 mg QD N=149Elaris EM-III, ELX/ELX 200 mg BID N=138Elaris EM-IV, ELX/ELX 150 mg QD N=142Elaris EM-IV, ELX/ELX 200 mg BID N=140DYS respondersa at end of pivotal study M6, n (%)b60 (40%)109 (80%)72 (51%)107 (76%)DYS respondersa after 12Mc of treatment, n (%)b61 (52%)86 (78%)62 (51%)88 (76%)NMPP respondersa end of pivotal study M6, n (%)b74 (50%)96 (71%)82 (58%)89 (64%)NMPP respondersa after 12Mc of treatment, n (%)b79 (68%)76 (69%)81 (66%)78 (67%)Safety during the extension treatment periodd, n (%)Any hypoestrogenic-related AEe,f32 (21%)25 (18%)30 (21%)29 (21%)Hot flushf6 (4.0%)8 (5.8%)7 (4.9%)11 (7.9%)Depressionf8 (5.4%)4 (2.9%)1 (0.7%)0 (0.0%)Insomniaf5 (3.4%)5 (3.6%)4 (2.8%)3 (2.1%)Any AEf111 (74%)102 (74%)117 (82%)109 (78%)AE = adverse event; BID = twice daily; ELX/ELX = women who were originally randomized to active treatment in the pivotal studies and continued to receive their assigned elagolix doses during the extension studies; DYS = dysmenorrhea; NMPP = non-menstrual pelvic pain; QD = once dailya Clinically meaningful response determined in the pivotal studies with a receiver operating characteristics analysis using the Patient Global Impression of Change; responders also required stable or decreased rescue analgesic useb Pivotal data is from women that enrolled in the extension studies; percentages calculated from observed, non-missing datac Treatment length was ≥ 12M for select women who continued in pivotal study ≥ 6M to repeat procedures and ensure eligibility for extension studyd Data from Elaris EM-IV are preliminary; the presentation will include final datae Non-bone, hypoestrogenic-related AEsf New incidences of AEs during the extension treatment period Open table in a new tab

To evaluate the long-term effect of elagolix, an oral, non-peptide gonadotropin-releasing hormone antagonist, on bone mineral density (BMD) in women with moderate/severe endometriosis-associated pain. Elaris EM-III and Elaris EM-IV were two extension studies of the 6-month (M) pivotal, phase 3 studies, which evaluated two elagolix doses (150 mg once daily [QD] and 200 mg twice daily [BID]) for an additional 6M (overall treatment period of 12M) and up to 12M post-treatment period. Presented data are from women who received elagolix in both the pivotal and extension studies. Study participants (Elaris EM-III, n=287; Elaris EM-IV, n=282) were premenopausal, 18-49 year-old women with endometriosis and a baseline BMD Z-score higher than -1.5. Lumbar spine BMD was measured by dual energy X-ray absorptiometry. A central reader evaluated images and numeric results, blinded to treatment groups. Baseline was prior to dosing in the previous pivotal studies. Due to enrollment timing in the extension studies, some women received >12M of treatment. Post-treatment analyses of BMD recovery are ongoing. Following 12M of treatment in Elaris EM-III and EM-IV, the mean BMD Z-score of the lumbar spine was 0.5 and 0.3 in the 150mg QD group respectively, and 0.2 and -0.04 in the 200mg BID group (Table) which is within the normal range of -2.0 to +2.0 (Ref 1). Following 12M of treatment in Elaris EM-III and EM-IV, there were 0.9% and 0.8% in the 150mg QD group respectively, and 13% and 11% in the 200mg BID group with a decrease in mean BMD ≥8%. In women with endometriosis-associated pain, long-term elagolix treatment was associated with a decrease in lumbar spine BMD, which was greater with 200mg BID.Tabled 1Changes in Lumbar Spine Bone Mineral Density in Women with Endometriosis-associated PainLumbar Spine Bone Mineral DensityElaris EM-III, Elagolix 150 mg QD, N=114Elaris EM-III, Elagolix 200 mg BID, N=108Elaris EM-IV, Elagolix 150 mg QD, N=122Elaris EM-IV, Elagolix 200 mg BID, N=111Mean Z-score at BL0.6a0.5c0.4e0.4fMean Z-score, M12 (extension M6)0.50.20.3-0.04Mean density at BL in gms/cm21.2b1.2d1.2e1.2fMean (95% CI) percentage change from BL to M12 (extension M6)-0.6 (-1.2, -0.04)-3.6 (-4.2, -3.0)-1.1 (-1.7, -0.6)-3.9 (-4.5, -3.3)No change or increase, n (%)49 (43%)16 (15%)43 (35%)17 (15%)Decrease ≤ 3%, n (%)46 (40%)30 (28%)49 (40%)26 (23%)Decrease >3, ≤ 5%, n (%)15 (13%)20 (19%)25 (20%)22 (20%)Decrease >5 , < 8%, n (%)3 (2.6%)28 (26%)4 (3.3%)33 (30%)Decrease ≥ 8% , n (%)1 (0.9%)14 (13%)1 (0.8%)13 (12%)BL = baseline; M=month. Data are preliminary; the presentation will include final data. (a) N=116; (b) N=117; (c) N=115; (d) N= 120; (e) N=127; (f) N=121 Open table in a new tab

BACKGROUNDEndometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies.METHODSWe performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary.RESULTSA total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P< 0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P < 0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P = 0.003 and P < 0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings.CONCLUSIONSBoth higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670.)

