Gonadotropin-Releasing Hormone Receptor Antagonist Mono- and Combination Therapy With Estradiol/Norethindrone Acetate Add-Back: Pharmacodynamics and Safety of OBE2109

Gonadotropin-Releasing Hormone Receptor Antagonist Mono- and Combination Therapy With... Abstract Context OBE2109 is a potent, oral gonadotropin-releasing hormone receptor antagonist being developed for the treatment of sex-hormone–dependent diseases in women. Objective We assessed the pharmacodynamics and safety of OBE2109 alone and combined with estradiol (E2)/norethindrone acetate (NETA) add-back therapy on E2 levels and vaginal bleeding. Design, Setting, and Participants This was a single-center, open-label, randomized, parallel-group study in 76 healthy premenopausal women. Interventions Women were randomly assigned to take the following doses (in milligrams) once daily for 6 weeks: OBE2109, 100 or 200; or OBE2109/E2/NETA, 100/0.5/0.1, or 100/1.0/0.5, or 200/1.0/0.5. Main Outcome Measures E2 concentrations, bleeding pattern, exploratory bone metabolism biomarkers, and adverse events. Results OBE2109 100 mg and 200 mg alone reduced E2 levels to reach median levels of 19.5 and 3.2 pg/mL, respectively, at week 4. Median E2 levels after combined OBE2109/add-back therapy ranged between 25 and 40 pg/mL. OBE2109 100 mg or 200 mg alone induced amenorrhea. By day 15, >85% of women had no vaginal bleeding during the last 4 weeks of treatment. Add-back therapy partially impaired bleeding control: The highest amenorrhea rate (53%) was observed with OBE2109 100 mg/1.0 mg/0.5 mg. The addition of E2/NETA, particularly at 1 mg/0.5 mg, mitigated the increase of two bone markers induced by OBE2109 200 mg. Conclusion OBE2109 promptly lowered E2 levels. Add-back therapy may be required to prevent adverse effects on bone in women treated with the 200-mg dose (at 100 mg in some women). These results provide a basis for OBE2109 regimen selection to treat sex-hormone–dependent diseases. Sex hormone–dependent diseases in women comprise infertility, endometriosis, uterine fibroids, breast cancer, and central precocious puberty (1). Among these, endometriosis and uterine fibroids are the most common, affecting approximately 10% to 15% and 5% to 21% of women worldwide, respectively (2). Endometriosis is characterized by the implantation of endometrial-like tissue outside the uterus and is associated with symptoms such as dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia (3, 4). Uterine fibroids are common benign uterine tumors whose occurrence leads to anemia caused by heavy bleeding, pelvic pain, pressure, dysmenorrhea, reduced quality of life, and infertility (5). Sex hormone suppression stops the growth of endometrial tissue and uterine fibroids, induces amenorrhea, and provides symptom relief. When considering suppressing estradiol (E2), Barbieri’s “estradiol threshold hypothesis” (6) suggests that partial suppression of E2 may be sufficient to control endometriosis symptoms without having to face the adverse effects that are similar to those experienced during menopause, such as bone mineral density (BMD) loss or hot flushes (6). The findings of the Riggs et al. (7) modeling study further support this hypothesis and those authors proposed that E2 levels between 20 and 50 pg/mL can be optimal to control symptoms of E2-dependent diseases while being sufficiently high to prevent hypoestrogenic effects. In addition, they concluded that serum E2 value at 4 weeks of treatment by a gonadotropin-releasing hormone (GnRH) analog is a reliable predictor of effect on BMD at 6 months. The ovarian production of estrogen (mainly E2) and progesterone (P4) are driven by luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and their release by the pituitary is regulated by GnRH. GnRH modulation, therefore, provides an indirect mechanism for affecting E2 and P4 levels. So far, the standard way to manipulate GnRH activity is by exposing the pituitary continuously to a GnRH agonist, which initially stimulates production of gonadal hormones for 1 to 2 weeks (“flare effect”) and eventually desensitizes the pituitary gland to GnRH (by causing GnRH-receptor downregulation). Pituitary desensitization markedly reduces the secretion of LH and FSH and thus induces a profound suppression of gonadal hormones (8, 9). Besides symptom relief, the hypoestrogenic state induced by GnRH agonists leads to a variety of adverse effects such as BMD loss or hot flushes, which affect compliance and limit the use of these treatments to 6 months, beyond which add-back therapy (ABT) is mandatory (10, 11). GnRH antagonist (GnRH-ATG) is a new class of drugs that could match the efficacy of GnRH agonists without their limitations (12). This class shows an absence of the flare effect, causes a rapid and sustained inhibition of gonadotropin secretion, and may allow, depending on the pharmacologic and pharmacokinetic properties of the individual antagonist, dose-dependent adjustment of gonadal hormone levels (eg, E2). ABT has its own contraindications and adverse effects; it is thus possible to achieve a balance of efficacious symptom relief and minimally associated BMD loss without ABT, at least in some patients (13). OBE2109 is a new GnRH-ATG administered orally once daily, which is being developed for the treatment of heavy menstrual bleeding associated with uterine fibroids and management of pain associated with endometriosis (14–16). OBE2109 has been shown to rapidly induce a dose-dependent decrease in LH, FSH, and E2 levels (17). Based on the compound’s high bioavailability and low pharmacokinetic (PK) variability, it seems adequate for predictable pharmacologic responses. The objective of the current study was to characterize the effect of continuous daily administrations of up to 200 mg of OBE2109 for 6 weeks on serum E2 levels, vaginal bleeding pattern, bone metabolism markers, and safety parameters of OBE2109 alone or in combination with either of two doses of E2/NETA ABT (0.5 mg/0.1 mg or 1 mg/0.5 mg) to healthy women of reproductive age with regular menstrual cycles. Materials and Methods Trial design The OBE2109 PK/pharmacodynamics (PD) study was an open-label, randomized, single-center phase 1 trial conducted at Biokinetics Europe (Belfast, Northern Ireland) from January to April 2017. The trial was approved by the Health and Social Care Research Ethics Committee A, Northern Ireland, and the UK health authority, and was carried out in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines. Participants The OBE2109 PK/PD study included healthy, premenopausal women aged 18 to 48 years, with body mass index ranging from 18.5 to 30 kg/m2 and regular menstrual cycles of 21 to 35 days. The main exclusion criteria were the history or presence of any significant disease or modification in baseline safety parameters, hormonal contraception during the 3 months before screening, and the use of any prescription or over-the-counter medication within 28 days before the first administration of OBE2109. All women provided written informed consent. Intervention and randomization After screening assessments and during the second half of the menstrual cycle, women received norethindrone (5 mg; Norethisterone; Wockhardt, Wrexham, UK) three times daily for 10 days to synchronize menstrual cycles. Upon confirmed withdrawal bleeding, women received a 6-week, open-label course of once-daily OBE2109 with or without ABT (Activella; Novo Nordisk, Bagsvaerd, Denmark; or Eviana; Isdin, Barcelona, Spain) according to one of the following regimens: OBE2109 100 mg (referred to hereafter as 100 mg); OBE2109 100 mg and Eviana [E2 0.5 mg/NETA 0.1 mg; referred to hereafter as 100 mg/low dose (LD)]; OBE2109 100 mg and Activella [E2 1 mg/NETA 0.5 mg; referred to hereafter as 100 mg/standard dose (STD)]; OBE2109 200 mg (referred to hereafter as 200 mg); and OBE2109 200 mg and Activella (E2 1 mg/NETA 0.5 mg; referred to hereafter as 200 mg/STD). The first 45 women were to be randomly allocated to 100 mg, 100 mg/LD, or 100 mg/STD in a 1:1:1 ratio. Another 30 women were then to be randomly assigned to either 200 mg or 200 mg/STD (1:1). Pharmacokinetic and pharmacodynamic end points We evaluated circulating E2, P4, OBE2109, metabolite KP017, and norethindrone levels predose weekly; E2 and P4 were also determined at the end-of-study visit. In addition, within-day variability of E2 levels was measured after treatment week 3. From the start of menstrual cycle synchronization to the end-of-study visit, participating women filled in a daily uterine bleeding diary. Bleeding was assessed using a semiquantitative bleeding scale, as follows: no bleeding, spotting (light staining, dark blood, no sanitary protection needed or only panty liner), bleeding (one to four completely soiled maxi sanitary towels or one to eight soiled tampons, or equivalent combination of the two), or heavy bleeding (more than four completely soiled maxi sanitary towels or eight soiled tampons, or equivalent combination of the two). Bone resorption and bone turnover markers were measured at baseline and after the 6-week treatment period. A schematic study flow diagram is presented in Fig. 1. A detailed schedule of events is presented in Supplemental Table 1. Figure 1. View largeDownload slide Study flow diagram describing key study events. D1, day 1; EOS, end-of-study visit; KP017, a metabolite of OBE2109; TID, three times daily. Figure 1. View largeDownload slide Study flow diagram describing key study events. D1, day 1; EOS, end-of-study visit; KP017, a metabolite of OBE2109; TID, three times daily. The primary end points of the study were the group comparison of serum E2 within-day variability and E2 trough levels over time. As secondary end points, we described the women’s bleeding patterns over time. To assess OBE2109’s potential to inhibit ovulation, we compared P4 trough levels over time as an indicator for ovulation. Changes from baseline of bone-specific alkaline phosphatase (B-ALP), procollagen 1 intact N-terminal propeptide (P1NP), collagen type 1 β-carboxy-telopeptide (CTX), and the deoxypyridinoline/creatinine ratio (cDPD) served as exploratory markers of bone metabolism. Exposure to OBE2109 and ABT was controlled by reviewing group trough OBE2109, KP017, and norethindrone (NET) plasma levels. All bioanalytical assessments of OBE2109, KP017, and NET were analyzed with liquid chromatography tandem-mass spectrometry at BioTrial BioAnalytical Services (Montreal, Canada) and E2 levels were analyzed by liquid chromatography tandem-mass spectrometry at Covance (Endocrine Sciences, Calabasas Hills, CA) using methods validated to the current US Food and Drug Administration