Relugolix Combination Tablets in Healthy Japanese Premenopausal Women: Pharmacokinetics, Pharmacodynamics, and Safety Profile.

The study protocol, consent form, and other related documents have been approved by the internal review board at each study site. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments. Informed consent was obtained from all participants in the study.

This study was conducted from July 2023 to January 2024 at two study sites in Japan. A total of 52 healthy premenopausal female participants were randomized to receive either relugolix combination tablets ( n  = 26) or relugolix alone ( n  = 26) (Figure  1 ). Of these, two participants in the relugolix combination tablet group (1 TEAE, 1 ‘other’) and four participants in the relugolix group (2 consent withdrawn, 1 TEAE, 1 ‘other’) discontinued during the treatment period. ‘Other’ reasons included difficulty visiting the study sites because of influenza virus or COVID‐19 infection. The remaining 24 participants in the relugolix combination tablet group and 22 participants in the relugolix group completed the follow‐up period. All 52 participants were included in the FAS, PKAS, and SS. One participant in the relugolix combination tablet group had a protocol violation involving administration of an overdose (treatment with an additional relugolix combination tablet and additional placebo tablet on Day 8), but was not excluded from the analyses. Disposition of participants. TEAE, treatment‐emergent adverse event. The demographic and baseline characteristics, including age, weight, BMI, menstrual cycle, and concentrations of FSH, LH, P4, and E2 were similar between the two treatment groups (Table  1 ). Demographics and baseline characteristics. Note: Data presented as mean (standard deviation) unless otherwise indicated. Abbreviations: BMI, body mass index; E2, estradiol; FSH, follicle‐stimulating hormone; LH, luteinizing hormone; P4, progesterone. The mean (SD) adherence to the study drugs was 99.53% (1.54%) in the relugolix combination tablet group and 99.05% (3.94%) in the relugolix group. The mean (SD) treatment durations were 41.7 (5.2) days and 38.3 (11.6) days in the relugolix combination tablet and relugolix groups, respectively. The pharmacokinetic parameters for relugolix, E2, E1, and NET are summarized in Table  S2 . The concentration‐time profiles of relugolix on Days 1, 22, and 43 after repeated treatment with relugolix combination tablets or relugolix alone are shown in Figure  2 . The mean relugolix concentrations on Days 1, 22, and 43 peaked 3 h after administration and then decreased over time in both groups. The trends in relugolix concentrations were similar in the two groups, with no notable differences in the levels or trends. Mean concentration‐time profile of relugolix in participants treated with relugolix combination tablets and relugolix monotherapy on (a) Days 1–2, (b) Days 22–23, and (c) Days 43–46. Error bars represent standard deviations. The mean relugolix C max and AUC 0‐24 ratios (relugolix combination tablet group/relugolix group) were both approximately 0.7–0.9. The relugolix C trough values on Days 2 and 43 reached a steady state by Day 8 in both treatment groups. The mean E2 concentrations were higher in the relugolix combination tablet group than in the relugolix group on Days 1, 22, and 43 (Figure  3 ). The mean E2 C trough fluctuated between 23.7 and 34.2 pg/mL on Days 2–43 in the relugolix combination tablet group, and decreased gradually in the relugolix group from 11.49 pg/mL on Day 2–6.10–7.78 pg/mL, which was lower than in the relugolix combination tablet group (Table  S2 ). The E2 C trough values on Days 22 and 43 were higher in the relugolix combination tablet group than in the relugolix group. The proportions of participants with E2 C avg  < 10 and < 20 pg/mL were 0% and 3.8% (1/26 participants), respectively, in the relugolix combination tablet group, and 80.8% (21/26) and 84.6% (22/26) in the relugolix group. Similar to E2, the mean E1 concentrations in the relugolix combination tablet group were higher than in the relugolix group on Days 1, 22, and 43 (Table  S2 ). Mean concentration–time profile of E2 