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Elagolix (ABT-620) M12-817 Clinical Study Report R&D/17/0779

2.0 Synopsis

AbbVie Inc. Individual Study Table Referring (For National Authority to Part of Dossier: Use Only) Name of Study Drug: Volume: Elagolix (ABT-620) Page: Name of Active Ingredient: Elagolix Title of Study: A Phase 3 Study to Evaluate the and Safety of Elagolix in Combination with /Norethindrone Acetate for the Management of Associated with Uterine Fibroids in Premenopausal Women Coordinating Investigator: Study Sites: 77 sites in the and Publications: 1 published abstract Studied Period (Years): Phase of Development: 3 First Subject First Visit: 03 February 2016 Last Subject Last Visit: 23 January 2019 Objectives: 1) to assess the efficacy, safety, and tolerability of elagolix 300 mg twice a day (BID) in combination with estradiol 1 mg/norethindrone acetate 0.5 mg (E2/NETA) once a day (QD) versus to reduce heavy menstrual bleeding (HMB) associated with uterine fibroids, 2) to characterize the impact of E2/NETA on the safety/tolerability (including bone mineral density [BMD] and other hypoestrogenic side effects) and efficacy of elagolix. Methodology: This Phase 3, randomized, double-blind, multicenter, placebo-controlled study was designed to evaluate the efficacy, safety, and tolerability of elagolix 300 mg BID in combination with E2/NETA QD in the management of HMB associated with uterine fibroids in premenopausal women 18 to 51 years of age, inclusive. The study consisted of 4 periods: 1) a Washout Period (if applicable), 2) a Screening Period of approximately 2.5 to 3.5 months prior to first dose of study drug, 3) a 6-month Treatment Period, and 4) a 12-month Post-Treatment Follow-Up (PTFU) Period for subjects who either prematurely discontinued from the Treatment Period or completed the Treatment Period but did not enroll in the extension study (Study M12-816).

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Methodology (Continued): Potential subjects were required to meet eligibility criteria and provide informed consent before washout (if applicable), or initiation of any screening or study-specific procedures. Subjects were to visit the site for assessments and testing during the Washout Period (for subjects who were taking exclusionary medications such as hormonal medications or antifibrinolytics that required washout), during the Screening Period (Initial Screening Visit and Screening Product Collection Visits), and Treatment Period (Day 1 [Randomization] and monthly during Month 1 through Month 6). Eligible subjects were randomized in a 1:1:2 ratio to 1 of 3 treatment groups: placebo, elagolix 300 mg BID, or elagolix 300 mg BID+E2/NETA QD. Eligible subjects who completed the 6-month Treatment Period were allowed to participate in a 6-month extension study in which all subjects received active treatment with either elagolix 300 mg BID alone or elagolix 300 mg BID+E2/NETA. Subjects who did not enroll in the extension study were to enter a 12-month PTFU Period with phone or on-site visits every month. All subjects, except those who were exempted per protocol, were to use at least 2 forms of nonhormonal contraception (nonhormonal dual contraception) consistently throughout the Washout (if applicable), Screening, Treatment Period, and PTFU Period and receive counseling on the importance of consistent, appropriate, and effective use of . was permitted after completion of the PTFU Month 2 Visit if menses had returned. Number of Subjects (Planned and Analyzed): 400 planned; 378 randomized; 378 analyzed. Placebo: 100 planned, 94 analyzed; elagolix 300 mg BID: 100 planned, 95 analyzed; elagolix 300 mg BID+E2/NETA: 200 planned, 189 analyzed. Diagnosis and Main Criteria for Inclusion: Premenopausal women, 18 to 51 years of age, inclusive, were eligible for enrollment if they had a diagnosis of uterine fibroids that was documented by a pelvic ultrasound acquired at Screening (specifically, an intramural, submucosal non-pedunculated fibroid with total diameter ≥ 2 cm [longest diameter]; a subserosal fibroid ≥ 4 cm; or multiple fibroids with a total uterine volume of ≥ 200 cm3 to ≤ 2,500 cm3), adequate endometrial biopsy with no clinically significant endometrial pathology, and HMB evidenced by menstrual blood loss (MBL) > 80 mL per as calculated by the alkaline hematin method. Subjects were excluded if they had menstrual cycles that were > 38 days in length for the 3 months before Screening; a clinically significant gynecological disorder; a BMD T-score of the lumbar spine, femoral neck, or total hip ≤ –1.5 at Screening; a myomectomy, uterine artery embolization, or high-intensity focused ultrasound within 6 months before Screening; or endometrial ablation within 1 year before Screening. Subjects with coexisting adenomyosis were eligible for this study regardless of the type of adenomyosis (i.e., focal, diffuse dominant [> 50% of the myometrium], or diffuse nondominant) as long as they had a qualifying fibroid and HMB as required per protocol. Test Product, Dose/Strength/Concentration, Mode of Administration and Lot Number: Orally administered tablets of elagolix 300 mg BID (lot numbers 16-000707, 15-004747) and orally administered over-encapsulated tablets of E2/NETA (1 mg/0.5 mg) QD (lot numbers 15-006127,16-001698,16-002891, 17-001331). Duration of Treatment: 6 months of treatment with a 12-month follow-up period for subjects who did not enroll in the extension study (Study M12-816).