guidance for bioanalytical validation. Lowest quantifiable concentrations were 10 ng/mL, 5 ng/mL, 10 pg/mL, and 1 pg/mL. For all analyses, 10 nonzero calibration standards were used to generate the calibration curve. Related coefficients of determination for the regressions throughout the study were ≥0.9965. Quality control samples for accuracy and precision were included in each analysis batch and met the acceptance criteria (i.e., two-thirds of quality controls within 85% to 115% of target, and ≤50% of quality controls at the same concentration outside 85% to 115% of the target). P4, CTX, P1NP, and B-ALP levels, and cDPD were assessed at a commercial laboratory using validated chemiluminescence or radioimmunoassay methods (The Doctors Laboratory, London, UK). Lowest quantifiable concentrations were 0.636 nmol/L, 10 pg/mL, 5 µg/L, 1.5 µg/L, and 7nM (for DPD), respectively. Safety end points Safety evaluations included the number and proportion of women experiencing treatment-emergent adverse events (AEs) and clinically important changes in standard clinical laboratory parameters, electrocardiogram, vital signs, or physical examination. A detailed schedule of measurements is provided in Supplemental Table 1. Statistical analysis E2 assessments of this open-label phase 1 study comparing different OBE2109 and ABT combinations were exploratory and no formal sample size calculation was performed. However, we considered a minimum of 12 evaluable women to be sufficient to reliably explore any differences between OBE2109 and ABT treatments; thus, we planned to enroll 15 women per group. We conducted safety analyses using all women who had at least one dose of OBE2109 and PD and PK assessments in women with at least one valid PD or PK observation without major protocol deviation. End points were summarized using descriptive statistics; standard formulae were used to generate PK parameters such as minimal or maximal concentrations, and area under the curve (AUC). Results Participants A total of 142 women were screened, of whom 87 entered menstrual cycle synchronization. The first 76 women were randomly assigned to either 100 mg, 100 mg/LD, 100 mg/STD, 200 mg, or 200mg/STD, and 73 women completed the treatment. A subject disposition diagram is presented in Supplemental Fig. 1. Demographics of the 76 participants were very similar: One woman was black, all the others were white; all were between 20 and 48 years of age (mean, 34 years), had a body mass index between 18.8 and 29.9 kg/m2, and a mean historical menstrual cycle length between 27 and 29 days (Table 1). Table 1. Participant Demographics   100 mg (n = 16)  100 mg/LD (n = 15)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Race, no. (%)             Black  0 (0.0)  1 (6.7)  0 (0.0)  0 (0.0)  0 (0.0)   White  16 (100.0)  14 (93.3)  15 (100.0)  15 (100.0)  15 (100.0)  Age, mean (range), y  34.6 (23–47)  34.1 (20–45)  34.7 (23–48)  33.5 (21–47)  36.3 (24–47)  Weight, mean (range), kg  61.8 (51.8–82.4)  67.5 (49.9–87.0)  63.0 (52.0–85.1)  61.0 (44.6–76.6)  66.3 (51.0–85.3)  BMI, mean (range), kg/m2  23.1 (19.3–29.5)  25.1 (20.6–29.4)  23.5 (20.0–29.4)  23.1 (18.8–28.8)  24.3 (18.9–29.0)  Menstrual cycle duration (history)a, d  28.7 (24–35)  27.4 (24–30)  27.9 (21–30)  28.8 (25–35)  28.8 (24–35)    100 mg (n = 16)  100 mg/LD (n = 15)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Race, no. (%)             Black  0 (0.0)  1 (6.7)  0 (0.0)  0 (0.0)  0 (0.0)   White  16 (100.0)  14 (93.3)  15 (100.0)  15 (100.0)  15 (100.0)  Age, mean (range), y  34.6 (23–47)  34.1 (20–45)  34.7 (23–48)  33.5 (21–47)  36.3 (24–47)  Weight, mean (range), kg  61.8 (51.8–82.4)  67.5 (49.9–87.0)  63.0 (52.0–85.1)  61.0 (44.6–76.6)  66.3 (51.0–85.3)  BMI, mean (range), kg/m2  23.1 (19.3–29.5)  25.1 (20.6–29.4)  23.5 (20.0–29.4)  23.1 (18.8–28.8)  24.3 (18.9–29.0)  Menstrual cycle duration (history)a, d  28.7 (24–35)  27.4 (24–30)  27.9 (21–30)  28.8 (25–35)  28.8 (24–35)  a Numbers of women with retrievable menstrual cycle history were 10 (100 mg), 12 (100 mg/LD), 11 (100 mg/STD), 13 (200 mg), and 15 (200 mg/STD). The mean and range were calculated over the last three menstrual cycles. If, for a given cycle, the woman could only provide a range, the median value was used. View Large Pharmacokinetics All women treated with OBE2109 at 100 mg and 200 mg were well exposed to the medication. Median trough levels of the weekly assessments were between 3250 and 4750 ng/mL for the OBE2109 100-mg group and between 6700 and 11,700 ng/mL for the OBE2109 200-mg group, and were approximately dose proportional. Similarly, the metabolite KP017 results were dose proportional (data not shown). All but one woman with ABT were consistently exposed to NET; weekly median trough levels were between 43.7 and 70.3 pg/mL and 239 to 463 pg/mL for the LD and STD groups, respectively. NET values were comparable with published data and were approximately dose dependent. Pharmacodynamics Estradiol levels Treatment with OBE2109 alone resulted in a swift dose-dependent reduction of E2 levels, with a median value of 19.5 pg/mL and E2 levels in 50% of women remaining >20 pg/mL in the 100-mg group and a median value of 3.2 pg/mL with all women <20 pg/mL in the 200-mg group after 4 weeks of administration (Table 2). All ABT regimens had E2 values between 25 and 40 pg/mL, with 200 mg/STD associated with the lowest levels and 100 mg/STD associated with the highest levels (Table 2; Supplemental Figs. 2 and 3). On day 55, 2 weeks after the end of OBE2109 treatment, all groups presented E2 levels indicating resumed ovarian activity, with minimal values of >40 pg/mL in all women. Table 2. Weekly Median E2 Levels and Week 4 Proportions of Subjects With E2 Values <20 pg/mL, 20–50 pg/mL, and >50 pg/mL E2 Level, pg/mL  100 mg (n = 14)  100 mg/LD (n = 14)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Predose  32.0 (16.0) [16.0–78.0]  26.5 (16.0) [9.9–63.0]  23.0 (11.0) [5.1–44.0]  21.0 (17.0) [3.9–46.0]  24.0 (19.0) [6.5–45.0]  Week 1  12.0 (10.3) [5.9–123.0]  24.5 (12.0) [13.0–62.0]  35.0 (21.0) [19.0–55.0]  4.6 (3.2) [1.5–18.0]  27.0 (19.0) [12.0–56.0]  Week 2  12.5 (8.3) [5.5–70.0]  30.0 (21.0) [14.0–168.0]  33.0 (24.0) [16.0–57.0]  2.7 (1.2) [1.7–17.0]  28.0 (19.0) [3.3–51.0]  Week 3  15.5 (8.5) [4.7–41.0]  36.0 (48.0) [13.0–308.0]  35.0 (23.0) [15.0–75.0]  3.5 (2.8) [0.5–18.0]  27.0 (13.0) [16.0–48.0]  Week 4  19.5 (16.0) [2.3–73.0]  28.5 (48.0) [16.0–404.0]  38.0 (22.0) [18.0–146.0]  3.2 (2.1) [1.6–17.0]  32.0 (31.0) [15.0–60.0]  Week 5  27.5 (39.3) [2.7–227.0]  38.5 (40.0) [18.0–156.0]  29.0 (16.0) [16.0–292.0]  2.5 (1.4) [1.1–17.0]  27.0 (35.0) [15.0–57.0]  Week 6  18.0 (20.6) [3.2–194.0]  39.5 (20.0) [16.0–233.0]  34.0 (24.0) [17.0–377.0]  3.1 (1.2) [1.4–18.0]  25.0 (17.0) [17.0–60.0]  Day 55 (end of study)  134.0 (248.0) [41.0–498.0]  100.0 (81.0) [45.0–353.0]  106.0 (116.0) [56.0–390.0]  137.5 (114.0) [59.0–343.0]  112.0 (118.0) [42.0–275.0]  Week 4: <20 pg/mL, %  50  21  7  100  29  Week 4: 20–50 pg/mL, %  36  50  80  0  50  Week 4: >50 pg/mL, %  14  29  13  0  21  E2 Level, pg/mL  100 mg (n = 14)  100 mg/LD (n = 14)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Predose  32.0 (16.0) [16.0–78.0]  26.5 (16.0) [9.9–63.0]  23.0 (11.0) [5.1–44.0]  21.0 (17.0) [3.9–46.0]  24.0 (19.0) [6.5–45.0]  Week 1  12.0 (10.3) [5.9–123.0]  24.5 (12.0) [13.0–62.0]  35.0 (21.0) [19.0–55.0]  4.6 (3.2) [1.5–18.0]  27.0 (19.0) [12.0–56.0]  Week 2  12.5 (8.3) [5.5–70.0]  30.0 (21.0) [14.0–168.0]  33.0 (24.0) [16.0–57.0]  2.7 (1.2) [1.7–17.0]  28.0 (19.0) [3.3–51.0]  Week 3  15.5 (8.5) [4.7–41.0]  36.0 (48.0) [13.0–308.0]  35.0 (23.0) [15.0–75.0]  3.5 (2.8) [0.5–18.0]  27.0 (13.0) [16.0–48.0]  Week 4  19.5 (16.0) [2.3–73.0]  28.5 (48.0) [16.0–404.0]  38.0 (22.0) [18.0–146.0]  3.2 (2.1) [1.6–17.0]  32.0 (31.0) [15.0–60.0]  Week 5  27.5 (39.3) [2.7–227.0]  38.5 (40.0) [18.0–156.0]  29.0 (16.0) [16.0–292.0]  2.5 (1.4) [1.1–17.0]  27.0 (35.0) [15.0–57.0]  Week 6  18.0 (20.6) [3.2–194.0]  39.5 (20.0) [16.0–233.0]  34.0 (24.0) [17.0–377.0]  3.1 (1.2) [1.4–18.0]  25.0 (17.0) [17.0–60.0]  Day 55 (end of study)  134.0 (248.0) [41.0–498.0]  100.0 (81.0) [45.0–353.0]  106.0 (116.0) [56.0–390.0]  137.5 (114.0) [59.0–343.0]  112.0 (118.0) [42.0–275.0]  Week 4: <20 pg/mL, %  50  21  7  100  29  Week 4: 20–50 pg/mL, %  36  50  80  0  50  Week 4: >50 pg/mL, %  14  29  13  0  21  Data given as median (IQR) [range] unless otherwise indicated. View Large Based on the conclusions of Barbieri (6) and Riggs et al. (7), we categorized the weekly trough E2 data as follows: <20 pg/mL, 20 to 50 pg/mL, and >50 pg/mL, and observed the highest proportion of women between 20 and 50 pg/mL with the 100 mg/STD regimen (Table 2; Supplemental Fig. 4). Furthermore, a full 24-hour profile at week 3 showed minimal intraday E2 levels in women treated with OBE2109 alone, whereas in women receiving OBE2109 and ABT, we noted significant daily fluctuations relating to peak-trough levels after administration of the ABT (Supplemental Fig. 5). The peak-and-trough fluctuations (PTFs) were lowest with 100 mg/LD (14 pg/mL, E2: 36 to 50 pg/mL), PTF of 100 mg/STD was approximately doubled (27 pg/mL, E2: 35 to 62 pg/mL) and, similarly, 200 mg/STD had a PTF of 25 pg/mL (E2: 27 to 52 pg/mL). Median (interquartile range) peak E2 concentrations were 27 (24) pg/mL, 54 (55) pg/mL, 65 (26) pg/mL, 5 (4) pg/mL, and 52 (30) pg/mL for the 100 mg, 100 mg/LD, 100 mg/STD, 200 mg, and 200 mg/STD groups, respectively. Median AUC values for the groups were 419 (438) pg ⋅ h/mL, 1036 (961) pg ⋅ h/mL, 1125 (484) pg ⋅ h/mL, 77 (40) pg ⋅ h/mL, and 897 (652) pg ⋅ h/mL, respectively. For information, a post hoc calculation of power was performed. Power for peak E2 and AUC was ≥0.917 for all comparisons between 100 mg, 200 mg, and all the ABT groups. For comparisons between ABT groups, power was between 0.083 and 0.327 (Supplemental Table 2). Bleeding pattern Administration of OBE2109 alone promptly stopped vaginal bleeding (Fig. 2). By day 6, >50% of women were in amenorrhea and by day 15, >85% were amenorrheic for the last 4 weeks of treatment. Similarly, 86% and 100% of women at 100 mg and 200 mg, respectively, were either in amenorrhea or had only spotting from day 4 onward. Additional ABT somewhat reduced the effects of OBE2109 on vaginal bleeding in a regimen-specific manner: We observed amenorrhea during the last 4 weeks of treatment in 21%, 53%, and 33% of women in the 100 mg/LD, 100 mg/STD, and 200 mg/STD groups, respectively; and 57%, 93%, and 67% had either amenorrhea or spotting only. Among ABT/OBE2109 combinations, 100 mg/STD had the highest proportion of women in amenorrhea or spotting only