ObjectiveTo evaluate the effect of elagolix, an oral, non-peptide gonadotropin-releasing hormone antagonist, on bone mineral density (BMD) in women with endometriosis-associated pain (EAP).DesignThese were two similar, double-blind, randomized, placebo-controlled, multicenter, 6-month, phase 3 studies (Studies 1 [North America] and 2 [global]) evaluating two doses of elagolix (150 mg once daily [QD] or 200 mg twice daily [BID]). Each study has an ongoing 6-month extension study.Materials and MethodsParticipants included in either study were premenopausal, 18-49 years old, surgically diagnosed with endometriosis, with a baseline BMD Z-score higher than -1.5. BMD of the lumbar spine, total hip and femoral neck was measured by dual energy X-ray absorptiometry (DXA) at baseline and month 6 with GE Lunar or Hologic equipment. Images were reviewed and evaluated by a central reader (different for each study), blinded to treatment groups. The mean percentage change from baseline to month 6 was analyzed using a one-way ANOVA. Treatment-emergent adverse events (AEs) were recorded.ResultsCompared with baseline, there was a dose-dependent decrease in lumbar spine BMD following 6 months of treatment with elagolix. The mean percentage change from baseline to month 6 was significantly different from placebo for each elagolix dose in both studies (Table). The proportion of participants with lumbar spine BMD decrease from baseline greater than 3% was also dose-dependent (Table). There were also dose-dependent deceases in BMD of the total hip and femoral neck.ConclusionsTabled 1Changes in Lumbar Spine Bone Mineral Density in Women with Endometriosis-associated PainLumbar Spine Bone Mineral DensitySTUDY1, PlaceboN=282STUDY1, Elagolix150 mg QD N=186STUDY1, Elagolix200 mg BID N=182STUDY2, PlaceboN=269STUDY2, Elagolix150 mg QD N=174STUDY2, Elagolix200 mg BID N=180Mean at BL, g/cm21.181.171.181.181.171.18Z-score at BLa0.470.560.540.460.260.41Mean (95% CI) percentage change from BL to M60.47 (0.16, 0.79)-0.32 (-0.70, 0.07)-2.61 (-3.00, -2.22)0.49 (0.20, 0.78)-0.71 (-1.07, -0.35)-2.45 (-2.81, -2.10)Mean (95% CI) difference from placebo in mean percentage change from BL to M6-0.79 (-1.29, -0.30)**-3.08 (-3.58, -2.59)***-1.20 (-1.67, -0.74)***-2.95 (-3.41, -2.49)***Number (%) of participants, categories of percentage change from BL to M6No change or increase165 (59)87 (47)34 (19)152 (57)64 (37)33 (18)Decrease ≤ 3%100 (35)78 (42)65 (36)104 (39)86 (49)68 (38)Decrease >3, ≤ 5%12 (4.3)14 (7.5)45 (25)10 (3.7)20 (11)49 (27)Decrease >5 , < 8%4 (1.4)6 (3.2)29 (16)bbbDecrease ≥ 8%1 (0.4)1 (0.5)9 (4.9)bbbBL = baseline; M=month; CI=confidence interval. Statistical significance vs. placebo is indicated for P<0.01 (**), P≤0.001 (***). a. Study 1 n: placebo=288, elagolix 150 QD=190, elagolix 200 BID = 188; Study 2 n: placebo=359, elagolix 150 QD=226, elagolix 200 BID=229. b. Due to the blinding status of individual participant treatment assignments, these data are unavailable until the presentation. Open table in a new tab ObjectiveTo evaluate the effect of elagolix, an oral, non-peptide gonadotropin-releasing hormone antagonist, on bone mineral density (BMD) in women with endometriosis-associated pain (EAP). To evaluate the effect of elagolix, an oral, non-peptide gonadotropin-releasing hormone antagonist, on bone mineral density (BMD) in women with endometriosis-associated pain (EAP). DesignThese were two similar, double-blind, randomized, placebo-controlled, multicenter, 6-month, phase 3 studies (Studies 1 [North America] and 2 [global]) evaluating two doses of elagolix (150 mg once daily [QD] or 200 mg twice daily [BID]). Each study has an ongoing 6-month extension study. These were two similar, double-blind, randomized, placebo-controlled, multicenter, 6-month, phase 3 studies (Studies 1 [North America] and 2 [global]) evaluating two doses of elagolix (150 mg once daily [QD] or 200 mg twice daily [BID]). Each study has an ongoing 6-month extension study. Materials