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Abstract

Objective

We aimed to assess long-term safety and tolerability of fezolinetant, a nonhormonal neurokinin 3 receptor antagonist, among Chinese women with vasomotor symptoms associated with menopause participating in the MOONLIGHT 3 trial.

Methods

In this phase 3 open-label study, women in menopause aged 40–65 years received fezolinetant 30 mg once daily for 52 weeks. The primary endpoint was frequency and severity of treatment-emergent adverse events (TEAEs), assessed at every visit through week 52 and one follow-up visit at week 55.

Results

Overall, 150 women were enrolled (mean age, 54 years) and 105 completed treatment. The frequency of TEAEs was 88.7%. Most TEAEs were mild (63.3%) or moderate (22.7%). The most common TEAE was upper respiratory tract infection (16.0%), followed by dizziness, headache, and protein urine present (10.7% each). There was no clinically relevant change (mean ± standard deviation) in endometrial thickness (baseline, 2.95 ± 1.11 mm; week 52, 2.94 ± 1.18 mm). Alanine aminotransferase and/or aspartate aminotransferase levels >3 times the upper limit of normal were reported in 1.4% of women; no Hy’s Law cases occurred.

Conclusions

Fezolinetant 30 mg once daily was generally safe and well tolerated over a 52-week period among women in China with vasomotor symptoms associated with menopause.

ClinicalTrials.gov Identifier: NCT04451226

Keywords

Fezolinetant vasomotor symptoms hot flashes,receptors neurokinin 3 nonhormonal therapy menopause China

Introduction

Vasomotor symptoms (VMS), commonly known as hot flashes or hot flushes and night sweats, affect approximately 57% of women aged 40 to 64 years worldwide.¹ The estimated prevalence rates of VMS vary regionally, ranging from 37% to 58% in Asia, 18% to 70% in South America, 33% to 83% in Australia, 39% to 77% in Africa, 56% to 97% in Europe, and 41% to 77% in North America.^1,2 The prevalence is higher in East Asia (an estimated 80%) than in Asia in general, with 55% of women reporting moderate to severe VMS.³ Consistent with these findings, a longitudinal, prospective, community-based study among women in Beijing found that ≥85.0% experienced VMS, and 50.3% and 60.4% of women experiencing VMS more than 3 times per day had moderate to severe hot flashes and night sweats, respectively.⁴ Such regional differences could be a result of variations in women’s knowledge and perception of or experience with VMS and its treatments, and/or differences in study designs and reporting mechanisms.^3,5 In addition to being widespread, VMS may negatively affect quality of life and interfere with sleep, daily activities, and productivity at home and at work.^2,6–12

Hormone therapy (HT) is the gold standard and most commonly used treatment for VMS, but its use is limited by an increased risk of cardiovascular events and certain cancers, as well as contraindications in some women.^13–17 Women in China generally use HT less frequently than women in Western countries.¹⁸ Instead, women in East Asia commonly use botanical or herbal medicines, including traditional Chinese medicine (TCM). In Beijing, botanical and traditional medicine/herbal products are the most common nonprescription treatments for VMS, reported in 17.3% of women. Overall, 60.8% of women experience moderate to severe VMS despite a substantial proportion reporting use of nonprescription treatments.³ In a survey of 3500 clinical staff members in health care facilities (i.e., doctors, nurses, managerial and technical staff) in China, most respondents were unaware of the reported risks and benefits of HT.¹⁸ Among 3426 orthopedists, obstetricians, gynecologists, general practitioners, and other physicians in China, fewer than 50% recommended HT for women experiencing symptoms of menopause.¹⁹ Furthermore, in a cross-sectional online survey of 4754 perimenopausal and postmenopausal women in Beijing, Seoul, and Taipei, more than half with moderate to severe VMS were untreated, and most women who were treated received nonprescription treatment (44.3% of perimenopausal women and 35.7% of postmenopausal women) versus prescription treatment (15.0% and 8.8%, respectively).³ Because HT is unsuitable for everyone and additional clinical evidence is needed to support the efficacy of TCM, there is an unmet need for effective nonhormonal alternatives to alleviate VMS.