in participants treated with relugolix combination tablets and relugolix monotherapy on (a) Days 1–2, (b) Days 22–23, and (c) Days 43–46. Error bars represent standard deviations. The patterns of NET concentrations in the relugolix combination tablet group were similar, with no notable changes on Days 1, 22, and 43 (Table  S2 ). Changes in endocrinological and bone metabolic parameters during the treatment period are summarized in Table  S1 . LH, FSH, and P4 levels showed comparable suppression in both treatment groups during the 6‐week treatment period. The 95% CI for the between‐group differences in least squares (LS) mean changes in LH, FSH, and P4 levels crossed zero at all time points, and the between‐group differences were therefore not significant. There were no significant changes in BAP from baseline in either group. The LS mean changes in CTx concentration from baseline on Days 22 and 43 were −0.0451 and −0.300 ng/mL, respectively, in the relugolix combination tablet group and 0.0666 and 0.2349 ng/mL in the relugolix group, showing that the CTx concentration increased on Day 43. The differences in changes in CTx concentrations from baseline between the groups were significant (between‐group difference in LS mean change from baseline on Day 22: −0.1117 [95% CI −0.1615 to −0.0619]; Day 43: −0.2649 [−0.3418 to −0.1880]). The results of the uterine bleeding assessment are shown in Figure  4 and Table  2 . The incidence of uterine bleeding was higher in the relugolix combination tablet group than in the relugolix group; however, many of the incidents were either spotting or light bleeding. Changes in numbers of participants with uterine bleeding by severity in the (a) relugolix combination tablet and (b) relugolix monotherapy groups during the treatment and follow‐up periods. Summary of uterine bleeding during Days 16–43. The incidence of hot flashes was lower in the relugolix combination tablet group than in the relugolix group (Figure  5 ). The cumulative mean number of hot flash events in the relugolix combination tablet group (2.0 times) was lower than that in the relugolix group (17.4 times), but the difference was not significant ( p  = 0.0630). Changes in numbers of participants with hot flashes by severity in the (a) relugolix combination tablet and (b) relugolix monotherapy groups during the treatment and follow‐up periods. The mean (SD) endometrial thicknesses were 9.0 (3.6) mm at baseline falling to 3.2 (1.3) mm by Day 44 in the relugolix combination tablet group, and 9.7 (3.9) mm at baseline falling to 1.9 (0.8) mm by Day 44 in the relugolix group. No participant had an endometrial thickness ≥ 10 mm in either treatment group. The thickness became similar to the baseline level on Days 64–84 in both groups. An overview of the TEAEs is presented in Table  3 . The incidence rates of TEAEs were 88.5% (23/26 participants) in the relugolix combination tablet group and 76.9% (20/26) in the relugolix group. All TEAEs were either mild or moderate in severity in both groups, and there were no deaths. Summary of treatment‐emergent adverse events. TEAEs occurring in at least two participants in the relugolix combination tablet or relugolix group, respectively, were intermenstrual bleeding (34.6% and 23.1%), hot flashes (23.1% and 53.8%), uterine hemorrhage (19.2% each), headache (15.4% and 30.8%), upper respiratory tract infection and vomiting (7.7% and 3.8%), and nausea, menstrual disorder, and heavy menstrual bleeding (3.8% and 11.5%). Moderate cholelithiasis, considered a serious TEAE, occurred in one participant (3.8%) in the relugolix combination tablet group, but was not considered to be related to the study drug. TEAEs leading to treatment discontinuation occurred in two participants (cholecystitis and cholelithiasis [serious] in one participant in the relugolix combination tablet group and hepatic function abnormality in one participant in the relugolix group). None of these three TEAEs was related to the study drugs. Other than the events reported as TEAEs, there were no notable abnormalities in clinical laboratory values, body weight, vital signs, 12‐lead ECG, gynecological examinations, or medical examinations.