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Reference Therapy, Dose/Strength/Concentration and Mode of Administration and Lot Number: Orally administered tablets of placebo for elagolix 300 mg BID (lot numbers 16-000708, 15-004564) and capsules of placebo for E2/NETA (1 mg/0.5 mg) QD (lot numbers 12-004118,16-003269) Criteria for Evaluation Efficacy: The primary endpoint was the percentage of responders, defined as subjects who met the following conditions:  MBL volume < 80 mL during the Final Month (the last 28 days prior to and including the Reference Day), and  ≥ 50% reduction in MBL volume from Baseline to the Final Month (the last 28 days prior to and including the Reference Day). A subject who prematurely discontinued study drug because of adverse events (AEs), "lack of efficacy," or "requires surgery or invasive intervention for treatment of uterine fibroids" was considered to be a nonresponder regardless of whether she met the aforementioned responder criteria or not. The ranked secondary efficacy endpoints were: 1. change from Baseline in MBL volume to the Final Month, 2. percentage of subjects with suppression of bleeding (no bleeding allowed, spotting allowed) at the Final Month, 3. change from Baseline in MBL volume to Month 6, 4. change from Baseline in MBL volume to Month 3, 5. percentage of subjects with baseline hemoglobin (Hgb) ≤ 10.5 g/dL who had an increase in Hgb > 2 g/dL at Month 6, and 6. change from Baseline in MBL volume to Month 1. Other efficacy endpoints during the Treatment Period included other analysis of MBL volume, , suppression of bleeding, control of bleeding, bleeding days, Hgb concentration, uterine and fibroid volume, and quality of life. Pharmacodynamic/Pharmacokinetic: Pharmacodynamic (PD) variables were concentrations of estradiol (E2), , luteinizing (LH), and follicle-stimulating hormone (FSH). Pharmacokinetic (PK) variables were plasma exposures to elagolix and norethindrone. Safety: Safety evaluations were BMD changes, AEs (including AEs of special interest [AESI]), clinical laboratory parameters (including and lipid profiles), vital signs, electrocardiograms, endometrial assessment (endometrial thickness and biopsy), ovarian cysts, Columbia- Severity Rating Scale (C-SSRS), , and product complaints.