Fezolinetant is an oral, nonhormonal neurokinin 3 (NK3) receptor antagonist treatment option for moderate to severe VMS and is approved in the United States, Europe, and Australia at a dose of 45 mg once daily.²⁰^–22 Current guidance from the Menopause Society includes fezolinetant as a recommended treatment for VMS based on good and consistent evidence.¹⁷ SKYLIGHT 1 and SKYLIGHT 2 were phase 3, multinational, randomized, double-blind, placebo-controlled trials that evaluated the efficacy and safety of fezolinetant 30 and 45 mg once daily in women aged 40 to 65 years for relief from moderate to severe VMS. Results from these studies showed that fezolinetant reduced the frequency and severity of VMS through week 12 and as early as week 1, compared with placebo controls.^23,24 In SKYLIGHT 4, a 52-week, phase 3, placebo-controlled, long-term safety and tolerability study of fezolinetant 30 and 45 mg once daily, no apparent safety signals were observed at either fezolinetant dose.²⁵ The frequency of treatment-emergent adverse events (TEAEs) was similar between placebo and both doses of fezolinetant, with most TEAEs of mild or moderate severity. Changes from baseline in endometrial thickness and bone health were comparable in control participants who received placebo and women who received fezolinetant.²⁵ These safety results were consistent with those from SKYLIGHT 1 and SKYLIGHT 2.^23,24

The objective of the MOONLIGHT 3 study was to evaluate the long-term safety and tolerability of fezolinetant 30 mg once daily over a 52-week period among women in China with VMS associated with menopause.

Methods

Study design

MOONLIGHT 3 (NCT04451226) was a phase 3, 52-week, single-arm, open-label, multicenter clinical study that assessed the long-term safety and tolerability of oral fezolinetant 30 mg once daily.

Participants were screened for eligibility ≤35 days before treatment initiation. The first dose of fezolinetant was supervised by study staff on day 1. Women were instructed to take fezolinetant once daily in the morning with water. On days when they returned to the study site for assessment visits, they took fezolinetant under staff supervision. During treatment, assessment visits occurred every 2 weeks for the first month and monthly thereafter. Women were assessed at an end-of-treatment visit (week 52). A final safety follow-up visit (week 55) took place 3 weeks after the last dose of the study drug was administered (Figure 1).

Figure 1.

Study design. The study comprised a screening period of up to 35 days; screening assessments were performed at visit 1. The study included a 52-week treatment period. Registration, which occurred at visit 2, was considered day 1 of the study. Visit 2b occurred at week 2 and included only liver biochemistry and international normalized ratio testing, and visits 3 to 15 occurred at approximately 4-week intervals. A follow-up visit was performed at week 55 (visit 16, 3 weeks after the last dose), and unscheduled visits were conducted if deemed necessary by the investigator.

Study population

This study was conducted at 34 centers in China, 31 of which enrolled women from July 2020 to August 2022. The study enrolled Chinese women aged 40 to 65 years who were in menopause, seeking medical treatment for relief of VMS associated with menopause, and had a body mass index of 16 to 38 kg/m². A full list of inclusion and exclusion criteria is shown in Table 1.

Table 1.

Inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
• Women aged 40 to 65 years in good general health based on medical history, general physical examination and ECG findings, laboratory values, and pelvic and breast examination results	• Use of a prohibited therapy (strong and moderate CYP1A2 inhibitors, HT, hormonal contraceptive, any treatment for VMS [prescription, over the counter, or herbal]) or not willing to wash out and discontinue such drugs for the full duration of the study
• Body mass index 16 to 38 kg/m² at screening• In menopause, per one of the following: (1) spontaneous amenorrhea for ≥12 consecutive months, (2) spontaneous amenorrhea for ≥6 months with biochemical criteria of menopause (FSH >40 IU/L), (3) bilateral oophorectomy ≥6 weeks prior to the screening visit (with or without hysterectomy), (4) FSH >40 IU/L if participant received hysterectomy but still has ovaries• Seeking treatment for relief from VMS associated with menopause• No clinically significant abnormal findings on mammogram (or echo) or Pap test (or equivalent cervical cytology)• Willing to undergo a TVU to evaluate the uterus and ovaries at screening and at week 52• Willing to undergo endometrial biopsy at screening and at week 52 with endometrial thickness >4 mm indicated via TVU• Willing to undergo an endometrial biopsy at any time during the study in the case of uterine bleeding• Negative urine pregnancy test result and serology panel (including hepatitis B virus surface antigen, hepatitis C virus antibody, and human immunodeficiency virus)• Agrees not to participate in another interventional study while participating in the present study	• Uncontrolled hypertension, defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg based on an average of two to three readings within the screening period; women with a medical history of well-controlled hypertension may be enrolled at the discretion of the investigator, and those who do not meet the criteria may, at the discretion of the investigator, be reassessed after initiation or review of antihypertensive measures• Unacceptable results of TVU assessment at screening (i.e., full length of endometrial cavity cannot be visualized or presence of a clinically significant abnormal findings)• For women with endometrial thickness >4 mm as indicated via TVU at screening, endometrial biopsy confirming presence of disordered proliferative endometrium, endometrial hyperplasia, endometrial cancer, or other clinically significant abnormal findings (biopsies with insufficient material for evaluation or unevaluable material are acceptable with endometrial thickness <8 mm)• History of undiagnosed uterine bleeding within the past 6 months• Active liver disease, jaundice, or elevated liver aminotransferases (ALT or AST), elevated total or direct bilirubin, elevated INR, or elevated ALP at screening. Women with mildly elevated ALT or AST up to 1.5 × ULN can be enrolled if total and direct bilirubin are normal. Women with mildly elevated ALP (up to 1.5 × ULN) may be enrolled if cholestatic liver disease is excluded and no cause other than fatty liver is diagnosed. Women with Gilbert’s syndrome with elevated total bilirubin may be enrolled as long as hemolysis is ruled out (i.e., direct bilirubin, hemoglobin, and reticulocytes are normal)• Creatinine >1.5 × ULN, or eGFR using the Modification of Diet in Renal Disease formula ≤59 mL/minute/1.73 m²• Any history of the following: malignant tumor, except nonmetastatic basal cell carcinoma of the skin; suicide attempt or suicidal behavior or ideation within 12 months of study enrollment; previous enrollment in a clinical trial with fezolinetant; seizures or other convulsive disorders; severe allergy, hypersensitivity, or intolerance to drugs in general, including the study drug and any of its excipients; or known substance abuse or alcohol addiction within 6 months of screening
	• Medical condition or chronic disease (including history of neurologic [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., moderate asthma], endocrine, or gynecologic disease) or malignancy that could confound interpretation of the study outcome or would make the patient unsuitable for participation
	• Previously received an investigational study drug within 28 days or five half-lives, whichever is longer, prior to screening
	• Unable or unwilling to complete the study procedures

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CYP, cytochrome P450; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; FSH, follicle-stimulating hormone; HT, hormone therapy; INR, international normalized ratio; TVU, transvaginal ultrasound; ULN, upper limit of normal; VMS, vasomotor symptoms.

Ethical considerations

This study was conducted in accordance with ethical principles of the Declaration of Helsinki of 1975 as revised in 2013, the Council for International Organizations of Medical Sciences Ethical Guidelines, and the International Conference for Harmonisation Good Clinical Practice standards. Study materials were approved by the institutional review boards/independent ethics committees at each site (listed in Supplemental Table S1), and written informed consent was obtained from each participant prior to initiation of any study-related procedures. We reported this work in accordance with the CONSORT 2010 statement.²⁶

Study endpoints and assessments

The primary endpoint was the frequency and severity of TEAEs. TEAEs were coded using the Medical Dictionary for Regulatory Activities®. The investigator determined the severity of TEAEs and their relatedness to fezolinetant. TEAEs of special interest were uterine bleeding, endometrial hyperplasia/cancer or disordered proliferative endometrium, thrombocytopenia or platelet count <150,000/µL, liver test elevation of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3× the upper limit of normal (ULN), and bone fractures.

Secondary endpoints included change from baseline in endometrial thickness, percentage of women with endometrial hyperplasia and/or endometrial cancer, physical examination findings, vital signs, electrocardiographic (ECG) parameters, and hematology, biochemistry, and urinalysis assessments including assessment of drug-induced liver injury (Hy’s Law). In studies where Hy’s Law is assessed, cases are identified using the following three criteria: the active treatment group has a higher frequency of AST or ALT elevation ≥3× ULN than controls, patients with such elevations also have elevated serum total bilirubin >2× ULN without cholestasis, and no preexisting conditions or alternative causes can explain these elevations.²⁷ Secondary endpoints also included mean changes in serum concentrations of bone-specific alkaline phosphatase (BSAP), procollagen type 1 amino-terminal propeptide (P1NP), and carboxy-terminal telopeptides of type I collagen (CTX), as well as Columbia Suicide Severity Rating Scale (C-SSRS) scores.