and MethodsParticipants included in either study were premenopausal, 18-49 years old, surgically diagnosed with endometriosis, with a baseline BMD Z-score higher than -1.5. BMD of the lumbar spine, total hip and femoral neck was measured by dual energy X-ray absorptiometry (DXA) at baseline and month 6 with GE Lunar or Hologic equipment. Images were reviewed and evaluated by a central reader (different for each study), blinded to treatment groups. The mean percentage change from baseline to month 6 was analyzed using a one-way ANOVA. Treatment-emergent adverse events (AEs) were recorded. Participants included in either study were premenopausal, 18-49 years old, surgically diagnosed with endometriosis, with a baseline BMD Z-score higher than -1.5. BMD of the lumbar spine, total hip and femoral neck was measured by dual energy X-ray absorptiometry (DXA) at baseline and month 6 with GE Lunar or Hologic equipment. Images were reviewed and evaluated by a central reader (different for each study), blinded to treatment groups. The mean percentage change from baseline to month 6 was analyzed using a one-way ANOVA. Treatment-emergent adverse events (AEs) were recorded. ResultsCompared with baseline, there was a dose-dependent decrease in lumbar spine BMD following 6 months of treatment with elagolix. The mean percentage change from baseline to month 6 was significantly different from placebo for each elagolix dose in both studies (Table). The proportion of participants with lumbar spine BMD decrease from baseline greater than 3% was also dose-dependent (Table). There were also dose-dependent deceases in BMD of the total hip and femoral neck. Compared with baseline, there was a dose-dependent decrease in lumbar spine BMD following 6 months of treatment with elagolix. The mean percentage change from baseline to month 6 was significantly different from placebo for each elagolix dose in both studies (Table). The proportion of participants with lumbar spine BMD decrease from baseline greater than 3% was also dose-dependent (Table). There were also dose-dependent deceases in BMD of the total hip and femoral neck. ConclusionsTabled 1Changes in Lumbar Spine Bone Mineral Density in Women with Endometriosis-associated PainLumbar Spine Bone Mineral DensitySTUDY1, PlaceboN=282STUDY1, Elagolix150 mg QD N=186STUDY1, Elagolix200 mg BID N=182STUDY2, PlaceboN=269STUDY2, Elagolix150 mg QD N=174STUDY2, Elagolix200 mg BID N=180Mean at BL, g/cm21.181.171.181.181.171.18Z-score at BLa0.470.560.540.460.260.41Mean (95% CI) percentage change from BL to M60.47 (0.16, 0.79)-0.32 (-0.70, 0.07)-2.61 (-3.00, -2.22)0.49 (0.20, 0.78)-0.71 (-1.07, -0.35)-2.45 (-2.81, -2.10)Mean (95% CI) difference from placebo in mean percentage change from BL to M6-0.79 (-1.29, -0.30)**-3.08 (-3.58, -2.59)***-1.20 (-1.67, -0.74)***-2.95 (-3.41, -2.49)***Number (%) of participants, categories of percentage change from BL to M6No change or increase165 (59)87 (47)34 (19)152 (57)64 (37)33 (18)Decrease ≤ 3%100 (35)78 (42)65 (36)104 (39)86 (49)68 (38)Decrease >3, ≤ 5%12 (4.3)14 (7.5)45 (25)10 (3.7)20 (11)49 (27)Decrease >5 , < 8%4 (1.4)6 (3.2)29 (16)bbbDecrease ≥ 8%1 (0.4)1 (0.5)9 (4.9)bbbBL = baseline; M=month; CI=confidence interval. Statistical significance vs. placebo is indicated for P<0.01 (**), P≤0.001 (***). a. Study 1 n: placebo=288, elagolix 150 QD=190, elagolix 200 BID = 188; Study 2 n: placebo=359, elagolix 150 QD=226, elagolix 200 BID=229. b. Due to the blinding status of individual participant treatment assignments, these data are unavailable until the presentation. Open table in a new tab BL = baseline; M=month; CI=confidence interval. Statistical significance vs. placebo is indicated for P<0.01 (**), P≤0.001 (***). a. Study 1 n: placebo=288, elagolix 150 QD=190, elagolix 200 BID = 188; Study 2 n: placebo=359, elagolix 150 QD=226, elagolix 200 BID=229. b. Due to the blinding status of individual participant treatment assignments, these data are unavailable until the presentation.