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Statistical Methods Efficacy: General Principles The full analysis set, which consists of all randomized subjects who received at least 1 dose of study drug, was used for efficacy analyses. The data from the full analysis set are presented by the treatment group assigned at the time of randomization, even if the subject did not receive the correct treatment or did not follow the protocol until completion. The full analysis set was used for all baseline and efficacy analyses. Primary Analysis of Primary Endpoint The primary endpoint was analyzed using a logistic regression model including treatment as the main effect and baseline MBL volume as a covariate. The missing Final Month MBL volume was imputed using multiple imputations for the primary analysis of the primary efficacy endpoint. Subset analyses of the primary endpoint were performed on the adenomyosis subsets, which consisted of subjects with coexisting adenomyosis, either at Baseline (N = 52) or at any time at Baseline or during the Treatment Period (N = 65). Analyses for Ranked Secondary and Other Efficacy Endpoints For the first ranked secondary efficacy endpoint, the change from Baseline to the Final Month in MBL volume obtained from the primary analysis after multiple imputation was summarized by treatment group and compared between each elagolix group and placebo, using 1-way analysis of covariance (ANCOVA) with treatment as the main effect and Baseline MBL volume as a covariate. For the third, fourth, and sixth ranked secondary endpoints, the comparison of change from Baseline in MBL volume to each month between each of the elagolix groups and placebo was performed on observed MBL volume using a MMRM model, with treatment, month, and an interaction between treatment and month as fixed-effect factors, and baseline MBL volume as a covariate. For other continuous efficacy variables, which include change and percent change from Baseline analyses, treatment group differences were analyzed using ANCOVA models with treatment group as the main effect and corresponding baseline value as a covariate. Categorical data were analyzed using Pearson's chi-square test, Fisher's exact test, or logistics regression, as appropriate. Pearson's chi-square test or Fisher's exact test (if ≥ 20% of the cells have expected counts less than 5) were used for the second and fifth secondary endpoints. Pharmacokinetic: Plasma concentration data at all visits for each subject were summarized based on available times after the last dose recorded at each visit. : Summary statistics of each hormone were determined at each study visit. The overall Month 1 to 6 mean/median hormone value was calculated using the median of each subject's hormone value measured at each of her monthly study visits (study visits Months 1 to 6). Safety: General Principles The safety analysis set, which consists of all randomized subjects who received at least 1 dose of study drug, was used for all safety analyses. All safety analyses were based on observed data. Each elagolix group was compared with placebo for all statistical comparisons with the exception of BMD changes, where the 2 elagolix groups were also compared with each other.

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Statistical Methods (Continued) Safety (Continued): Adverse Events The number and percentage of subjects who had AEs were tabulated by primary system organ class and MedDRA preferred term (version 21.0) for each treatment group. The overall incidence of AEs was summarized as were AEs by severity and relationship to study drug. AESIs defined by prespecified company MedDRA query (CMQ) categories, standardized MedDRA query (SMQ) categories, and a product MedDRA query (PMQ) category, were summarized by treatment group. AEs were also summarized for the PTFU Period. Clinical Laboratory Variables Including Lipids All laboratory variables were summarized with mean, median, standard deviation, minimum and maximum by treatment group. For laboratory values of interest, mean changes from Baseline for each elagolix group were compared with placebo using a 1-way ANOVA with treatment group as the main effect; comparisons were summarized for each visit. Shift tables for changes from Baseline to maximum values and to final visit values were provided based on Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 grades. Results for subjects who met potentially clinically significant (PCS) values were summarized. Select laboratory parameters were also summarized for the PTFU Period. Hepatotoxicity The number and percentage of subjects in each treatment group with maximum on-treatment values that met prespecified criteria compared with the upper limit of normal were summarized. Vital Signs Including Weight Analyses of mean changes in vital signs, including weight, were similar to those for clinical laboratory variables. Results for subjects who met PCS values were summarized. Analysis of BMD The percent change from Baseline to Month 6 of the Treatment Period was compared using an ANCOVA with treatment as the main effect and baseline BMD as a covariate. Two-sided 95% confidence intervals were constructed for the differences in percent change from Baseline to Month 6. T- and Z-scores were summarized. BMD changes were also summarized for the PTFU Period. Endometrial Biopsy and Thickness The number and percentage of subjects in each category of endometrial biopsy results were summarized for each treatment group. Changes in endometrial thickness were analyzed. The mean change from Baseline was compared between each elagolix group and placebo using a 1-way ANOVA with treatment as the main effect. Results obtained from TAU/TVU and MRI were analyzed separately. Ovarian Cysts The number and percentage of subjects with predefined complex and simple ovarian cysts were summarized for each treatment group at each relevant visit in the Treatment and PTFU Periods. Results obtained from TAU/TVU and MRI were analyzed separately. C-SSRS C-SSRS data were summarized as observed by treatment group. Pregnancy and outcomes were listed.