Demographics were collected at screening. TEAE monitoring occurred at all visits and continued until week 55 (i.e., 21 days after the last dose of fezolinetant) or until screen failure, as determined by the investigator. Endometrial health was assessed as the change in endometrial thickness from baseline (defined as the last nonmissing measurement on or prior to the first dose of fezolinetant) to week 52. The percentage of women with endometrial hyperplasia and/or endometrial cancer (determined using transvaginal ultrasound [TVU] and follow-up biopsy, if necessary) at screening and week 52 was also considered part of overall endometrial health. Women with endometrial thickness >4 mm on TVU at screening and week 52 and those who experienced uterine bleeding during treatment underwent endometrial biopsy. Full physical examinations were performed at screening, week 52, and week 55. Symptom-directed physical examinations and vital signs were assessed at all visits through week 48, excluding the first day of treatment. ECGs were obtained at screening, visit 2 (registration), and week 52. Liver biochemistry and coagulation panels were the only tests administered on the first day of treatment and at all other visits. Bone marker laboratory assessments were administered at registration, week 52, and week 55. The C-SSRS was administered at screening, registration, and weeks 12, 24, 48, 52, and 55.

Statistical analyses

Based on the International Conference on Harmonisation E1 guideline for this objective,²⁸ the target number of cases was set to 150, ensuring that at least 100 women were exposed to 1 year of treatment. The safety analysis set included all women who received at least 1 dose of fezolinetant and had any data reported after the first dose; this set was used to summarize demographic and baseline characteristics and all safety- and tolerability-related variables. Summary statistics are presented for all safety endpoints.

Results

Study population and treatment exposure

A total of 150 women were enrolled in the study. All women received fezolinetant 30 mg. Of those, 45 (30.0%) discontinued the study, mostly owing to withdrawal of consent (n = 33); thus, 105 (70.0%) completed the study (Figure 2). The mean age of study participants was 54 years. Most women (54.7%) were aged 51 to 55 years, and most (95.2%) had never received prior HT (Table 2). The median duration of treatment exposure was 364 days, and the median overall treatment compliance was 99.7%.

Figure 2.

Participant disposition.

Table 2.

Demographics and baseline characteristics: safety analysis set.

Characteristic	Fezolinetant 30 mg (N = 150)
Age, years
Mean (SD)	53.8 (3.6)
Median (range)	54 (44–64)
Age category, n (%)
40 to 45 years	2 (1.3)
46 to 50 years	23 (15.3)
51 to 55 years	82 (54.7)
56 to 60 years	36 (24.0)
61 to 65 years	7 (4.7)
BMI, kg/m²
Mean (SD)	23.7 (3.06)
Median (range)	23.3 (17.9–33.8)
BMI category, n (%)
<18.5 kg/m²	3 (2.0)
18.5 to 24.9 kg/m²	100 (66.7)
25 to 29.9 kg/m²	41 (27.3)
≥30 kg/m²	6 (4.0)
Tobacco history, n (%)
Former smoker	1 (0.7)
Current smoker	2 (1.3)
Never smoked	147 (98.0)
Prior hormone replacement therapy,^a n (%)
Yes	7 (4.8)
No	139 (95.2)
Oophorectomy, n (%)
Yes	2 (1.3)
No	148 (98.7)
Hysterectomy, n (%)
Yes	12 (8.0)
No	138 (92.0)

Prior hormone replacement therapy missing for four women.

BMI, body mass index; SD, standard deviation.

Treatment-emergent adverse events

The overall frequency of TEAEs among the 150 study participants was 88.7% (Table 3). In total, 63.3% of women experienced mild TEAEs, 22.7% experienced moderate TEAEs, and 2.7% experienced severe TEAEs. The most common TEAEs were upper respiratory tract infection, dizziness, headache, protein urine present, and insomnia. Half of the women experienced fezolinetant-related TEAEs, and 10.0% experienced serious TEAEs. No severe TEAEs or serious TEAEs (preferred term) were reported in more than one woman. Among TEAEs of special interest, bone fractures, endometrial thickening or adenocarcinoma, and uterine bleeding occurred in ≤3.3% of women. Liver test elevation occurred in 13 women (8.7%). Of those, elevations of ALT and/or AST >3× ULN occurred in 2 of 139 (1.4%) women with available data. Fourteen (9.3%) women had thrombocytopenia or platelets <150,000/µL. No bleeding or bruising was reported for these women. TEAEs leading to treatment discontinuation were reported in seven women (4.7%); no TEAEs (preferred term) led to treatment discontinuation for more than one woman. No deaths were reported.