during the last 4 weeks of treatment. Individual bleeding patterns are presented in Supplemental Fig. 6. Figure 2. View largeDownload slide Incidence of women with amenorrhea and amenorrhea and spotting, during the last 4 weeks of treatment. Bleeding was assessed daily using the following semiquantitative bleeding scale: no bleeding, spotting, bleeding, or heavy bleeding. Amenorrhea was defined as no bleeding, and amenorrhea plus spotting comprised the categories no bleeding and spotting. (a) Percentage of women in amenorrhea; (b) percentage of women with amenorrhea plus spotting for groups 100 mg (blue), 100 mg/LD (light blue), 100 mg/STD (green), 200 mg (pink), and 200 mg/STD (red). Figure 2. View largeDownload slide Incidence of women with amenorrhea and amenorrhea and spotting, during the last 4 weeks of treatment. Bleeding was assessed daily using the following semiquantitative bleeding scale: no bleeding, spotting, bleeding, or heavy bleeding. Amenorrhea was defined as no bleeding, and amenorrhea plus spotting comprised the categories no bleeding and spotting. (a) Percentage of women in amenorrhea; (b) percentage of women with amenorrhea plus spotting for groups 100 mg (blue), 100 mg/LD (light blue), 100 mg/STD (green), 200 mg (pink), and 200 mg/STD (red). Progesterone levels We observed low P4 levels in all groups, indicating absence of ovulation throughout the treatment period; P4 levels ranged between 0.2 and 10 nmol/L, with the exception of one woman treated with 100 mg and another with 100 mg/LD. These two women also had increases in E2 levels and experienced bleeding. On day 55, 2 weeks after the end of treatment, median (interquartile range) P4 levels in women treated with 100 mg, 100 mg/LD, and 100 mg/STD were 5.3 (15.6), 6.4 (48.6), and 1.3 (2.1) nmol/L, respectively; and thus were higher than in groups treated with 200 mg [0.7 (0.6) nmol/L] or 200 mg/STD [0.5 (0.5) nmol/L], respectively. Relationships among E2, hot flushes, and amenorrhea In the context of the E2 categories described earlier, the relationships among each E2 category, hot flushes, and bleeding control are presented in Table 3. Of the women with E2 levels >20 pg/mL at week 4, only one (<2%) reported some hot flushes, whereas of women with E2 levels <20 pg/mL, 57% reported hot flushes. Amenorrhea was also related to E2 levels with 80%, 49%, and 9% of amenorrhea in women with E2 levels <20 pg/mL, between 20 and 50 pg/mL, and >50 pg/mL, respectively. When considering amenorrhea and spotting only, there was no difference between women with E2 levels <20 pg/mL and women with E2 between 20 pg/mL and 50 pg/mL, with a rate of about 90% in both groups. Table 3. Incidence of Amenorrhea/Spotting at Week 4 and Hot Flushes per Estradiol-Level Category AEs by E2 Category, pg/mL  100 mg  100 mg/LD  100 mg/STD  200 mg  200 mg/STD  All  Women with hot flushes, No.  14  14  15  15  14  73   <20  4/7 (57)  1/3 (33)  0/1 (0)  8/15 (53)  1/4 (25)  14/30 (47)   20–50  0/5 (0)  0/7 (0)  0/12 (0)  0/0 (0)  1/7 (14)  1/31 (3)   >50  0/2 (0)  0/4 (0)  0/2 (0)  0/0 (0)  0/3 (0)  0/11 (0)  Women with amenorrhea, No.  14  14  15  15  14  73   <20  7/7 (100)  2/3 (67)  1/1 (100)  13/15 (87)  1/4 (25)  24/30 (80)   20–50  5/5 (100)  1/7 (14)  7/12 (58)  0/0  2/7 (29)  15/31 (48)   >50  0/2 (0)  0/4 (0)  0/2 (0)  0/0  1/3 (33)  1/11 (9)  Women with amenorrhea plus spotting, No.  14  14  15  15  14  73   <20  7/7 (100)  2/3 (67)  1/1 (100)  15/15 (100)  3/4 (75)  28/30 (93)   20–50  5/5 (100)  6/7 (86)  12/12 (100)  0/0  4/7 (57)  27/31 (87)   >50  0/2 (0)  0/4 (0)  1/2 (50)  0/0  2/3 (67)  3/11 (27)  AEs by E2 Category, pg/mL  100 mg  100 mg/LD  100 mg/STD  200 mg  200 mg/STD  All  Women with hot flushes, No.  14  14  15  15  14  73   <20  4/7 (57)  1/3 (33)  0/1 (0)  8/15 (53)  1/4 (25)  14/30 (47)   20–50  0/5 (0)  0/7 (0)  0/12 (0)  0/0 (0)  1/7 (14)  1/31 (3)   >50  0/2 (0)  0/4 (0)  0/2 (0)  0/0 (0)  0/3 (0)  0/11 (0)  Women with amenorrhea, No.  14  14  15  15  14  73   <20  7/7 (100)  2/3 (67)  1/1 (100)  13/15 (87)  1/4 (25)  24/30 (80)   20–50  5/5 (100)  1/7 (14)  7/12 (58)  0/0  2/7 (29)  15/31 (48)   >50  0/2 (0)  0/4 (0)  0/2 (0)  0/0  1/3 (33)  1/11 (9)  Women with amenorrhea plus spotting, No.  14  14  15  15  14  73   <20  7/7 (100)  2/3 (67)  1/1 (100)  15/15 (100)  3/4 (75)  28/30 (93)   20–50  5/5 (100)  6/7 (86)  12/12 (100)  0/0  4/7 (57)  27/31 (87)   >50  0/2 (0)  0/4 (0)  1/2 (50)  0/0  2/3 (67)  3/11 (27)  Data given as absolute number (%), unless otherwise indicated. View Large Exploratory markers of bone metabolism After 6 weeks of treatment, mean cDPD increased by 47% and 34% in the 100-mg and 200-mg OBE2109-only groups, respectively, and by 25%, 18%, and 17% in the 100 mg/LD, 100 mg/STD, and 200 mg/STD groups, respectively. Similarly, CTX levels trended toward higher increases in the OBE2109-alone groups (68% and 89% for 100 and 200 mg, respectively) and lower increases when ABT was coadministered (44%, 31%, and 24% in the 100 mg/LD, 100 mg/STD, and 200 mg/STD groups, respectively; Supplemental Fig. 7). Values of bone markers B-ALP and P1NP generally decreased after OBE2109 treatment with no obvious pattern and, therefore, are not reported here. Safety OBE2109 and ABT was well tolerated in all groups. Between 69% and 93% of women in each treatment group reported at least one AE, with the 100-mg group reporting the fewest and the 100-mg/STD group reporting the most (Table 4). All AEs were of mild or moderate severity; there were no severe or serious AEs and, except for one woman who withdrew consent and experienced vomiting, no AE that led to the discontinuation of a participant. The eight most frequently reported AEs (n ≥ 5) were headache, hot flushes, vomiting, viral respiratory tract infection, oropharyngeal pain, fatigue, nausea, and mood swings (Table 4). There was no obvious correlation between headache incidence and treatment regimen. The overall incidence of hot flushes was low and correlated with higher doses of OBE2109 and lower doses or absence of ABT. All except one hot flush were of mild intensity and none led to the discontinuation of treatment. The highest incidence of vomiting/nausea and fatigue was observed in the 200-mg group; no other relevant associations between AEs and treatment groups were observed. Table 4. Overall and Most Frequently Reported (n ≥ 5) Treatment-Emergent Adverse Events Description  100 mg (n = 16)  100 mg/LD (n = 15)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Total (N = 76)  Any TEAE  11 (68.8) [26]  11 (73.3) [19]  14 (93.3) [32]  13 (86.7) [45]  13 (86.7) [36]  62 (81.6) [158]  Headache  5 (31.3) [6]  8 (53.3) [9]  10 (66.7) [11]  6 (40.0) [9]  6 (40.0) []7  35 (46.1) [42]  Hot flush  4 (25.0) [4]  1 (6.7) [1]  0 (0.0) [0]  8 (53.3) [8]  2 (13.3) [2]  15 (19.7) [1]5  Vomiting  2 (12.5) [2]  1 (6.7) [1]  2 (13.3) [2]  6 (40.0) [6]  1 (6.7) [1]  12 (15.8) [12]  Respiratory tract infection  3 (18.8) [3]  0 (0.0) [0]  2 (13.3) [2]  3 (20.0) [3]  2 (13.3) [2]  10 (13.2) [10]  Oropharyngeal pain  2 (12.5) [2]  1 (6.7) [1]  1 (6.7) [1]  1 (6.7) [1]  2 (13.3) [2]  7 (9.2) [7]  Fatigue  0 (0.0) [0]  0 (0.0) [0]  1 (6.7) [1]  3 (20.0) [4]  2 (13.3) [2]  6 (7.9) [7]  Nausea  0 (0.0) [0]  1 (6.7) [1]  0 (0.0) [0]  2 (13.3) [2]  2 (13.3) [2]  5 (6.6) [5]  Mood swings  0 (0.0) [0]  0 (0.0) [0]  1 (6.7) [1]  0 (0.0) [0]  4 (26.7) [4]  5 (6.6) [5]  Description  100 mg (n = 16)  100 mg/LD (n = 15)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Total (N = 76)  Any TEAE  11 (68.8) [26]  11 (73.3) [19]  14 (93.3) [32]  13 (86.7) [45]  13 (86.7) [36]  62 (81.6) [158]  Headache  5 (31.3) [6]  8 (53.3) [9]  10 (66.7) [11]  6 (40.0) [9]  6 (40.0) []7  35 (46.1) [42]  Hot flush  4 (25.0) [4]  1 (6.7) [1]  0 (0.0) [0]  8 (53.3) [8]  2 (13.3) [2]  15 (19.7) [1]5  Vomiting  2 (12.5) [2]  1 (6.7) [1]  2 (13.3) [2]  6 (40.0) [6]  1 (6.7) [1]  12 (15.8) [12]  Respiratory tract infection  3 (18.8) [3]  0 (0.0) [0]  2 (13.3) [2]  3 (20.0) [3]  2 (13.3) [2]  10 (13.2) [10]  Oropharyngeal pain  2 (12.5) [2]  1 (6.7) [1]  1 (6.7) [1]  1 (6.7) [1]  2 (13.3) [2]  7 (9.2) [7]  Fatigue  0 (0.0) [0]  0 (0.0) [0]  1 (6.7) [1]  3 (20.0) [4]  2 (13.3) [2]  6 (7.9) [7]  Nausea  0 (0.0) [0]  1 (6.7) [1]  0 (0.0) [0]  2 (13.3) [2]  2 (13.3) [2]  5 (6.6) [5]  Mood swings  0 (0.0) [0]  0 (0.0) [0]  1 (6.7) [1]  0 (0.0) [0]  4 (26.7) [4]  5 (6.6) [5]  Data given as no. (%) of women experiencing AEs [number of TEAEs]. Abbreviation: TEAE, treatment-emergent adverse event. View Large There were no clinically relevant changes from baseline in physical examination, vital signs, electrocardiogram, and clinical laboratory parameters. In particular, there were no noteworthy changes in lipid measurements, including total cholesterol, low-density, lipoprotein cholesterol, high-density lipoprotein, cholesterol, and triglycerides in any group. Discussion Treatment with GnRH-ATGs is aimed at reducing E2 levels sufficiently to alleviate endometriosis or uterine fibroid symptoms, but not excessively to limit any adverse impact on BMD. To achieve this balance, Barbieri (6) postulated the optimal E2 range for the management of endometriosis to be between 20 and 50 pg/mL and PD modeling by Riggs et al. (7) confirmed this range to be relevant. Even more specifically, Riggs et al. (7) had established that estradiol measured at 1 to 2 months after treatment initiation was a reliable predictor of 6-month BMD change. Although Barbieri and Riggs et al. reported on endometriosis studies only, we are hypothesizing that targeting an E2 range of 20 to 50 pg/mL would be a valid target for patients with uterine fibroid for whom bleeding control is warranted. In the context of the development of the GnRH-ATG OBE2109, the goal of our study was to establish the effect of OBE2109 alone or coadministered with E2/NETA ABT on E2 levels, bleeding pattern, and safety in healthy women of reproductive age. In addition, we aimed at supporting the relevance of the targeted E2 levels based on incidence of hot flushes, amenorrhea, and exploratory biomarkers of bone metabolism. OBE2109 at 100-mg and 200-mg doses rapidly and dose dependently reduced E2 levels, with all women treated with 200 mg having E2 levels <20 pg/mL and ∼50% of women treated with 100 mg having E2 levels remaining >20 pg/mL. The clinical observations matched well with the serum E2 levels because >50% of women with E2 levels <20 pg/mL reported hot flushes, whereas none reported hot flushes when E2 level was >20 pg/mL. In addition, 81% of women, regardless of E2 level, reported bleeding control as evidenced by amenorrhea or only spotting. E2 level <20 pg/mL is expected to require ABT; therefore, this was