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Summary/Conclusions Efficacy Results: Primary Efficacy Endpoint The primary efficacy endpoint was achieved. Elagolix 300 mg BID+E2/NETA reduced MBL volume to < 80 mL and by ≥ 50% from Baseline in a clinically meaningful and statistically significantly larger proportion of subjects compared with placebo at Final Month during the Treatment Period (76.5% vs. 10.5%, respectively, P < 0.001). Ranked Secondary Efficacy Endpoints Elagolix 300 mg BID+E2/NETA met all 6 ranked secondary endpoints: 1. Change from Baseline in MBL volume to the Final Month of –168.8 mL compared with –4.3 mL for placebo (P < 0.001), 2. Proportion of subjects with suppression of bleeding (no bleeding allowed, spotting allowed) at the Final Month of 61.0% compared with 4.7% for placebo (P < 0.001), 3. Change from Baseline in MBL volume to Month 6 of –198.1 mL compared with +28.5 mL for placebo (P < 0.001), 4. Change from Baseline in MBL volume to Month 3 of –200.3 mL compared with –14.2 mL for placebo (P < 0.001), 5. Proportion of subjects with baseline Hgb ≤ 10.5 g/dL and increase from Baseline > 2 g/dL at Month 6 of 50.0% compared with 20.8% for placebo (P = 0.017), and 6. Change from Baseline in MBL volume to Month 1 of –127.0 mL compared with –2.1 mL for placebo (P < 0.001). Other Efficacy Endpoints Related to MBL and Fibroid and Uterine Volume Compared with placebo, elagolix 300 mg BID+E2/NETA statistically significantly:  reduced mean MBL volume from Baseline to Month 1 and each month thereafter,  led to amenorrhea, suppression of bleeding, and control of bleeding in a higher proportion of subjects at the Final Month compared with placebo,  increased Hgb by > 2 g/dL in women with baseline Hgb ≤ 10.5 g/dL in a higher proportion of subjects at Months 4, 5, and 6, and  reduced mean uterine volume from Baseline to Month 6 in the MRI subset. Additionally, elagolix 300 mg BID+E2/NETA showed a higher proportion of subjects with cumulative amenorrhea and cumulative suppression of bleeding compared with that of placebo at every time point beginning at Month 2. Of all subjects who received elagolix 300 mg BID+E2/NETA during the Treatment Period and entered the PTFU Period (N = 59), the majority (84.7%) reported a first post-treatment menses within 2 months after stopping elagolix. This analysis was also conducted in subjects who were either amenorrheic or had suppression of bleeding at the Final Month, and the majority (93.3% and 88.2%, respectively) of these subjects also reported their first post-treatment menses within 2 months after stopping study drug. The mean volume of the first post-treatment menses was 185.1 mL. In the subsets of subjects with coexisting adenomyosis, results of the primary endpoint were consistent with the results of the primary analysis of the full analysis set.