Table 3.

Overview of treatment-emergent adverse events: safety analysis set

TEAEs, n (%)	Fezolinetant 30 mg (N = 150)
Overall TEAEs	133 (88.7)
Study drug-related TEAEs	75 (50.0)
Serious TEAEs^a	15 (10.0)
Study drug-related serious TEAEs^b	2 (1.3)
TEAEs leading to treatment discontinuation	7 (4.7)
Death	0
Most common (≥10%) TEAEs^c
Upper respiratory tract infection	24 (16.0)
Dizziness	16 (10.7)
Headache	16 (10.7)
Protein urine present	16 (10.7)
Insomnia	15 (10.0)
TEAEs, by severity^d
Mild	95 (63.3)
Moderate	34 (22.7)
Severe	4 (2.7)
TEAEs of special interest^c
Bone fracture	4 (2.7)
Endometrial hyperplasia/cancer or disordered proliferative endometrium	5 (3.3)
Endometrial thickening	4 (2.7)
Endometrial adenocarcinoma	1 (0.7)
Uterine bleeding	5 (3.3)
Liver test elevation^e	13 (8.7)
Thrombocytopenia or platelets <150,000/µL	14 (9.3)

MedDRA System Organ Class: gastrointestinal disorders (three women; 2.0%); musculoskeletal and connective tissue disorders (three women; 2.0%); benign and malignant neoplasms (two women; 1.3%); cardiac disorders (two women; 1.3%); hepatobiliary disorders (two women; 1.3%); injury, poisoning, and procedural complications (two women; 1.3%); endocrine disorder (one woman; 0.7%); eye disorder (one woman; 0.7%); infection and infestation (one woman; 0.7%); psychiatric disorder (one woman; 0.7%); and renal and urinary disorder (one woman; 0.7%).

Coronary artery disease and liver injury were reported in one woman each.

MedDRA version 23.0 preferred terms are shown.

Mild: no disruption of normal daily activities; moderate: affects normal daily activities; severe: inability to perform daily activities.

Liver function tests included ALT, AST, ALP, and total bilirubin.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.

Endometrial health

There was minimal change in endometrial thickness from baseline to week 52 (Figure 3). Overall, five women (3.3%) reported TEAEs under the category of endometrial hyperplasia/cancer or disordered proliferative endometrium (Table 3). Of these women, four experienced nonserious, fezolinetant-related endometrial thickening and one experienced endometrial carcinoma, which was considered not related to fezolinetant.

Figure 3.

Endometrial thickness from baseline to week 52: safety analysis set. Error bars show standard deviation. SD, standard deviation.

Physical examination findings, vital signs, and ECG parameters

There were no clinically relevant changes throughout the study in weight, body mass index (Figure 4a and 4b), sitting systolic blood pressure or diastolic blood pressure, or pulse rate (Figure 5a, 5b, and 5c). Mean (standard deviation [SD]) quantitative interval measures of the ECG parameters were unchanged from baseline (66.9 [8.6] bpm) to week 52 (66.6 [7.9] bpm).

Figure 4.

Changes in (a) weight and (b) body mass index across 4-week intervals from baseline to the week 55 follow-up visit: safety analysis set. Upper fence shows 1.5 × IQR above 75th percentile. Box shows 25th percentile (lower edge) to 75th percentile (upper edge). Inside box: line shows median and symbol shows mean. Lower fence shows 1.5 × IQR below 25th percentile. BMI, body mass index; IQR, interquartile range.

Figure 5.

Changes in (a) systolic blood pressure, (b) diastolic blood pressure, and (c) pulse rate across 4-week intervals from baseline to the week 55 follow-up visit: safety analysis set. Upper fence shows 1.5 × IQR above 75th percentile. Box shows 25th percentile (lower edge) to 75th percentile (upper edge). Inside box: line shows median and symbol shows mean. Lower fence shows 1.5 × IQR below 25th percentile. bpm, beats per minute; IQR, interquartile range.