assessed by coadministering two strengths of ABT. ABT increased serum E2 levels within the targeted range and reduced the incidence of hot flushes. However, it somehow partially compromised bleeding control: More than half the women reported some spotting or breakthrough bleeding, in contrast with none in the groups without ABT. This partial impairment of bleeding control by ABT, associated with the well-established contraindications and AEs of ABT, further supports the therapeutic relevance of assessing two regimen of administration for the GnRH-ATG class: a moderate dose not requiring ABT (i.e., 100 mg/day for OBE2109) and a higher dose, which will require systematic ABT (i.e., 200 mg/day for OBE2109) (18). The relevance of the E2 levels is further supported by the minimal within-day variations of E2 when OBE2109 was administered alone, showing constant, stable, and dose-dependent inhibition of E2 throughout the 24-hour dosing interval. Variations observed in combination with ABT corresponded to the E2 dose administered and were comparable to the reported PK E2 profile of the ABTs Activella and Eviana, respectively (19). E2 concentration-time curves at 200 mg seemed to be lower and less variable than those observed for the GnRH-ATG elagolix (AbbVie, Chicago, IL) at 200 mg twice daily in a similar setting, and 100 mg/STD or 200 mg/STD profiles were comparable, albeit seemingly less variable than profiles published for relugolix (Myovant Sciences, Basel, Switzerland) 40 mg/STD ABT (20, 21). With the exception of one woman treated at 100 mg and one at 100 mg/LD, P4 levels remained at anovulatory concentrations (i.e., ≤10 nmol/L) over the 6-week dosing period for all regimens. Treatment effect was readily reversible when stopping OBE2109 administration; at 2 weeks after the OBE2109 treatment period, E2 levels indicated resumption of ovarian activity in all women with E2 minimal values >40 pg/mL. At this time, P4 levels had also started to rise in groups treated at 100 mg but were still low in groups treated at 200 mg. OBE2109 was well tolerated; all AEs were of mild or moderate severity. The most commonly reported AEs were headache and hot flushes, the latter being consistent with GnRH-ATG pharmacology. Hot flush incidence was higher with 100 or 200 mg of OBE2109 alone. There were no menopause-like changes in lipid levels in any of the groups. The addition of standard ABT seemed to mitigate an OBE2109-related rise in CTX level and cDPD, indicating reduced bone resorption and turnover. Overall, a dose of 100 mg/STD resulted in the fewest reported hot flushes and low CTX and cDPD values. Our study was exploratory and has limitations such as the arbitrarily set number of women per group, restricting the presentation of study results to descriptive analyses and precluding hypothesis testing of, for example, group differences of intraday variations of E2 levels. Conclusion OBE2109 at 100 mg and 200 mg rapidly reduced E2 to the levels required to treat hormone-dependent diseases such as uterine fibroids and endometriosis. E2 profiles showed constant dose-dependent suppression with low variability and rapidly resulted in controlled uterine bleeding. E2 levels at 4 weeks of treatment correlated well with the observed occurrence of hot flushes and the bleeding control. E2 levels between 20 and 50 pg/mL resulted in amenorrhea with or without spotting in ∼90% of women, without occurrence of hot flushes. This further supports the estradiol threshold hypothesis (6). It also suggests that monitoring E2 levels may be a convenient method for following women treated with OBE2109 and for deciding whether ABT is necessary. Finally, these data suggest OBE2109 at 100 mg/day provides the opportunity to treat a substantial proportion for patients without the need for ABT. The addition of ABT restored E2 to levels required for protecting bone, but it partially reduced bleeding control; this reduction partially depended on the ABT regimen. Abbreviations: ABT add-back therapy AE adverse event AUC area under the curve B-ALP bone-specific alkaline phosphatase BMD bone mineral density cDPD deoxypyridinoline/creatinine ratio CTX collagen type 1 β-carboxy-telopeptide E2 estradiol FSH follicle-stimulating hormone GnRH gonadotropin-releasing hormone GnRH-ATG gonadotropin-releasing hormone antagonist LD low dose LH luteinizing hormone NET norethindrone NETA norethindrone acetate P1NP procollagen 1 intact N-terminal propeptide P4 progesterone PD pharmacodynamics PK pharmacokinetic PTF peak-and-trough fluctuation STD standard dose. Acknowledgments We thank the clinical site BioKinetic Europe and their statistics partner Staburo, in particular, Maeve McQuillan (BioKinetic Europe) and Josef Höfler (Staburo), for support and contributions to the study. Clinical Trial Information: EudraCT Number: 2016-004732-38 (registered 1 January 2017). Author Contributions: O.P. conceived the study and drafted the manuscript; N.F. acquired the data; all authors analyzed and interpreted the data, critically revised the manuscript, and approved the final version. Disclosure Summary: Funding for the study was provided by ObsEva, which also contributed to the study design, research, and interpretation of data; and the writing, reviewing, and approving of the publication. ObsEva contracted the clinical conduct of the study to BioKinetics Europe. O.P., L.M., J.-P.G., and E.L. are employees of ObsEva; N.F. is an employee of BioKinetics Europe. References 1. Conn PM, Crowley WF, Jr. Gonadotropin-releasing hormone and its analogues. N Engl J Med . 1991; 324( 2): 93– 103. Google Scholar CrossRef Search ADS PubMed  2. Gao X, Outley J, Botteman M, Spalding J, Simon JA, Pashos CL. Economic burden of endometriosis. Fertil Steril . 2006; 86( 6): 1561– 1572. Google Scholar CrossRef Search ADS PubMed  3. Giudice LC. Clinical practice. Endometriosis. N Engl J Med . 2010; 362( 25): 2389– 2398. Google Scholar CrossRef Search ADS PubMed  4. Johnson NP, Hummelshoj L; World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod . 2013; 28( 6): 1552– 1568. Google Scholar CrossRef Search ADS PubMed  5. Stewart EA. Uterine fibroids. Lancet . 2001; 357( 9252): 293– 298. Google Scholar CrossRef Search ADS PubMed  6. Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol . 1992; 166( 2): 740– 745. Google Scholar CrossRef Search ADS PubMed  7. Riggs MM, Bennetts M, van der Graaf PH, Martin SW. Integrated pharmacometrics and systems pharmacology model-based analyses to guide GnRH receptor modulator development for management of endometriosis. CPT Pharmacometrics Syst Pharmacol . 2012; 1( 9): e11. Google Scholar CrossRef Search ADS PubMed  8. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science . 1978; 202( 4368): 631– 633. Google Scholar CrossRef Search ADS PubMed  9. Maggi R, Cariboni AM, Marelli MM, Moretti RM, Andrè V, Marzagalli M, Limonta P. GnRH and GnRH receptors in the pathophysiology of the human female reproductive system. Hum Reprod Update . 2016; 22( 3): 358– 381. Google Scholar CrossRef Search ADS   10. Pierce SJ, Gazvani MR, Farquharson RG. Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up. Fertil Steril . 2000; 74( 5): 964– 968. Google Scholar CrossRef Search ADS PubMed  11. Soliman AM, Bonafede M, Farr AM, Castelli-Haley J, Winkel C. Analysis of adherence, persistence, and surgery among endometriosis patients treated with leuprolide acetate plus norethindrone acetate add-back therapy. J Manag Care Spec Pharm . 2016; 22( 5): 573– 587. Google Scholar CrossRef Search ADS PubMed  12. Ezzati M, Carr BR. Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain. Womens Health (Lond) . 2015; 11( 1): 19– 28. Google Scholar CrossRef Search ADS PubMed  13. Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, Diamond MP, Surrey E, Johnson NP, Watts NB, Gallagher JC, Simon JA, Carr BR, Dmowski WP, Leyland N, Rowan JP, Duan WR, Ng J, Schwefel B, Thomas JW, Jain RI, Chwalisz K. Treatment of endometriosis-associated pain with Elagolix, an oral GnRH antagonist. N Engl J Med . 2017; 377( 1): 28– 40. Google Scholar CrossRef Search ADS PubMed  14. ClinicalTrials.gov. NCT03070951. Efficacy and safety of OBE2109 in subjects with heavy menstrual bleeding associated with uterine fibroids (PRIMROSE 2). https://clinicaltrials.gov/ct2/show/NCT03070951?term=obseva&rank=2. Accessed 16 August 2017. 15. ClinicalTrials.gov. NCT03070899. Efficacy and safety of OBE2109 in subjects with heavy menstrual bleeding associated with uterine fibroids (PRIMROSE 1). https://clinicaltrials.gov/ct2/show/NCT03070899?term=obseva&rank=3. Accessed 16 August 2017. 16. ClinicalTrials.gov. NCT02778399. A study to assess the efficacy and safety of OBE2109 in subjects with endometriosis (EDELWEISS). https://clinicaltrials.gov/ct2/show/NCT02778399?term=obseva&rank=4. Accessed 16 August 2017. 17. ObsEva. Form F-1 registration statement. ObsEva. 2016; http://services.corporate-ir.net/SEC/Document.Service?id=P3VybD1hSFIwY0RvdkwyRndhUzUwWlc1cmQybDZZWEprTG1OdmJTOWtiM2R1Ykc5aFpDNXdhSEEvWVdOMGFXOXVQVkJFUmlacGNHRm5aVDB4TVRNd01URTBOaVp6ZFdKemFXUTlOVGM9JnR5cGU9MiZmbj1PYnNFdmFTQV9GMV8yMDE2MTIzMC5wZGY=. Accessed 16 August 2017. 18. Donnez J, Taylor RN, Taylor HS. Partial suppression of estradiol: a new strategy in endometriosis management? Fertil Steril . 2017; 107( 3): 568– 570. Google Scholar CrossRef Search ADS PubMed  19. Australian Government, Department on Health and Ageing. Australian Public Assessment Report for Kliovance low oestradiol/norethisterone acetate Novo Nordisk Pharmaceuticals Pty Ltd. 18 January 2012. https://www.tga.gov.au/sites/default/files/auspar-kliovance.pdf. Accessed 5 December 2017. 20. Ng J, Chwalisz K, Carter DC, Klein CE. Dose-dependent suppression of gonadotropins and ovarian hormones by Elagolix in healthy premenopausal women. J Clin Endocrinol Metab . 2017; 102( 5): 1683– 1691. Google Scholar CrossRef Search ADS PubMed  21. Lukes A, Johnson B, Jones L, Berg J, Williams R, Bock B, Morton K, Langenberg A, Mudd P, Jr. P-287 Pharmacokinetics, pharmacodynamics, and safety of relugolix, a potent oral once-daily gonadotropin-releasing hormone (GnRH) receptor antagonist, as monotherapy and in combination with estradiol/norethindrone acetate add-back therapy. Hum Reprod . 2017; 32: 2. Google Scholar PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Gonadotropin-Releasing Hormone Receptor Antagonist Mono- and Combination Therapy With Estradiol/Norethindrone Acetate Add-Back: Pharmacodynamics and Safety of OBE2109

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Oxford University Press
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
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1945-7197
D.O.I.