To evaluate the women's perspective on the improvement of endometriosis-associated pain (EAP) based on the Numeric Rating Scale (NRS) and Patient Global Impression of Change (PGIC) assessments and effects on dyspareunia (DYSP) during treatment with elagolix, an oral, non-peptide gonadotropin-releasing hormone antagonist. These were two similar, double-blind, randomized, placebo-controlled, multicenter, 6-month, phase 3 studies (Studies 1 and 2) evaluating 150 mg once daily (QD) or 200 mg twice daily (BID) doses of elagolix. These studies included premenopausal women, age 18-49, with surgically diagnosed endometriosis and moderate/severe EAP. Rescue analgesics were allowed. Participants recorded EAP on the NRS (0-10, none to worst) and DYSP (0-3, none to severe, or not applicable) in a daily electronic diary. The PGIC, assessed monthly, is a scale of change (scores 1-7, very much improved to very much worse). The clinically meaningful response for DYSP was determined with a receiver operating characteristics analysis using the PGIC as the anchor. In Studies 1 and 2, 871 and 815 participants were randomized and treated, and 653 (75%) and 631 (77%) completed 6 months of treatment, respectively. Compared to placebo, a significant decrease from baseline in the NRS mean pain score was seen at months 3 and 6 with elagolix treatment in both studies (Table, month 6 only). Compared to placebo, significantly more women reported much or very much improvement in pain on the PGIC scale at months 3 and 6 (Table, month 6 only). DYSP was not an inclusion criterion; 76% of women (666/871) reported a history of DYSP at screening in Study 1. Compared to placebo, the responder rate for DYSP was significantly higher with elagolix 200 mg BID at months 3 and 6 in both studies (Table, month 6 only), and not significant versus placebo with 150 mg QD. The effects of elagolix on these secondary pain endpoints were dose-dependent in both studies. In women with endometriosis, 6 months of elagolix treatment led to a dose-dependent improvement in EAP, when self-assessed using NRS and PGIC scales, and DYSP, which was statistically significantly improved for elagolix 200 mg BID compared to placebo.Tabled 1Secondary Endpoints: NRS, PGIC, and DYSPSecondary Pain ParametersSTUDY1, Placebo N=374STUDY1, Elagolix 150 mg QD N=249STUDY1, Elagolix 200 mg BID N=248STUDY2, Placebo N=360STUDY2, Elagolix 150 mg QD N=226STUDY2, Elagolix 200 mg BID N=229NRS, mean (SD) score at BL5.58 (1.57)5.72 (1.73)5.48 (1.59)5.56 (1.76)5.69 (1.78)5.33 (1.78)NRS, mean (SD) score at M64.48 (2.24)3.98 (2.60)2.96 (2.55)4.03 (2.35)3.42 (2.51)2.59 (2.39)NRS, LS mean (SE) change from BL to M6-1.15 (0.11)-1.80 (0.14)***-2.75 (0.14)***-1.60 (0.11)-2.28 (0.14)***-2.87 (0.14)***PGIC Response at M3,a n/N [%]100/346 [29]120/229 [52] ***165/227 [73] ***108/333 [32]118/211 [56]***156/209 [75]***PGIC Response at M6,a n/N [%]95/308 [31]115/207 [56] ***149/200 [75] ***116/326 [36]123/213 [58]***159/210 [76]***DYSP, mean (SD) score at BL1.51 (0.83)1.52 (0.82)1.55 (0.86)1.45 (0.83)1.48 (0.88)1.43 (0.85)DYSP, LS mean (SE) change from BL to M6b-0.29 (0.05)-0.41 (0.06)-0.60 (0.06)***-0.36 (0.05)-0.42 (0.06)-0.69 (0.06)***DYSP, responders at M6, n [%]90 [33]74 [40]81 [50]*100 [39]65 [40]92 [56]**NRS = numeric rating scale; PGIC = Patient Global Impression of Change; DYSP = dyspareunia; BL = baseline; M = month; QD = once daily; BID = twice daily; LS = least squares. Statistical significance vs. placebo is indicated for P<0.05 (*), P<0.01 (**), P<0.001 (***). Ns vary for each time point and will be reported in the presentation. NRS and DYSP change from baseline p-values derived from a mixed-model with repeated measures analysis with treatment as a main effect and baseline value as a covariate. DYSP responder p-values derived from a logistic regression with treatment as a main effect and baseline value as a covariate. PGIC p-values derived from a chi-square test. a. Proportion of participants whose response was "very much improved" or "much improved" on the PGIC. Open table in a new tab