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Summary/Conclusions (Continued) Efficacy Results (Continued): Other Efficacy Endpoints - Patient-Reported Outcomes On the Symptom Quality of Life Questionnaire (UFS-QOL), elagolix 300 mg BID+E2/NETA statistically significantly lowered mean symptom severity scores and increased all mean HRQL scores (i.e., improved quality of life) compared with placebo at Month 6. On the Work Productivity and Activity Impairment Questionnaire: Uterine Fibroids (WPAI:UF), elagolix 300 mg BID+E2/NETA reduced the amount of time that work productivity was impaired due to uterine fibroid symptoms (i.e., it increased work productivity) at Month 6. Compared with placebo, elagolix 300 mg BID+E2/NETA showed a statistically significantly greater mean reduction from Baseline to Month 6 in presenteeism, work productivity loss, and activity impairment. On the Patient Global Impression of Change on Menstrual Bleeding (PGIC-MB), a statistically significantly larger proportion of subjects responded with "very much improved" or "much improved" in the elagolix 300 mg BID+E2/NETA group than in the placebo group at Month 6. Although there were numeric differences in the secondary variables between elagolix 300 mg BID+E2/NETA and elagolix 300 mg BID alone, similar and clinically meaningful results were observed. Pharmacokinetic Results: Following administration of elagolix 300 mg BID alone or with E2/NETA, plasma concentrations of elagolix remained constant throughout the Treatment Period. Norethindrone plasma concentrations remained at steady state throughout the Treatment Period. A treatment-dependent suppression of was observed in the elagolix 300 mg BID alone and elagolix 300 mg BID+E2/NETA groups. Treatment with elagolix 300 mg BID alone or with E2/NETA suppressed estradiol, LH, and FSH levels compared with placebo; however, FSH was suppressed less in the elagolix 300 mg BID alone group than in the elagolix 300 mg BID+E2/NETA group. Safety Results: Adverse Events The incidence of AEs in the elagolix 300 mg BID+E2/NETA group was generally similar to that of placebo with the exception of known hypoestrogenic effects that are consistent with the mechanism of action and known pharmacologic properties of elagolix. The majority of treatment-emergent AEs were nonserious and mild or moderate in severity. Both subject-reported data and AE data showed that AEs of hot flush and/or occurred in a greater percentage of subjects in the elagolix groups than in the placebo group, but the incidence and severity with elagolix 300 mg BID+E2/NETA were lower than with elagolix 300 mg BID. The addition of E2/NETA to elagolix reduced the incidence and severity of hot flush and/or night sweats throughout the Treatment Period. In addition, the median time to onset for AEs of hot flush or night sweats in the elagolix 300 mg BID+E2/NETA group was delayed compared with the elagolix 300 mg BID group. No AEs of suicide or suicidal ideation were reported in any treatment group at any time during the study.

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Summary/Conclusions (Continued) Safety Results (Continued): Ten of 189 subjects in the elagolix 300 mg BID+E2/NETA group compared with 1/94 subjects in the placebo group and 1/95 subjects in the elagolix 300 mg BID group had AEs of , affect lability, , or depressed . One of the 10 subjects in the elagolix 300 mg BID+E2/NETA group had an AE of affect lability that began as moderate but led to study drug discontinuation when it worsened to severe; the investigator considered the moderate AE to be a normal variant for the subject and the severe AE to be in increase in symptoms; no medication was prescribed and she was not referred to a mental health care provider. Eight of 189 subjects in the elagolix 300 mg BID+E2/NETA group compared with 2/94 subjects in the placebo group and 6/95 subjects in the elagolix 300 mg BID group had AEs of mood altered or mood swings. One subject, who was in the elagolix 300 mg BID+E2/NETA group, had a moderate nonserious AE of thrombosis (left calf) for which study drug was discontinued. She was treated with apixaban, and the event resolved. Twelve subjects had SAEs: 1/94 subject (1.1%) in the placebo group; 4/95 subjects (4.2%) in the elagolix 300 mg BID group; and 7/189 subjects (3.7%) in the elagolix 300 mg BID+E2/NETA group. No pattern of SAEs was observed, and all SAE preferred terms were reported for 1 subject each. Only 1 subject in the elagolix 300 mg BID+E2/NETA group discontinued study drug because of SAEs (anemia and dysfunctional uterine bleeding). No deaths were reported at any time during the study. Laboratory Parameters Mean Hgb values increased from Baseline with elagolix 300 mg BID+E2/NETA treatment as a result of the reduction of HMB; mean hemoglobin values for placebo were generally similar to Baseline throughout the Treatment Period. While mean platelet values decreased from Baseline with elagolix 300 mg BID+E2/NETA, no individual subject's values decreased to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3 or greater. With the exception of a moderate AE of platelet count decreased reported in 1 subject in the elagolix 300 mg group (94 × 103/UL), no AE related to low platelets was reported. No AEs of spontaneous bleeding were reported. Compared with placebo, treatment with elagolix 300 mg BID+E2/NETA increased the mean values of LDL-C, triglycerides, and apolipoprotein B; however, the magnitude of the effects on LDL-C and triglycerides in the elagolix 300 mg BID+E2/NETA group was lower than in the elagolix 300 mg BID group except at Month 6 for LDL-C. Apolipoprotein B values were higher in the elagolix 300 mg BID+E2/NETA group than in the elagolix 300 mg BID group. The mean increases in LDL-C and apolipoprotein B occurred in the first 3 months of elagolix treatment and then stabilized. Triglyceride values in the elagolix 300 mg BID+E2/NETA group also stabilized within the first 3 months but were variable in the elagolix 300 mg group; this variability was not clinically meaningful. One subject (elagolix 300 mg BID group) discontinued study drug because of a lipid value (severe AE of blood triglycerides increased [370 mg/dL]) along with blood pressure increased; her triglyceride level decreased to Grade 1 after discontinuation of study drug. No AEs of pancreatitis were reported. Mean LDL-C and apolipoprotein B values in the elagolix 300 mg BID+E2/NETA group returned to near baseline levels by PTFU Month 3. No major adverse cardiac events (MACE) occurred.