10.1210/jc.2017-01875
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Abstract

Abstract Context OBE2109 is a potent, oral gonadotropin-releasing hormone receptor antagonist being developed for the treatment of sex-hormone–dependent diseases in women. Objective We assessed the pharmacodynamics and safety of OBE2109 alone and combined with estradiol (E2)/norethindrone acetate (NETA) add-back therapy on E2 levels and vaginal bleeding. Design, Setting, and Participants This was a single-center, open-label, randomized, parallel-group study in 76 healthy premenopausal women. Interventions Women were randomly assigned to take the following doses (in milligrams) once daily for 6 weeks: OBE2109, 100 or 200; or OBE2109/E2/NETA, 100/0.5/0.1, or 100/1.0/0.5, or 200/1.0/0.5. Main Outcome Measures E2 concentrations, bleeding pattern, exploratory bone metabolism biomarkers, and adverse events. Results OBE2109 100 mg and 200 mg alone reduced E2 levels to reach median levels of 19.5 and 3.2 pg/mL, respectively, at week 4. Median E2 levels after combined OBE2109/add-back therapy ranged between 25 and 40 pg/mL. OBE2109 100 mg or 200 mg alone induced amenorrhea. By day 15, >85% of women had no vaginal bleeding during the last 4 weeks of treatment. Add-back therapy partially impaired bleeding control: The highest amenorrhea rate (53%) was observed with OBE2109 100 mg/1.0 mg/0.5 mg. The addition of E2/NETA, particularly at 1 mg/0.5 mg, mitigated the increase of two bone markers induced by OBE2109 200 mg. Conclusion OBE2109 promptly lowered E2 levels. Add-back therapy may be required to prevent adverse effects on bone in women treated with the 200-mg dose (at 100 mg in some women). These results provide a basis for OBE2109 regimen selection to treat sex-hormone–dependent diseases. Sex hormone–dependent diseases in women comprise infertility, endometriosis, uterine fibroids, breast cancer, and central precocious puberty (1). Among these, endometriosis and uterine fibroids are the most common, affecting approximately 10% to 15% and 5% to 21% of women worldwide, respectively (2). Endometriosis is characterized by the implantation of endometrial-like tissue outside the uterus and is associated with symptoms such as dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia (3, 4). Uterine fibroids are common benign uterine tumors whose occurrence leads to anemia caused by heavy bleeding, pelvic pain, pressure, dysmenorrhea, reduced quality of life, and infertility (5). Sex hormone suppression stops the growth of endometrial tissue and uterine fibroids, induces amenorrhea, and provides symptom relief. When considering suppressing estradiol (E2), Barbieri’s “estradiol threshold hypothesis” (6) suggests that partial suppression of E2 may be sufficient to control endometriosis symptoms without having to face the adverse effects that are similar to those experienced during menopause, such as bone mineral density (BMD) loss or hot flushes (6). The findings of the Riggs et al. (7) modeling study further support this hypothesis and those authors proposed that E2 levels between 20 and 50 pg/mL can be optimal to control symptoms of E2-dependent diseases while being sufficiently high to prevent hypoestrogenic effects. In addition, they concluded that serum E2 value at 4 weeks of treatment by a gonadotropin-releasing hormone (GnRH) analog is a reliable predictor of effect on BMD at 6 months. The ovarian production of estrogen (mainly E2) and progesterone (P4) are driven by luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and their release by the pituitary is regulated by GnRH. GnRH modulation, therefore, provides an indirect mechanism for affecting E2 and P4 levels. So far, the standard way to manipulate GnRH activity is by exposing the pituitary continuously to a GnRH agonist, which initially stimulates production of gonadal hormones for 1 to 2 weeks (“flare effect”) and eventually desensitizes the pituitary gland to GnRH (by causing GnRH-receptor downregulation). Pituitary desensitization markedly reduces the secretion of LH and FSH and thus induces a profound suppression of gonadal hormones (8, 9). Besides symptom relief, the hypoestrogenic state induced by GnRH agonists leads to a variety of adverse effects such as BMD loss or hot flushes, which affect compliance and limit the use of these treatments to 6 months, beyond which add-back therapy (ABT) is mandatory (10, 11). GnRH antagonist (GnRH-ATG) is a new class of drugs that could match the efficacy of GnRH agonists without their limitations (12). This class shows an absence of the flare effect, causes a rapid and sustained inhibition of gonadotropin secretion, and may allow, depending on the pharmacologic and pharmacokinetic properties of the individual antagonist, dose-dependent adjustment of gonadal hormone levels (eg, E2). ABT has its own contraindications and adverse effects; it is thus possible to achieve a balance of efficacious symptom relief and minimally associated BMD loss without ABT, at least in some patients (13). OBE2109 is a new GnRH-ATG administered orally once daily, which is being developed for the treatment of heavy menstrual bleeding associated with uterine fibroids and management of pain associated with endometriosis (14–16). OBE2109 has been shown to rapidly induce a dose-dependent decrease in LH, FSH, and E2 levels (17). Based on the compound’s high bioavailability and low pharmacokinetic (PK) variability, it seems adequate for predictable pharmacologic responses. The objective of the current study was to characterize the effect of continuous daily administrations of up to 200 mg of OBE2109 for 6 weeks on serum E2 levels, vaginal bleeding pattern, bone metabolism markers, and safety parameters of OBE2109 alone or in combination with either of two doses of E2/NETA ABT (0.5 mg/0.1 mg or 1 mg/0.5 mg) to healthy women of reproductive age with regular menstrual cycles. Materials and Methods Trial design The OBE2109 PK/pharmacodynamics (PD) study was an open-label, randomized, single-center phase 1 trial conducted at Biokinetics Europe (Belfast, Northern Ireland) from January to April 2017. The trial was approved by the Health and Social Care Research Ethics Committee A, Northern Ireland, and the UK health authority, and was carried out in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines. Participants The OBE2109 PK/PD study included healthy, premenopausal women aged 18 to 48 years, with body mass index ranging from 18.5 to 30 kg/m2 and regular menstrual cycles of 21 to 35 days. The main exclusion criteria were the history or presence of any significant disease or modification in baseline safety parameters, hormonal contraception during the 3 months before screening, and the use of any prescription or over-the-counter medication within 28 days before the first administration of OBE2109. All women provided written informed consent. Intervention and randomization After screening assessments and during the second half of the menstrual cycle, women received norethindrone (5 mg; Norethisterone; Wockhardt, Wrexham, UK) three times daily for 10 days to synchronize menstrual cycles. Upon confirmed withdrawal bleeding, women received a 6-week, open-label course of once-daily OBE2109 with or without ABT (Activella; Novo Nordisk, Bagsvaerd, Denmark; or Eviana; Isdin, Barcelona, Spain) according to one of the following regimens: OBE2109 100 mg (referred to hereafter as 100 mg); OBE2109 100 mg and Eviana [E2 0.5 mg/NETA 0.1 mg; referred to hereafter as 100 mg/low dose (LD)]; OBE2109 100 mg and Activella [E2 1 mg/NETA 0.5 mg; referred to hereafter as 100 mg/standard dose (STD)]; OBE2109 200 mg (referred to hereafter as 200 mg); and OBE2109 200 mg and Activella (E2 1 mg/NETA 0.5 mg; referred to hereafter as 200 mg/STD). The first 45 women were to be randomly allocated to 100 mg, 100 mg/LD, or 100 mg/STD in a 1:1:1 ratio. Another 30 women were then to be randomly assigned to either 200 mg or 200 mg/STD (1:1). Pharmacokinetic and pharmacodynamic end points We evaluated circulating E2, P4, OBE2109, metabolite KP017, and norethindrone levels predose weekly; E2 and P4 were also determined at the end-of-study visit. In addition, within-day variability of E2 levels was measured after treatment week 3. From the start of menstrual cycle synchronization to the end-of-study visit, participating women filled in a daily uterine bleeding diary. Bleeding was assessed using a semiquantitative bleeding scale, as follows: no bleeding, spotting (light staining, dark blood, no sanitary protection needed or only panty liner), bleeding (one to four completely soiled maxi sanitary towels or one to eight soiled tampons, or equivalent combination of the two), or heavy bleeding (more than four completely soiled maxi sanitary towels or eight soiled tampons, or equivalent combination of the two). Bone resorption and bone turnover markers were measured at baseline and after the 6-week treatment period. A schematic study flow diagram is presented in Fig. 1. A detailed schedule of events is presented in Supplemental Table 1. Figure 1. View largeDownload slide Study flow diagram describing key study events. D1, day 1; EOS, end-of-study visit; KP017, a metabolite of OBE2109; TID, three times daily. Figure 1. View largeDownload slide Study flow diagram describing key study events. D1, day 1; EOS, end-of-study visit; KP017, a metabolite of OBE2109; TID, three times daily. The primary end points of the study were the