Hematology, biochemistry, and urinalysis assessments

No total bilirubin elevation >2× ULN occurred (Table 4). No trends in ALT or AST increases were observed over time, and no Hy’s Law cases were reported. Most elevations of ALT or AST were transient or isolated and asymptomatic. There were no clinically relevant changes from baseline in any hematology, biochemistry, or urinalysis assessments except for increased gamma-glutamyl transferase levels in one woman, decreased white blood cell and platelet counts in one woman, and increased blood lactate dehydrogenase levels in one woman, all of which resulted in treatment discontinuation.

Table 4.

Overview of liver safety assessments: safety analysis set

Parameter, n (%)	Fezolinetant 30 mg (N = 150)
Women with nonmissing data (n = 139)^a
ALT
>3 × ULN	2 (1.4)
>5 × ULN	1 (0.7)
>8 × ULN	1 (0.7)
>10 × ULN	0
AST
>3 × ULN	2 (1.4)
>5 × ULN	1 (0.7)
>8 × ULN	0
ALP
>1.5 × ULN	0
Total bilirubin
>2 × ULN	0

All women who received at least 1 dose of fezolinetant and for whom any data were reported after the first dose of fezolinetant (safety analysis set) are included; 139 women had ≥1 nonmissing value during treatment.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

Bone marker analyses

Analysis of serum concentrations of BSAP, P1NP, and CTX revealed that mean concentrations of bone markers were generally unchanged from baseline (Figure 6). Bone fractures were reported in four women (2.7%); of those, two women had serious fractures, which were considered unrelated to fezolinetant.

Figure 6.

Serum concentrations of bone markers from baseline to week 52: safety analysis set. Six women are missing in calculation of the change from baseline because they did not have baseline measurements. Error bars show standard deviation.

C-SSRS scores

No suicidal ideation or behavior or self-injurious behavior without suicidal intent were reported at the time of assessment.

Discussion

In this 52-week study among 150 Chinese menopausal women seeking treatment for VMS associated with menopause, fezolinetant 30 mg once daily was well tolerated, with an acceptable safety profile, supporting its use in this population. TEAEs were generally mild or moderate (86.0%) and were reported in 88.7% of women. The most common TEAEs (≥10%) were upper respiratory infection, dizziness, headache, protein urine present, and insomnia. TEAEs led to treatment discontinuation in <5% of women.

Treatment with fezolinetant did not cause clinically meaningful changes from baseline among secondary endpoints. FDA guidance recommends that studies assessing estrogen-based treatments for VMS associated with menopause closely monitor endometrial health because estrogen can cause risks to endometrial health in some individuals.²⁹ Fezolinetant, a nonhormonal treatment, did not cause clinically relevant changes from baseline in endometrial thickness in this 52-week study. There were no cases of Hy’s Law. Elevations of AST and/or ALT >3× ULN were reported in 2 (1.4%) women and were transient; one occurrence resolved while on treatment and the other resolved after treatment discontinuation. Vital signs, physical examination findings, ECG parameters, biochemical measures, and suicidal ideation/behavior or self-injurious behavior were generally unchanged throughout the study.

We observed a relatively higher frequency of TEAEs in MOONLIGHT 3 compared with other fezolinetant studies, which may be owing to the single-arm and open-label design. Notwithstanding, the safety findings were generally consistent with data from non-Asian women in the larger 52-week SKYLIGHT 4 study among 1830 women, 611 of whom received fezolinetant 30 mg.²⁵ In both studies, mild TEAEs were more common than moderate and severe TEAEs,²⁵ which demonstrates the tolerability of fezolinetant across studies. Furthermore, endometrial thickening, endometrial hyperplasia, and elevated liver enzymes and bilirubin levels were infrequent in both studies.²⁵ The MOONLIGHT 1 trial examined the efficacy and safety of fezolinetant 30 mg among women in East Asia. Co-primary efficacy endpoints were not met, potentially because the placebo response was higher than expected; nevertheless, fezolinetant 30 mg once daily was generally safe and well tolerated when administered for up to 24 weeks.³⁰ These clinical trial data taken together show that fezolinetant 30 mg was generally safe and well tolerated when administered for up to 52 weeks in Chinese women.