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Summary/Conclusions (Continued) Safety Results (Continued): As defined in the and Drug Administration's Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 2009, no cases of severe liver injury (i.e., irreversible liver failure that is fatal or requires liver transplantation) were reported in any subject in any group, and no subject met the biochemical criteria for Hy's law. Four subjects had transient elevations in liver transaminases during the Treatment Period that were ≥ 3  ULN or ≥ 5  ULN. None of these subjects had concurrent elevations in bilirubin. No pattern in time to onset of transaminase elevations was identified. In addition, none of the transaminase elevations was symptomatic, and all declined within 1 to 4 months after peak values, regardless of whether or not the subject continued elagolix treatment. One of these 4 subjects, who was in the elagolix 300 mg BID+E2/NETA group, discontinued study drug because of liver transaminase elevations; her levels returned to normal after study drug was discontinued. No other subject discontinued study drug because of liver transaminase elevations. Subjects with Discontinuation ALT and/or AST Subjects with Due to AE of ≥ 3 × ULN to ALT and/or AST Elevated Liver Treatment < 5 × ULN ≥ 5 × ULN Enzymes Placebo 0 0 0 Elagolix 300 mg BID 1 0 0 Elagolix 300 mg BID+E2/NETA 1 2 1 AE = adverse event: ALT = ; AST = aspartate transaminase; BID = twice a day; E2/NETA = estradiol/norethindrone acetate; ULN = upper limit of normal

Vital Signs The percentages of subjects who met sponsor-defined PCS values for systolic and diastolic blood pressure were higher in the elagolix 300 mg BID+E2/NETA group than in the placebo group. Seven of the 12 subjects who met sponsor-defined criteria for PCS values over 3 consecutive visits during the Treatment Period for blood pressure were in the elagolix 300 mg BID+E2/NETA group; however, 4 of these subjects had a history of hypertension. None of these subjects discontinued study drug. No subject met the criteria for sponsor-defined PCS values over 3 consecutive visits for heart rate or weight. Electrocardiograms One subject in the elagolix 300 mg BID+E2/NETA group had a clinically significant post-baseline ECG result, which was reported as a nonserious, moderate AE of QRS axis abnormal on Day 183. The ECG was repeated on Day 198 (Post 15) with the same abnormal results as Day 183. She was seen by a family practitioner and no diagnostic and/or therapeutic procedures were performed. The subject also had nonserious mild AEs of chest discomfort and cardiac flutter on Day 189, both of which resolved on Day 233 (Post 50). The subject completed both the Treatment Period and the PTFU Period.

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Summary/Conclusions (Continued) Safety Results (Continued): Bone Mineral Density The addition of E2/NETA to elagolix 300 mg BID resulted in mean decreases in BMD from Baseline to Month 6 that were not statistically significantly different from placebo for each anatomic location (lumbar spine, total hip, and femoral neck). Mean decreases with elagolix 300 mg BID alone were statistically significantly different from placebo at the lumbar spine and total hip. In addition, mean decreases in the elagolix 300 mg BID+E2/NETA group were statistically significantly smaller than in the elagolix 300 mg BID group for lumbar spine and total hip, and numerically smaller than with elagolix 300 mg BID for the femoral neck. Mean percent decreases from Baseline in BMD to Month 6 in the elagolix 300 mg BID+E2/NETA group were statistically significantly smaller than in the elagolix 300 mg BID group at lumbar spine and total hip and were not statistically significantly different from placebo. LS Mean Percent Decreases in BMD From Baseline to Month 6 Lumbar Treatment N Spine N Total Hip N Femoral Neck Placebo 68 –0.06 68 0.03 68 –0.10 Elagolix 300 mg BID 65 –2.94*# 66 –1.80*# 66 –1.19 Elagolix 300 mg BID+E2/NETA 147 –0.61 146 –0.12 146 –0.39 BID = twice a day; BMD = bone mineral density; E2/NETA = estradiol/norethindrone acetate; LS = least squares * P value ≤ 0.05 for test of difference between mean percent change from Baseline for elagolix 300 mg BID and elagolix 300 mg BID+E2/NETA is from an ANCOVA model with treatment as the main effect and baseline value as a covariate for Month 6 during the Treatment Period. # P value ≤ 0.05 for test of difference between mean percent change from Baseline for placebo and elagolix 300 mg BID is from an ANCOVA model with treatment as the main effect and baseline value as a covariate for Month 6 during the Treatment Period.