The present results demonstrated that relugolix, E2, E1, and NET levels were similar in participants treated with relugolix combination tablets compared with those previously reported in an overseas clinical pharmacological study [ 16 ], indicating that Japanese women can be treated with the relugolix combination tablet at the same doses of relugolix, E2, and NETA as used in other countries. In addition to showing similar E2, E1, and NET levels to overseas studies, the trends in mean relugolix concentrations throughout the treatment period were similar in participants treated with relugolix combination tablets and relugolix monotherapy. This finding was supported by the fact that the mean C max and AUC 0‐24 ratios of relugolix (relugolix combination tablet/relugolix) were within the range of 0.7–0.9. The results of endocrinological investigations of LH, FSH, and P4 also found no significant between‐group differences in concentration–time profiles. These results, therefore, suggest that the pharmacological action of relugolix in combination with E2 and NETA is equivalent to that of relugolix given as monotherapy. The current results elucidated the effects of adding E2 and NETA. The mean E2 concentrations fluctuated between 20 and 50 pg/mL and were higher during the treatment period in the relugolix combination tablet group than in the relugolix group. E2 concentrations within this range are expected to reduce the risk of vasomotor symptoms and bone loss without affecting the effectiveness of relugolix [ 14 , 15 ]. Regarding bone loss, we found no significant change between baseline and the end of the treatment period in the relugolix combination tablet group, compared with an increase in levels of the bone turnover marker CTx in the relugolix group, suggesting increased bone resorption. Although subjectively evaluated, the present results demonstrated that the cumulative mean incidence of hot flashes during the study period was less in the relugolix combination tablet group than in the relugolix group, suggesting that the relugolix combination reduced vasomotor symptoms. The present results therefore indicate that the addition of E2 (1 mg) reduced the incidence of relugolix‐related side effects due to hypoestrogenic status, including vasomotor symptoms and bone loss. The addition of E2 may have increased the risk of uterine bleeding, and the incidence of uterine bleeding was accordingly higher in the relugolix combination group than in the relugolix group. It is unlikely, however, that the increased risk of uterine bleeding would discourage women from continuing the treatment, because most women experienced only mild symptoms (spotting or light bleeding, likely caused by E2 affecting the endometrium). Our results indicated that the addition of NETA (0.5 mg) inhibited E2‐induced endometrial proliferation. NETA is added to relugolix to inhibit E2‐induced proliferation of the endometrium, mimicking the action of progesterone, and is quickly metabolized to its pharmacologically active form, NET [ 17 ]. The present results showed no notable change in NET levels, and the endometrium was thinner at the end of treatment than at baseline in both groups. It therefore appears that the addition of NETA suppressed the endometrial proliferation caused by long‐term treatment with E2. Overall, the present results demonstrated that the addition of E2 and NETA to relugolix achieved E2 concentrations of 20–50 pg/mL and reduced the incidence of hot flashes without causing any clinically meaningful changes in the pharmacokinetic profile of relugolix, endocrinological/bone‐turnover markers, or endometrial thickness. Compared with relugolix monotherapy, however, the relugolix combination tablet increased the number of participants with spotting or light uterine bleeding. This study has some limitations. First, we did not examine the efficacy of relugolix in combination with E2 and NETA in terms of improving uterine fibroid or endometriosis symptoms because this study included only healthy women. In addition, although we examined the impact of E2 on uterine bleeding, the frequency and severity of uterine bleeding caused by E2 may differ between healthy women and those with uterine fibroids or endometriosis. Second, the inhibitory effect of NETA on endometrial proliferation was not fully evaluated because participants were only treated with the study drugs for 6 weeks, which was not long enough to draw any firm conclusions. In addition, the effects of E2 on suppressing relugolix‐caused bone loss need to be investigated for longer than 6 months, with bone mineral density as an outcome measure. We expect that these limitations will be overcome upon completion of our three ongoing phase III clinical studies in patients with uterine fibroids and endometriosis (jRCT2071240087, jRCT 2031240570, and jRCT2031250206). In conclusion, the present study investigated the applicability of using overseas‐approved relugolix combination tablets in Japanese women. The results demonstrated that administration of the same formulation at the reported overseas dosage and via the same route had similar pharmacokinetic and pharmacodynamic properties. Relugolix was also shown to be safe and well tolerated in combination tablet form, with no new safety concerns, and its favorable safety and efficacy profiles suggest that this combination tablet could be suitable for long‐term use in Japanese patients. In conclusion, the present results suggest that relugolix combination tablets may offer a new treatment option for Japanese patients with uterine fibroids or endometriosis.