group comparison of serum E2 within-day variability and E2 trough levels over time. As secondary end points, we described the women’s bleeding patterns over time. To assess OBE2109’s potential to inhibit ovulation, we compared P4 trough levels over time as an indicator for ovulation. Changes from baseline of bone-specific alkaline phosphatase (B-ALP), procollagen 1 intact N-terminal propeptide (P1NP), collagen type 1 β-carboxy-telopeptide (CTX), and the deoxypyridinoline/creatinine ratio (cDPD) served as exploratory markers of bone metabolism. Exposure to OBE2109 and ABT was controlled by reviewing group trough OBE2109, KP017, and norethindrone (NET) plasma levels. All bioanalytical assessments of OBE2109, KP017, and NET were analyzed with liquid chromatography tandem-mass spectrometry at BioTrial BioAnalytical Services (Montreal, Canada) and E2 levels were analyzed by liquid chromatography tandem-mass spectrometry at Covance (Endocrine Sciences, Calabasas Hills, CA) using methods validated to the current US Food and Drug Administration guidance for bioanalytical validation. Lowest quantifiable concentrations were 10 ng/mL, 5 ng/mL, 10 pg/mL, and 1 pg/mL. For all analyses, 10 nonzero calibration standards were used to generate the calibration curve. Related coefficients of determination for the regressions throughout the study were ≥0.9965. Quality control samples for accuracy and precision were included in each analysis batch and met the acceptance criteria (i.e., two-thirds of quality controls within 85% to 115% of target, and ≤50% of quality controls at the same concentration outside 85% to 115% of the target). P4, CTX, P1NP, and B-ALP levels, and cDPD were assessed at a commercial laboratory using validated chemiluminescence or radioimmunoassay methods (The Doctors Laboratory, London, UK). Lowest quantifiable concentrations were 0.636 nmol/L, 10 pg/mL, 5 µg/L, 1.5 µg/L, and 7nM (for DPD), respectively. Safety end points Safety evaluations included the number and proportion of women experiencing treatment-emergent adverse events (AEs) and clinically important changes in standard clinical laboratory parameters, electrocardiogram, vital signs, or physical examination. A detailed schedule of measurements is provided in Supplemental Table 1. Statistical analysis E2 assessments of this open-label phase 1 study comparing different OBE2109 and ABT combinations were exploratory and no formal sample size calculation was performed. However, we considered a minimum of 12 evaluable women to be sufficient to reliably explore any differences between OBE2109 and ABT treatments; thus, we planned to enroll 15 women per group. We conducted safety analyses using all women who had at least one dose of OBE2109 and PD and PK assessments in women with at least one valid PD or PK observation without major protocol deviation. End points were summarized using descriptive statistics; standard formulae were used to generate PK parameters such as minimal or maximal concentrations, and area under the curve (AUC). Results Participants A total of 142 women were screened, of whom 87 entered menstrual cycle synchronization. The first 76 women were randomly assigned to either 100 mg, 100 mg/LD, 100 mg/STD, 200 mg, or 200mg/STD, and 73 women completed the treatment. A subject disposition diagram is presented in Supplemental Fig. 1. Demographics of the 76 participants were very similar: One woman was black, all the others were white; all were between 20 and 48 years of age (mean, 34 years), had a body mass index between 18.8 and 29.9 kg/m2, and a mean historical menstrual cycle length between 27 and 29 days (Table 1). Table 1. Participant Demographics   100 mg (n = 16)  100 mg/LD (n = 15)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Race, no. (%)             Black  0 (0.0)  1 (6.7)  0 (0.0)  0 (0.0)  0 (0.0)   White  16 (100.0)  14 (93.3)  15 (100.0)  15 (100.0)  15 (100.0)  Age, mean (range), y  34.6 (23–47)  34.1 (20–45)  34.7 (23–48)  33.5 (21–47)  36.3 (24–47)  Weight, mean (range), kg  61.8 (51.8–82.4)  67.5 (49.9–87.0)  63.0 (52.0–85.1)  61.0 (44.6–76.6)  66.3 (51.0–85.3)  BMI, mean (range), kg/m2  23.1 (19.3–29.5)  25.1 (20.6–29.4)  23.5 (20.0–29.4)  23.1 (18.8–28.8)  24.3 (18.9–29.0)  Menstrual cycle duration (history)a, d  28.7 (24–35)  27.4 (24–30)  27.9 (21–30)  28.8 (25–35)  28.8 (24–35)    100 mg (n = 16)  100 mg/LD (n = 15)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Race, no. (%)             Black  0 (0.0)  1 (6.7)  0 (0.0)  0 (0.0)  0 (0.0)   White  16 (100.0)  14 (93.3)  15 (100.0)  15 (100.0)  15 (100.0)  Age, mean (range), y  34.6 (23–47)  34.1 (20–45)  34.7 (23–48)  33.5 (21–47)  36.3 (24–47)  Weight, mean (range), kg  61.8 (51.8–82.4)  67.5 (49.9–87.0)  63.0 (52.0–85.1)  61.0 (44.6–76.6)  66.3 (51.0–85.3)  BMI, mean (range), kg/m2  23.1 (19.3–29.5)  25.1 (20.6–29.4)  23.5 (20.0–29.4)  23.1 (18.8–28.8)  24.3 (18.9–29.0)  Menstrual cycle duration (history)a, d  28.7 (24–35)  27.4 (24–30)  27.9 (21–30)  28.8 (25–35)  28.8 (24–35)  a Numbers of women with retrievable menstrual cycle history were 10 (100 mg), 12 (100 mg/LD), 11 (100 mg/STD), 13 (200 mg), and 15 (200 mg/STD). The mean and range were calculated over the last three menstrual cycles. If, for a given cycle, the woman could only provide a range, the median value was used. View Large Pharmacokinetics All women treated with OBE2109 at 100 mg and 200 mg were well exposed to the medication. Median trough levels of the weekly assessments were between 3250 and 4750 ng/mL for the OBE2109 100-mg group and between 6700 and 11,700 ng/mL for the OBE2109 200-mg group, and were approximately dose proportional. Similarly, the metabolite KP017 results were dose proportional (data not shown). All but one woman with ABT were consistently exposed to NET; weekly median trough levels were between 43.7 and 70.3 pg/mL and 239 to 463 pg/mL for the LD and STD groups, respectively. NET values were comparable with published data and were approximately dose dependent. Pharmacodynamics Estradiol levels Treatment with OBE2109 alone resulted in a swift dose-dependent reduction of E2 levels, with a median value of 19.5 pg/mL and E2 levels in 50% of women remaining >20 pg/mL in the 100-mg group and a median value of 3.2 pg/mL with all women <20 pg/mL in the 200-mg group after 4 weeks of administration (Table 2). All ABT regimens had E2 values between 25 and 40 pg/mL, with 200 mg/STD associated with the lowest levels and 100 mg/STD associated with the highest levels (Table 2; Supplemental Figs. 2 and 3). On day 55, 2 weeks after the end of OBE2109 treatment, all groups presented E2 levels indicating resumed ovarian activity, with minimal values of >40 pg/mL in all women. Table 2. Weekly Median E2 Levels and Week 4 Proportions of Subjects With E2 Values <20 pg/mL, 20–50 pg/mL, and >50 pg/mL E2 Level, pg/mL  100 mg (n = 14)  100 mg/LD (n = 14)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Predose  32.0 (16.0) [16.0–78.0]  26.5 (16.0) [9.9–63.0]  23.0 (11.0) [5.1–44.0]  21.0 (17.0) [3.9–46.0]  24.0 (19.0) [6.5–45.0]  Week 1  12.0 (10.3) [5.9–123.0]  24.5 (12.0) [13.0–62.0]  35.0 (21.0) [19.0–55.0]  4.6 (3.2) [1.5–18.0]  27.0 (19.0) [12.0–56.0]  Week 2  12.5 (8.3) [5.5–70.0]  30.0 (21.0) [14.0–168.0]  33.0 (24.0) [16.0–57.0]  2.7 (1.2) [1.7–17.0]  28.0 (19.0) [3.3–51.0]  Week 3  15.5 (8.5) [4.7–41.0]  36.0 (48.0) [13.0–308.0]  35.0 (23.0) [15.0–75.0]  3.5 (2.8) [0.5–18.0]  27.0 (13.0) [16.0–48.0]  Week 4  19.5 (16.0) [2.3–73.0]  28.5 (48.0) [16.0–404.0]  38.0 (22.0) [18.0–146.0]  3.2 (2.1) [1.6–17.0]  32.0 (31.0) [15.0–60.0]  Week 5  27.5 (39.3) [2.7–227.0]  38.5 (40.0) [18.0–156.0]  29.0 (16.0) [16.0–292.0]  2.5 (1.4) [1.1–17.0]  27.0 (35.0) [15.0–57.0]  Week 6  18.0 (20.6) [3.2–194.0]  39.5 (20.0) [16.0–233.0]  34.0 (24.0) [17.0–377.0]  3.1 (1.2) [1.4–18.0]  25.0 (17.0) [17.0–60.0]  Day 55 (end of study)  134.0 (248.0) [41.0–498.0]  100.0 (81.0) [45.0–353.0]  106.0 (116.0) [56.0–390.0]  137.5 (114.0) [59.0–343.0]  112.0 (118.0) [42.0–275.0]  Week 4: <20 pg/mL, %  50  21  7  100  29  Week 4: 20–50 pg/mL, %  36  50  80  0  50  Week 4: >50 pg/mL, %  14  29  13  0  21  E2 Level, pg/mL  100 mg (n = 14)  100 mg/LD (n = 14)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Predose  32.0 (16.0) [16.0–78.0]  26.5 (16.0) [9.9–63.0]  23.0 (11.0) [5.1–44.0]  21.0 (17.0) [3.9–46.0]  24.0 (19.0) [6.5–45.0]  Week 1  12.0 (10.3) [5.9–123.0]  24.5 (12.0) [13.0–62.0]  35.0 (21.0) [19.0–55.0]  4.6 (3.2) [1.5–18.0]  27.0 (19.0) [12.0–56.0]  Week 2  12.5 (8.3) [5.5–70.0]  30.0 (21.0) [14.0–168.0]  33.0 (24.0) [16.0–57.0]  2.7 (1.2) [1.7–17.0]  28.0 (19.0) [3.3–51.0]  Week 3  15.5 (8.5) [4.7–41.0]  36.0 (48.0) [13.0–308.0]  35.0 (23.0) [15.0–75.0]  3.5 (2.8) [0.5–18.0]  27.0 (13.0) [16.0–48.0]  Week 4  19.5 (16.0) [2.3–73.0]  28.5 (48.0) [16.0–404.0]  38.0 (22.0) [18.0–146.0]  3.2 (2.1) [1.6–17.0]  32.0 (31.0) [15.0–60.0]  Week 5  27.5 (39.3) [2.7–227.0]  38.5 (40.0) [18.0–156.0]  29.0 (16.0) [16.0–292.0]  2.5 (1.4) [1.1–17.0]  27.0 (35.0) [15.0–57.0]  Week 6  18.0 (20.6) [3.2–194.0]  39.5 (20.0) [16.0–233.0]  34.0 (24.0) [17.0–377.0]  3.1 (1.2) [1.4–18.0]  25.0 (17.0) [17.0–60.0]  Day 55 (end of study)  134.0 (248.0) [41.0–498.0]  100.0 (81.0) [45.0–353.0]  106.0 (116.0) [56.0–390.0]  137.5 (114.0) [59.0–343.0]  112.0 (118.0) [42.0–275.0]  Week 4: <20 pg/mL, %  50  21  7  100  29  Week 4: 20–50 pg/mL, %  36  50  80  0  50  Week 4: >50 pg/mL, %  14  29  13  0  21  Data given as median (IQR) [range] unless