Fezolinetant 30 mg was previously identified as the lowest effective dose for reducing VMS frequency and severity, based on data available at the time, including data from a placebo-controlled, phase 2b study.³¹ Subsequent data from the SKYLIGHT trials, which became available after MOONLIGHT 3 began, showed that fezolinetant 45 mg generally improved efficacy relative to the 30 mg dose.^23,24 Fezolinetant was well tolerated, and safety was consistent across the 30 and 45 mg doses²⁴ in MOONLIGHT 3 as well as in the 52-week SKYLIGHT 4 trial.²⁵ Based on these results, fezolinetant was approved in the United States, Europe, and Australia at a dose of 45 mg once daily.²⁰^–²²

Limitations of this study include the lack of a placebo control group, without which the safety and tolerability of fezolinetant cannot be comparatively assessed. Notably, the safety profile in this study was generally similar to that in other studies of fezolinetant 30 mg that included placebo controls.^25,30 Only one dose was tested in this study, whereas multiple doses were administered in other studies. Therefore, we cannot derive information from the current study about how various doses may affect safety and tolerability differently or whether any of the observed TEAEs were dose-dependent. Finally, this study was conducted among Chinese women; thus, the findings may not be generalizable to a non-Chinese population.

Conclusions

In this phase 3 study, fezolinetant, a nonhormonal NK3 receptor antagonist, had an acceptable safety profile and was well tolerated in Chinese women with VMS associated with menopause, which is consistent with findings from MOONLIGHT 1 among women in East Asia.³⁰ TEAEs were generally mild to moderate in severity. No clinically relevant changes from baseline were observed in endometrial thickness or bone health, and no cases of Hy’s Law were identified. MOONLIGHT 3 provides additional evidence for the safety of fezolinetant over a 52-week period in a Chinese population. Fezolinetant shows promise as a safe nonhormonal treatment for women who experience VMS associated with menopause.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241246624 - Supplemental material for Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial

Supplemental material, sj-pdf-1-imr-10.1177_03000605241246624 for Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial by Qi Yu, Fang Ming, Jiezhi Ma, Yiling Cai, Liping Wang, Mulan Ren, Jun Zhang, Xiao Ma, Kentaro Miyazaki, Weizhong He and Xuegong Wang in Journal of International Medical Research

Supplemental Material

sj-pdf-2-imr-10.1177_03000605241246624 - Supplemental material for Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial

Supplemental material, sj-pdf-2-imr-10.1177_03000605241246624 for Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial by Qi Yu, Fang Ming, Jiezhi Ma, Yiling Cai, Liping Wang, Mulan Ren, Jun Zhang, Xiao Ma, Kentaro Miyazaki, Weizhong He and Xuegong Wang in Journal of International Medical Research

Supplemental Material

sj-pdf-3-imr-10.1177_03000605241246624 - Supplemental material for Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial

Supplemental material, sj-pdf-3-imr-10.1177_03000605241246624 for Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial by Qi Yu, Fang Ming, Jiezhi Ma, Yiling Cai, Liping Wang, Mulan Ren, Jun Zhang, Xiao Ma, Kentaro Miyazaki, Weizhong He and Xuegong Wang in Journal of International Medical Research

Footnotes

Acknowledgements

The authors thank the study investigators and staff,and all women who participated in the study. The authors also thank Tianyu Zhou for valuable contributions to the study design,as well as acquisition,analysis,and interpretation of the data. MedDRA® trademark is registered by ICH.

Author Contributions

Study design: XW,JZ,XM,KM,WH

Study principal investigator: QY

Data acquisition: All authors

Data analysis: XW,JZ,XM,KM,WH

Data interpretation: All authors

Manuscript preparation: All authors

All authors participated in the critical review and revision of this manuscript and provided approval of the manuscript for submission.

Data availability statement

Researchers may request access to anonymized participant-level data,trial-level data,and protocols of Astellas-sponsored clinical trials at www.clinicalstudydatarequest.com . For the Astellas criteria on data sharing see:

Declaration of conflicting interests

Weizhong He was an employee of Astellas Pharma Global Development,Inc.,at the time of the study. Kentaro Miyazaki is an employee of Astellas Pharma,Inc.,Xuegong Wang is an employee of Astellas Pharma Global Development,Inc.,and Xiao Ma is an employee of Astellas (China) Investment Co,Ltd. The remaining authors have no conflicts of interest to disclose.