Uterine fibroids and endometriosis are common sex‐hormone‐dependent diseases in women of reproductive age, leading to a reduced quality of life and potential infertility [ 1 , 2 , 3 ]. Relugolix is a gonadotropin‐releasing hormone (GnRH) receptor antagonist that is widely used in the treatment of uterine fibroids and endometriosis, and it improves symptoms by suppressing the secretion of estrogen and progesterone [ 4 , 5 , 6 ]. This suppression of estrogen levels, however, leads to unfavorable side effects, such as vasomotor symptoms and loss of bone mineral density, and especially in relation to the risk of bone loss, relugolix should thus not be administered for longer than 6 months [ 7 ]. In Japan, currently, no drugs are available for the long‐term symptomatic management of uterine fibroids, and no drugs are available if patients cannot tolerate the hypoestrogenic side effects of GnRH analogs. Therefore, there is a need to develop drugs that can be used over a long period of time, with a low risk of vasomotor symptoms and loss of bone mineral density. Relugolix combination tablets provide an add‐back therapy including estradiol (E2) to reduce the risk of bone loss, and norethindrone acetate (NETA) to suppress estrogen‐induced endometrial proliferation. The drug has been developed with the aim of enabling long‐term treatment beyond 6 months. Previous studies (the LIBERTY study [ 8 ] in patients with uterine fibroids and the SPIRIT study [ 9 ] in patients with endometriosis) demonstrated lower incidence rates of bone loss and vasomotor symptoms in patients treated with relugolix combination tablets than in those treated with relugolix alone. Furthermore, long‐term extension studies have demonstrated the sustained efficacy and safety of relugolix combination tablets after 52 weeks and 104 weeks, respectively [ 10 , 11 ]. Relugolix combination tablets have accordingly been approved for the treatment of uterine fibroids and endometriosis in the EU and the USA [ 12 , 13 ]. As noted, relugolix improves the symptoms of uterine fibroids and endometriosis by reducing estrogen and progesterone levels, and if the E2 dose in the relugolix combination tablets is not optimum, its beneficial effect on symptoms may thus be reduced. It is therefore critical to maintain E2 concentrations in the range of 20–50 pg/mL [ 14 , 15 ], which is thought to reduce side effects such as bone loss without compromising the effectiveness of relugolix. This study aimed to investigate if the previous results of overseas studies of treatment with relugolix combination tablet were applicable to healthy premenopausal Japanese women treated at the same dosage.

Yutaka Osuga has received research funding from ASKA Pharmaceutical Co. Ltd. Hiroyasu Hozumi, Masaki Fujisawa, Kazuhiro Shimomiya, and Rieko Azuma are employees of ASKA Pharmaceutical Co. Ltd.

This was a randomized, double‐blind, double‐dummy, active comparator‐controlled, parallel‐group, phase I/II study to compare the pharmacokinetic, pharmacodynamic, and safety profiles of repeated administration of once daily relugolix combination tablets and relugolix monotherapy for 6 weeks in healthy premenopausal Japanese women. Healthy Japanese premenopausal women, aged ≥ 18 years and ≤ 45 years, with normal menstrual cycles (≥ 25 days and ≤ 38 days), at least two menstrual cycles with ≥ 3 and ≤ 7 consecutive days of bleeding during the 3 months before enrollment, and weighing ≥ 40 kg, with a body mass index (BMI) of ≥ 17.6 kg/m 2 and < 25.0 kg/m 2 , were enrolled in the study. Women were excluded if they had any of the following: undiagnosed uterine bleeding; current or previous osteoporosis, osteopenia, or other metabolic bone diseases; impaired gastrointestinal, hepatic, or renal function that might affect the absorption, metabolism, or excretion of the study drugs; previous cholecystectomy; taken oral contraceptives, sex hormone drugs, or danazol within 3 months of screening; taken injectable hormonal contraceptives, GnRH analogs, or aromatase inhibitors within 6 months of screening; or used an intrauterine device (IUD) or intrauterine system (IUS). Participants who were taking acetaminophen or ibuprofen for menstrual pain or other conditions before the start of the study were allowed to continue the treatment at the same dosage. The following drugs were prohibited from 3 months prior to screening until the end of the follow‐up period: oral contraceptives, sex hormones (e.g., norethisterone [NET], NETA, medroxyprogesterone, estrogen preparations, other progestins), or danazol. Participants were not allowed to take the following drugs from 6 months before screening until the end of the follow‐up period: injectable hormonal contraceptives, GnRH analogs, or aromatase inhibitors, and were not allowed to use IUDs or IUSs. The study consisted of the screening period (Days −45 to −1), 6‐week treatment period (Days 1–46), and follow‐up period (Days 47–84) (Figure  S1 ). Eligible participants were randomized (1:1) using permuted block randomization. Participants in the relugolix combination tablet group were administered one relugolix combination tablet (relugolix 40 mg, E2 1 mg, NETA 0.5 mg) and one relugolix placebo