To evaluate the effect of elagolix, an oral, non-peptide gonadotropin-releasing hormone antagonist, on the quality of life (QoL) in women with moderate/severe endometriosis-associated pain (EAP). These were two similar, double-blind, randomized, placebo-controlled, multicenter, 6-month, phase 3 studies (Studies 1 [North America] and 2 [global]) evaluating two doses of elagolix (150 mg once daily [QD] or 200 mg twice daily [BID]). Each study has an ongoing 6-month extension study. Participants were 18-49 year-old women with surgically diagnosed endometriosis and moderate/severe EAP. Following a screening period, 871 and 815 women in Studies 1 and 2, respectively, were randomized to receive placebo, elagolix 150 mg QD or 200 mg BID and treated for 6 months. The Endometriosis Health Profile (EHP-30) is a self-administered questionnaire used to measure health related QoL in women with endometriosis (scale of 0 [never] to 4 [always]). In this study, all 5 dimensions (pain, control and powerlessness, social support, emotional well-being, and self-image) of the core component, and 1 (sexual intercourse) from the modular component were assessed at baseline and months 1, 3 and 6 during the treatment period. The effect of elagolix on change from baseline of the 6 dimension scores was analyzed using an analysis of covariance model while controlling for baseline values. In each of the 6 EHP-30 dimensions, each dose of elagolix showed greater reductions from baseline (greater improvements in health status) than placebo at months 1, 3 and 6 in a dose-dependent manner (Table, month 6 only). Compared to placebo, these changes were significantly different for elagolix 200 mg BID for all EHP-30 dimensions, whereas the changes were significantly different for elagolix 150 mg QD for all dimensions except self-image and sexual intercourse dimension in both studies (Table). Over the course of 6 months, treatment with elagolix resulted in significant, dose-dependent improvements in QoL, based on the EHP-30 questionnaire.Tabled 1EHP-30 Dimension Mean Scores at Baseline and Mean Change from Baseline to Month 6 in Studies 1 and 2EHP-30 Dimension(BL Mean Score; LS Mean Change from BL to M6)STUDY1Placebo N=374STUDY1Elagolix 150 mg QD N=249STUDY1Elagolix 200 mg BID N=248STUDY2Placebo N=360STUDY2Elagolix 150 mg QD N=226STUDY2Elagolix 200 mg BID N=229Pain57.6; -15.458.1; -28.0***58.3; -40.5***55.2; -19.554.2; -28.2***53.6; -36.4***Control and Powerlessness66.9; -21.270.3; -34.7***71.2; -50.7***62.3; -24.761.1; -31.0**60.5; -41.5***Emotional Well-being47.4; -13.050.2; -20.0***51.1; -27.8***46.3; -14.444.9; -20.8**46.2; -25.3***Social Support51.3; -12.855.7; -20.3**57.9; -32.6***50.7; -13.748.9; -19.3*50.0; -26.3***Self-image48.7; -11.351.9; -15.450.3; -27.9***44.8; -13.945.2; -15.244.1; -22.7***Sexual Intercourse64.3; -11.662.8; -16.370.2; -29.1***59.1; -14.156.9; -17.160.2; -28.2***EHP=Endometriosis Health Profile; BL = baseline; M = month; LS = least squares. The Ns in the treatment group header represent the number randomized and treated; the Ns for change from BL at M6 of each treatment group vary for each dimension and will be reported in the presentation. Decreases in the mean change from BL reflect improvements in QoL on the given dimension. Statistical significance on the mean change from BL to M6 vs. placebo was analyzed by an ANCOVA model and indicated by two-sided P-values of P≤0.05 (*), P≤0.01(**), P<0.001 (***). Open table in a new tab