otherwise indicated. View Large Based on the conclusions of Barbieri (6) and Riggs et al. (7), we categorized the weekly trough E2 data as follows: <20 pg/mL, 20 to 50 pg/mL, and >50 pg/mL, and observed the highest proportion of women between 20 and 50 pg/mL with the 100 mg/STD regimen (Table 2; Supplemental Fig. 4). Furthermore, a full 24-hour profile at week 3 showed minimal intraday E2 levels in women treated with OBE2109 alone, whereas in women receiving OBE2109 and ABT, we noted significant daily fluctuations relating to peak-trough levels after administration of the ABT (Supplemental Fig. 5). The peak-and-trough fluctuations (PTFs) were lowest with 100 mg/LD (14 pg/mL, E2: 36 to 50 pg/mL), PTF of 100 mg/STD was approximately doubled (27 pg/mL, E2: 35 to 62 pg/mL) and, similarly, 200 mg/STD had a PTF of 25 pg/mL (E2: 27 to 52 pg/mL). Median (interquartile range) peak E2 concentrations were 27 (24) pg/mL, 54 (55) pg/mL, 65 (26) pg/mL, 5 (4) pg/mL, and 52 (30) pg/mL for the 100 mg, 100 mg/LD, 100 mg/STD, 200 mg, and 200 mg/STD groups, respectively. Median AUC values for the groups were 419 (438) pg ⋅ h/mL, 1036 (961) pg ⋅ h/mL, 1125 (484) pg ⋅ h/mL, 77 (40) pg ⋅ h/mL, and 897 (652) pg ⋅ h/mL, respectively. For information, a post hoc calculation of power was performed. Power for peak E2 and AUC was ≥0.917 for all comparisons between 100 mg, 200 mg, and all the ABT groups. For comparisons between ABT groups, power was between 0.083 and 0.327 (Supplemental Table 2). Bleeding pattern Administration of OBE2109 alone promptly stopped vaginal bleeding (Fig. 2). By day 6, >50% of women were in amenorrhea and by day 15, >85% were amenorrheic for the last 4 weeks of treatment. Similarly, 86% and 100% of women at 100 mg and 200 mg, respectively, were either in amenorrhea or had only spotting from day 4 onward. Additional ABT somewhat reduced the effects of OBE2109 on vaginal bleeding in a regimen-specific manner: We observed amenorrhea during the last 4 weeks of treatment in 21%, 53%, and 33% of women in the 100 mg/LD, 100 mg/STD, and 200 mg/STD groups, respectively; and 57%, 93%, and 67% had either amenorrhea or spotting only. Among ABT/OBE2109 combinations, 100 mg/STD had the highest proportion of women in amenorrhea or spotting only during the last 4 weeks of treatment. Individual bleeding patterns are presented in Supplemental Fig. 6. Figure 2. View largeDownload slide Incidence of women with amenorrhea and amenorrhea and spotting, during the last 4 weeks of treatment. Bleeding was assessed daily using the following semiquantitative bleeding scale: no bleeding, spotting, bleeding, or heavy bleeding. Amenorrhea was defined as no bleeding, and amenorrhea plus spotting comprised the categories no bleeding and spotting. (a) Percentage of women in amenorrhea; (b) percentage of women with amenorrhea plus spotting for groups 100 mg (blue), 100 mg/LD (light blue), 100 mg/STD (green), 200 mg (pink), and 200 mg/STD (red). Figure 2. View largeDownload slide Incidence of women with amenorrhea and amenorrhea and spotting, during the last 4 weeks of treatment. Bleeding was assessed daily using the following semiquantitative bleeding scale: no bleeding, spotting, bleeding, or heavy bleeding. Amenorrhea was defined as no bleeding, and amenorrhea plus spotting comprised the categories no bleeding and spotting. (a) Percentage of women in amenorrhea; (b) percentage of women with amenorrhea plus spotting for groups 100 mg (blue), 100 mg/LD (light blue), 100 mg/STD (green), 200 mg (pink), and 200 mg/STD (red). Progesterone levels We observed low P4 levels in all groups, indicating absence of ovulation throughout the treatment period; P4 levels ranged between 0.2 and 10 nmol/L, with the exception of one woman treated with 100 mg and another with 100 mg/LD. These two women also had increases in E2 levels and experienced bleeding. On day 55, 2 weeks after the end of treatment, median (interquartile range) P4 levels in women treated with 100 mg, 100 mg/LD, and 100 mg/STD were 5.3 (15.6), 6.4 (48.6), and 1.3 (2.1) nmol/L, respectively; and thus were higher than in groups treated with 200 mg [0.7 (0.6) nmol/L] or 200 mg/STD [0.5 (0.5) nmol/L], respectively. Relationships among E2, hot flushes, and amenorrhea In the context of the E2 categories described earlier, the relationships among each E2 category, hot flushes, and bleeding control are presented in Table 3. Of the women with E2 levels >20 pg/mL at week 4, only one (<2%) reported some hot flushes, whereas of women with E2 levels <20 pg/mL, 57% reported hot flushes. Amenorrhea was also related to E2 levels with 80%, 49%, and 9% of amenorrhea in women with E2 levels <20 pg/mL, between 20 and 50 pg/mL, and >50 pg/mL, respectively. When considering amenorrhea and spotting only, there was no difference between women with E2 levels <20 pg/mL and women with E2 between 20 pg/mL and 50 pg/mL, with a rate of about 90% in both groups. Table 3. Incidence of Amenorrhea/Spotting at Week 4 and Hot Flushes per Estradiol-Level Category AEs by E2 Category, pg/mL  100 mg  100 mg/LD  100 mg/STD  200 mg  200 mg/STD  All  Women with hot flushes, No.  14  14  15  15  14  73   <20  4/7 (57)  1/3 (33)  0/1 (0)  8/15 (53)  1/4 (25)  14/30 (47)   20–50  0/5 (0)  0/7 (0)  0/12 (0)  0/0 (0)  1/7 (14)  1/31 (3)   >50  0/2 (0)  0/4 (0)  0/2 (0)  0/0 (0)  0/3 (0)  0/11 (0)  Women with amenorrhea, No.  14  14  15  15  14  73   <20  7/7 (100)  2/3 (67)  1/1 (100)  13/15 (87)  1/4 (25)  24/30 (80)   20–50  5/5 (100)  1/7 (14)  7/12 (58)  0/0  2/7 (29)  15/31 (48)   >50  0/2 (0)  0/4 (0)  0/2 (0)  0/0  1/3 (33)  1/11 (9)  Women with amenorrhea plus spotting, No.  14  14  15  15  14  73   <20  7/7 (100)  2/3 (67)  1/1 (100)  15/15 (100)  3/4 (75)  28/30 (93)   20–50  5/5 (100)  6/7 (86)  12/12 (100)  0/0  4/7 (57)  27/31 (87)   >50  0/2 (0)  0/4 (0)  1/2 (50)  0/0  2/3 (67)  3/11 (27)  AEs by E2 Category, pg/mL  100 mg  100 mg/LD  100 mg/STD  200 mg  200 mg/STD  All  Women with hot flushes, No.  14  14  15  15  14  73   <20  4/7 (57)  1/3 (33)  0/1 (0)  8/15 (53)  1/4 (25)  14/30 (47)   20–50  0/5 (0)  0/7 (0)  0/12 (0)  0/0 (0)  1/7 (14)  1/31 (3)   >50  0/2 (0)  0/4 (0)  0/2 (0)  0/0 (0)  0/3 (0)  0/11 (0)  Women with amenorrhea, No.  14  14  15  15  14  73   <20  7/7 (100)  2/3 (67)  1/1 (100)  13/15 (87)  1/4 (25)  24/30 (80)   20–50  5/5 (100)  1/7 (14)  7/12 (58)  0/0  2/7 (29)  15/31 (48)   >50  0/2 (0)  0/4 (0)  0/2 (0)  0/0  1/3 (33)  1/11 (9)  Women with amenorrhea plus spotting, No.  14  14  15  15  14  73   <20  7/7 (100)  2/3 (67)  1/1 (100)  15/15 (100)  3/4 (75)  28/30 (93)   20–50  5/5 (100)  6/7 (86)  12/12 (100)  0/0  4/7 (57)  27/31 (87)   >50  0/2 (0)  0/4 (0)  1/2 (50)  0/0  2/3 (67)  3/11 (27)  Data given as absolute number (%), unless otherwise indicated. View Large Exploratory markers of bone metabolism After 6 weeks of treatment, mean cDPD increased by 47% and 34% in the 100-mg and 200-mg OBE2109-only groups, respectively, and by 25%, 18%, and 17% in the 100 mg/LD, 100 mg/STD, and 200 mg/STD groups, respectively. Similarly, CTX levels trended toward higher increases in the OBE2109-alone groups (68% and 89% for 100 and 200 mg, respectively) and lower increases when ABT was coadministered (44%, 31%, and 24% in the 100 mg/LD, 100 mg/STD, and 200 mg/STD groups, respectively; Supplemental Fig. 7). Values of bone markers B-ALP and P1NP generally decreased after OBE2109 treatment with no obvious pattern and, therefore, are not reported here. Safety OBE2109 and ABT was well tolerated in all groups. Between 69% and 93% of women in each treatment group reported at least one AE, with the 100-mg group reporting the fewest and the 100-mg/STD group reporting the most (Table 4). All AEs were of mild or moderate severity; there were no severe or serious AEs and, except for one woman who withdrew consent and experienced vomiting, no AE that led to the discontinuation of a participant. The eight most frequently reported AEs (n ≥ 5) were headache, hot flushes, vomiting, viral respiratory tract infection, oropharyngeal pain, fatigue, nausea, and mood swings (Table 4). There was no obvious correlation between headache incidence and treatment regimen. The overall incidence of hot flushes was low and correlated with higher doses of OBE2109 and lower doses or absence of ABT. All except one hot flush were of mild intensity and none led to the discontinuation of treatment. The highest incidence of vomiting/nausea and fatigue was observed in the 200-mg group; no other relevant associations between AEs and treatment groups were observed. Table 4. Overall and Most Frequently Reported (n ≥ 5) Treatment-Emergent Adverse Events Description  100 mg (n = 16)  100 mg/LD (n = 15)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Total (N = 76)  Any TEAE  11 (68.8) [26]  11 (73.3) [19]  14 (93.3) [32]  13 (86.7) [45]  13 (86.7) [36]  62 (81.6) [158]  Headache  5 (31.3) [6]  8 (53.3) [9]  10 (66.7) [11]  6 (40.0) [9]  6 (40.0) []7  35 (46.1) [42]  Hot flush  4 (25.0) [4]  1 (6.7) [1]  0 (0.0) [0]  8 (53.3) [8]  2 (13.3) [2]  15 (19.7) [1]5  Vomiting  2 (12.5) [2]  1 (6.7) [1]  2 (13.3) [2]  6 (40.0) [6]  1 (6.7) [1]  12 (15.8) [12]  Respiratory tract infection  3 (18.8) [3]  0 (0.0) [0]  2 (13.3) [2]  3 (20.0) [3]  2 (13.3) [2]  10 (13.2) [10]  Oropharyngeal pain  2 (12.5) [2]  1 (6.7) [1]  1 (6.7) [1]  1 (6.7) [1]  2 (13.3) [2]  7 (9.2) [7]  Fatigue  0 (0.0) [0]  0 (0.0) [0]  1 (6.7) [1]  3 (20.0) [4]  2 (13.3) [2]  6 (7.9) [7]  Nausea  0 (0.0) [0]  1 (6.7) [1]  0 (0.0) [0]  2 (13.3) [2]  2 (13.3) [2]  5 (6.6) [5]  Mood swings  0 (0.0) [0]  0 (0.0) [0]  1 (6.7) [1]  0 (0.0) [0]  4 (26.7) [4]  5 (6.6) [5]  Description  100 mg (n = 16)  100 mg/LD (n = 15)  100 mg/STD (n = 15)  200 mg (n = 15)  200 mg/STD (n = 15)  Total (N = 76)  Any TEAE  11 (68.8) [26]  11 (73.3) [19]  14 (93.3) [32]  13 (86.7) [45]  13 (86.7) [36]  62 (81.6) [158]  Headache  5 (31.3) [6]  8 (53.3) [9]  10 (66.7) [11]  6 (40.0) [9]  6 (40.0) []7  35 (46.1) [42]  Hot flush  4 (25.0) [4]  1 (6.7) [1]  0 (0.0) [0]  8 (53.3) [8]  2 (13.3) [2]  15 (19.7) [1]5  Vomiting  2 (12.5) [2]  1 (6.7) [1]  2 (13.3) [2]  6 (40.0) [6]  1 (6.7) [1]  12 (15.8) [12]  Respiratory tract infection  3 (18.8) [3]  0 (0.0) [0]  2 (13.3) [2]  3 (20.0) [3]  2 (13.3) [2]  10 (13.2) [10]  Oropharyngeal pain  2 (12.5) [2]  1 (6.7) [1]  1 (6.7) [1]  1 (6.7) [1]  2 (13.3) [2]  7 (9.2) [7]  Fatigue  0 (0.0) [0]  0 (0.0) [0]  1 (6.7) [1]  3 (20.0) [4]  2 (13.3) [2]  6 (7.9) [7]  Nausea  0 (0.0) [0]  1 (6.7) [1]  0 (0.0) [0]  2 (13.3) [2]  2 (13.3) [2]  5 (6.6) [5]  Mood swings  0 (0.0) [0]  0 (0.0) [0]  1 (6.7) [1]  0 (0.0) [0]  4 (26.7) [4]  5 (6.6) [5]  Data given as no. (%) of women experiencing AEs [number of TEAEs]. Abbreviation: TEAE, treatment-emergent adverse event. View Large There were no clinically relevant changes from baseline in physical examination, vital signs, electrocardiogram, and clinical laboratory parameters. In particular, there were no noteworthy changes in lipid measurements, including total cholesterol, low-density, lipoprotein cholesterol, high-density lipoprotein, cholesterol, and triglycerides in any group. Discussion Treatment with GnRH-ATGs is aimed at reducing E2 levels sufficiently to alleviate endometriosis or uterine fibroid symptoms, but not excessively to limit any adverse impact on BMD. To achieve this balance, Barbieri (6) postulated the optimal E2 range for the management of endometriosis to be between 20 and 50 pg/mL and PD modeling by Riggs et al. (7) confirmed this range to be relevant. Even more specifically, Riggs et al. (7) had established that estradiol measured at 1 to 2 months after treatment initiation was a reliable predictor of 6-month BMD change. Although Barbieri and Riggs et al. reported on endometriosis studies only, we are hypothesizing that targeting an E2 range of 20 to 50 pg/mL would be a valid target for patients with uterine fibroid for whom bleeding control is warranted. In the context of the development of the GnRH-ATG OBE2109, the goal of our study was to establish the effect of OBE2109 alone or coadministered with E2/NETA ABT on E2 levels, bleeding pattern, and safety in healthy women of reproductive age. In addition, we aimed at supporting the relevance of the targeted E2 levels based on incidence of hot flushes, amenorrhea, and exploratory biomarkers of bone metabolism. OBE2109 at 100-mg and 200-mg doses rapidly and dose dependently reduced E2 levels, with all women treated with 200 mg having E2 levels <20 pg/mL and ∼50% of women treated with 100 mg having E2 levels remaining >20 pg/mL. The clinical observations matched well with the serum E2 levels because >50% of women with E2 levels <20 pg/mL reported hot flushes, whereas none reported hot flushes when E2 level was >20 pg/mL. In addition, 81% of women, regardless of E2 level, reported bleeding control as evidenced by amenorrhea or only spotting. E2 level <20 pg/mL is expected to require ABT; therefore, this was assessed by coadministering two strengths of ABT. ABT increased serum E2 levels within the targeted range and reduced the incidence of hot flushes. However, it somehow partially compromised bleeding control: More than half the women reported some spotting or breakthrough bleeding, in contrast with none in the groups without ABT. This partial impairment of bleeding control by ABT, associated with the well-established contraindications and AEs of ABT, further supports the therapeutic relevance of assessing two regimen of administration for the GnRH-ATG class: a moderate dose not requiring ABT (i.e., 100 mg/day for OBE2109) and a higher dose, which will require systematic ABT (i.e., 200 mg/day for OBE2109) (18). The relevance of the E2 levels is further supported by the minimal within-day variations of E2 when OBE2109 was administered alone, showing constant, stable, and dose-dependent inhibition of E2 throughout the 24-hour dosing interval. Variations observed in combination with ABT corresponded to the E2 dose administered and were comparable to the reported PK E2 profile of the ABTs Activella and Eviana, respectively (19). E2 concentration-time curves at 200 mg seemed to be lower and less variable than those observed for the GnRH-ATG elagolix (AbbVie, Chicago, IL) at 200 mg twice daily in a similar setting, and 100 mg/STD or 200 mg/STD profiles were comparable, albeit seemingly less variable than profiles published for relugolix (Myovant Sciences, Basel, Switzerland) 40 mg/STD ABT (20, 21). With the exception of one woman treated at 100 mg and one at 100 mg/LD, P4 levels remained at anovulatory concentrations (i.e., ≤10 nmol/L) over the 6-week dosing period for all regimens. Treatment effect was readily reversible when stopping OBE2109 administration; at 2 weeks after the OBE2109 treatment period, E2 levels indicated resumption of ovarian activity in all women with E2 minimal values >40 pg/mL. At this time, P4 levels had also started to rise in groups treated at 100 mg but were still low in groups treated at 200 mg. OBE2109 was well tolerated; all AEs were of mild or moderate severity. The most commonly reported AEs were headache and hot flushes, the latter being consistent with GnRH-ATG pharmacology. Hot flush incidence was higher with 100 or 200 mg of OBE2109 alone. There were no menopause-like changes in lipid levels in any of the groups. The addition of standard ABT seemed to mitigate an OBE2109-related rise in CTX level and cDPD, indicating reduced bone resorption and turnover. Overall, a dose of 100 mg/STD resulted in the fewest reported hot flushes and low CTX and cDPD values. Our study was exploratory and has limitations such as the arbitrarily set number of women per group, restricting the presentation of study results to descriptive analyses and precluding hypothesis testing of, for example, group differences of intraday variations of E2 levels. Conclusion OBE2109 at 100 mg and 200 mg rapidly reduced E2 to the levels required to treat hormone-dependent diseases such as uterine fibroids and endometriosis. E2 profiles showed constant dose-dependent suppression with low variability and rapidly resulted in controlled uterine bleeding. E2 levels at 4 weeks of treatment correlated well with the observed occurrence of hot flushes and the bleeding control. E2 levels between 20 and 50 pg/mL resulted in amenorrhea with or without spotting in ∼90% of women, without occurrence of hot flushes. This further supports the estradiol threshold hypothesis (6). It also suggests that monitoring E2 levels may be a convenient method for following women treated with OBE2109 and for deciding whether ABT is necessary. Finally, these data suggest OBE2109 at 100 mg/day provides the opportunity to treat a substantial proportion for patients without the need for ABT. The addition of ABT restored E2 to levels required for protecting bone, but it partially reduced bleeding control; this reduction partially depended on the ABT regimen. Abbreviations: ABT add-back therapy AE adverse event AUC area under the curve B-ALP bone-specific alkaline phosphatase BMD bone mineral density cDPD deoxypyridinoline/creatinine ratio CTX collagen type 1 β-carboxy-telopeptide E2 estradiol FSH follicle-stimulating hormone GnRH gonadotropin-releasing hormone GnRH-ATG gonadotropin-releasing hormone antagonist LD low dose LH luteinizing hormone NET norethindrone NETA norethindrone acetate P1NP procollagen 1 intact N-terminal propeptide P4 progesterone PD pharmacodynamics PK pharmacokinetic PTF peak-and-trough fluctuation STD standard dose. Acknowledgments We thank the clinical site BioKinetic Europe and their statistics partner Staburo, in particular, Maeve McQuillan (BioKinetic Europe) and Josef Höfler (Staburo), for support and contributions to the study. Clinical Trial Information: EudraCT Number: 2016-004732-38 (registered 1 January 2017). Author Contributions: O.P. conceived the study and drafted the manuscript; N.F. acquired the data; all authors analyzed and interpreted the data, critically revised the manuscript, and approved the final version. Disclosure Summary: Funding for the study was provided by ObsEva, which also contributed to the study design, research, and interpretation of data; and the writing, reviewing, and approving of the publication. ObsEva contracted the clinical conduct of the study to BioKinetics Europe. O.P., L.M., J.-P.G., and E.L. are employees of ObsEva; N.F. is an employee of BioKinetics Europe. References 1. Conn PM, Crowley WF, Jr. Gonadotropin-releasing hormone and its analogues. N Engl J Med . 1991; 324( 2): 93– 103. Google Scholar CrossRef Search ADS PubMed  2. Gao X, Outley J, Botteman M, Spalding J, Simon JA, Pashos CL. Economic burden of endometriosis. Fertil Steril . 2006; 86( 6): 1561– 1572. Google Scholar CrossRef Search ADS PubMed  3. Giudice LC. Clinical practice. Endometriosis. 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Feb 1, 2018

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