tablet, and participants in the relugolix group were administered one relugolix tablet (relugolix 40 mg) and one relugolix combination placebo tablet, orally once daily for 6 weeks. The first dose was administered between 1 and 5 days after the start of menstruation. Participants were examined after ≥ 10 h of fasting and the study drugs were then administered with 200 mL of water, followed by fasting for 2 h (on Days 1, 2, 22, 23, and 43) or 1 h (on Days 8, 15, 29, and 36). On the other days, participants took the study drugs 1 h before breakfast on an empty stomach. The study endpoints are summarized in Figure  S1 . The pharmacokinetic endpoints were the concentrations of relugolix, NET, E2, and estrone (E1). The pharmacokinetic parameters were maximum concentration ( C max ), area under the concentration‐time curve from time zero to 24 h (AUC 0‐24 ), average concentration ( C avg ), trough observed concentration ( C trough ), time to reach the maximum concentration ( T max ), and elimination half‐life ( t 1/2 ) for relugolix and NET, and C max , AUC 0‐24 , C avg , C trough , T max , and t 1/2 for E2 and E1. The concentrations were measured using liquid chromatography tandem‐mass spectrometry. The lower limits of quantification were 0.05 ng/mL for relugolix, 2.5 pg/mL for E2, 5 pg/mL for E1, and 0.05 ng/mL for NET. The pharmacodynamic endpoints were the concentrations of endocrinological factors (luteinizing hormone [LH], follicle‐stimulating hormone [FSH], and progesterone [P4]) and bone‐turnover markers (bone alkaline phosphatase [BAP] and type I collagen C‐terminal telopeptide [CTx]). The safety outcome measures were uterine bleeding, hot flashes, treatment‐emergent adverse events (TEAEs), body weight, vital signs, 12‐lead electrocardiogram (ECG), laboratory tests, gynecological examinations (cervical cytology, transvaginal ultrasound, and breast examination), and medical examinations. Participants were instructed to record the worst uterine bleeding symptom of the day as “none, spotting, light bleeding, bleeding, or heavy bleeding” and hot flashes including sweating as “yes/no; mild, moderate, or severe” in their participant's diary, every day from the day of providing consent until the day of final observation. The investigators also recorded if menstruation restarted after the end of treatment, and the date when it started. Based on unpublished data used to evaluate the pharmacodynamic parameters of relugolix in premenopausal Japanese women, we determined that 20 participants in each treatment group were required to evaluate the pharmacokinetic and pharmacodynamic parameters of relugolix, NET, E2, and E1. Considering dropouts, the number of participants in each treatment group was set at 24. The full analysis set (FAS) included all participants, excluding those who were not given a study drug, who met any of the exclusion criteria, were not healthy premenopausal Japanese women, or who did not undergo endocrinological or bone marker examination. The pharmacodynamic analysis set (PKAS) included all participants, and the safety analysis set (SS) included all participants who were treated with the study drugs. Pharmacokinetic parameters were analyzed in the PKAS. The mean and standard deviation (SD) were calculated for each parameter. For relugolix, a mixed effect model was applied to the logarithmic transformation of C max and AUC 0‐24 to calculate the 90% confidence intervals (CI) of the between‐group differences in geometric means. For E2 and E1 C trough values, between‐group differences in the change from baseline were analyzed using mixed models for repeated measures (MMRM) with the baseline value as a covariate. For E2, the proportions of participants with C avg and C trough  < 10 pg/mL or < 20 pg/mL were also calculated. Pharmacodynamic analyses were conducted in the FAS. Summary statistics were calculated for the percentage change in endocrinological parameters and bone metabolism markers from baseline. Pharmacodynamic parameters were analyzed using MMRM with baseline values as covariates to determine between‐group differences in change from baseline. Safety outcome measures were analyzed in the SS. The numbers and proportions of participants in each group with uterine bleeding were calculated according to severity. For the analysis of hot flashes, the cumulative mean number of recurrences in each group was calculated using the Nelson‐Aalen estimator, and a normal approximation method was used for intergroup comparisons. TEAEs were coded according to the Medical Dictionary of Regulatory Activities Ver. 26.1, and the number of each event, number of participants, and incidence rate were obtained. The significance level was set at 0.05 for two‐sided tests. Missing values were not imputed. The analyses were carried out using SAS Ver. 9.4 or later (SAS Institute Inc., Cary, NC, USA). The pharmacokinetic analyses were carried out using Phoenix WinNonlin Program Ver. 8.3 or later (Certara USA Inc., Princeton, NJ, USA).

Table S1: Changes in endocrine and bone metabolism parameters during the treatment period. Table S2: Pharmacokinetic parameters of relugolix, E2, E1, and NET. Figure S1: Overview of the study and endpoints.