A higher percentage of subjects in the elagolix 300 mg BID group than in the elagolix 300 mg BID+E2/NETA group had > 3% BMD decrease in any anatomic location at Month 6. Seven subjects had a ≥ 8% BMD decrease during the Treatment Period for any anatomic location; 3 subjects in the elagolix 300 mg BID group and 4 subjects in the elagolix 300 mg BID+E2/NETA group; none of these subjects had bone fractures. No subject in the elagolix 300 mg BID+E2/NETA group had a > 5% decrease in BMD at lumbar spine at PTFU Month 6, and no subject in the elagolix 300 mg BID+E2/NETA group had a ≥ 8% decrease in BMD at lumbar spine at PTFU Month 12. Endometrial Safety Compared with placebo, treatment with elagolix 300 mg BID+E2/NETA decreased mean endometrial thickness over time and was not associated with adverse changes on endometrial biopsy. Ovarian Cysts No elagolix-treated subject had a treatment-emergent AE of ovarian cyst, and no subject in any treatment group had a post-treatment AE of ovarian cyst.

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Summary/Conclusions (Continued) Safety Results (Continued): Pregnancy One subject in the elagolix 300 mg BID+E2/NETA group had a positive serum on Day 1; however, the investigator stated that the subject was not pregnant and attributed the positive serum pregnancy test result to the subject's use of subcutaneous human chorionic injections for weight loss. Conclusions: The primary efficacy endpoint was achieved. Elagolix 300 mg BID+E2/NETA (1 mg/0.5 mg) QD reduced MBL volume to < 80 mL and ≥ 50% from Baseline in a clinically meaningful and statistically significantly larger proportion of subjects compared with placebo at Final Month during the Treatment Period (76.5% vs. 10.5%, respectively). Elagolix 300 mg BID+E2/NETA also met all 6 ranked secondary endpoints related to reduction of HMB. Statistically significant and clinically meaningful effects of elagolix 300 mg BID+E2/NETA were observed for most other efficacy parameters related to reduction of HMB. Analysis showed reductions in MBL volume that started at Month 1 and continued thereafter; higher proportions of subjects with amenorrhea, suppression of bleeding, and control of bleeding; increased Hgb by > 2 g/dL in women with baseline Hgb ≤ 10.5 g/dL in a higher proportion of women; and reductions in mean uterine volume in the MRI subset. Treatment with elagolix 300 mg BID+E2/NETA was generally well tolerated. The addition of E2/NETA to elagolix 300 mg BID reduced the incidence and severity of hot flush or night sweats, delayed the median time to onset of hot flush or night sweats, and decreased the extent of increases in LDL-C and triglycerides. Decreases in BMD were statistically significantly smaller in the elagolix 300 mg BID+E2/NETA group than in the elagolix 300 mg BID group and were not statistically different from placebo. Elevations in liver transaminases were transient and asymptomatic with no pattern in time to onset, were not associated with elevations in bilirubin, and declined irrespective of study drug discontinuation. No subject met the biochemical criteria for Hy's law. The results of this study demonstrate that elagolix 300 mg BID+E2/NETA provides significant benefit with a manageable safety profile in the management of HMB associated with uterine fibroids in premenopausal women and represents an important new medical option for these women.

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