Funding

This study was sponsored by Astellas Pharma Inc. Medical writing and editorial support were provided by Hannah L. Mayberry,PhD,Jessica D. Herr,PharmD,and Matthew Weddig from Echelon Brand Communications,LLC,an OPEN Health company,and funded by Astellas Pharma Inc.

Supplemental material

Supplemental material for this article is available online.

References

Makara-Studzińśka

Kryś-Noszczyk

Jakiel

Epidemiology of the symptoms of menopause - an intercontinental review. Prz Menopauzalny 2014; 13: 203–211. doi: 10.5114/pm.2014.43827.

Nappi

Kroll

Siddiqui

, et al. Global cross-sectional survey of women with vasomotor symptoms associated with menopause: prevalence and quality of life burden. Menopause 2021; 28: 875–882. doi: 10.1097/gme.0000000000001793.

Chae

Hsiao

, et al. Prevalence, severity, and associated factors in women in East Asia with moderate-to-severe vasomotor symptoms associated with menopause. Menopause 2022; 29: 553–563. doi: 10.1097/gme.0000000000001949.

Luo

Tang

, et al. Vasomotor symptoms in aging Chinese women: findings from a prospective cohort study. Climacteric 2020; 23: 46–52. doi: 10.1080/13697137.2019.1628734.

Huang

, et al. The Asian Menopause Survey: knowledge, perceptions, hormone treatment and sexual function. Maturitas 2010; 65: 276–283. doi: 10.1016/j.maturitas.2009.11.015.

Blumel

Chedraui

Baron

, Collaborative Group for Research of the Climacteric in Latin America (REDLINC)et al. A large multinational study of vasomotor symptom prevalence, duration, and impact on quality of life in middle-aged women. Menopause 2011; 18: 778–785. doi: 10.1097/gme.0b013e318207851d.

Gartoulla

Bell

Worsley

, et al. Moderate-severely bothersome vasomotor symptoms are associated with lowered psychological general wellbeing in women at midlife. Maturitas 2015; 81: 487–492. doi: 10.1016/j.maturitas.2015.06.004.

Whiteley

Wagner

Bushmakin

, et al. Impact of the severity of vasomotor symptoms on health status, resource use, and productivity. Menopause 2013; 20: 518–524. doi: 10.1097/GME.0b013e31827d38a5.

Whiteley

DiBonaventura

Wagner

, et al. The impact of menopausal symptoms on quality of life, productivity, and economic outcomes. J Womens Health (Larchmt) 2013; 22: 983–990. doi: 10.1089/jwh.2012.3719.

10.

DiBonaventura

Chandran

Hsu

, et al. Burden of vasomotor symptoms in France, Germany, Italy, Spain, and the United Kingdom. Int J Womens Health 2013; 5: 261–269. doi: 10.2147/IJWH.S39027.

11.

English

Stoykova

Slota

, et al. Qualitative study: burden of menopause-associated vasomotor symptoms (VMS) and validation of PROMIS sleep disturbance and sleep-related impairment measures for assessment of VMS impact on sleep. J Patient Rep Outcomes 2021; 5: 37. doi: 10.1186/s41687-021-00289-y.

12.

Utian

WH.

Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes 2005; 3: 47. doi: 10.1186/1477-7525-3-47.

13.

De Villiers

Hall

Pinkerton

, et al. Revised global consensus statement on menopausal hormone therapy. Maturitas 2016; 91: 153–155. doi: 10.1016/j.maturitas.2016.06.001.

14.

“The 2022 Hormone Therapy Position Statement of The North American Menopause Society” Advisory Panel. The 2022 Hormone Therapy Position Statement of The North American Menopause Society. Menopause 2022; 29: 767–794. doi: 10.1097/gme.0000000000002028.

15.

Ameye

Antoine

Paesmans

, et al. Menopausal hormone therapy use in 17 European countries during the last decade. Maturitas 2014; 79: 287–291. doi: 10.1016/j.maturitas.2014.07.002.

16.

Baber

Panay

Fenton

, IMS Writing Group. 2016 IMS recommendations on women's midlife health and menopause hormone therapy. Climacteric 2016; 19: 109–150. doi: 10.3109/13697137.2015.1129166.

17.

“The 2023 Nonhormone Therapy Position Statement of The North American Menopause Society” Advisory Panel . The 2023 Nonhormone Therapy Position Statement of The North American Menopause Society. Menopause 2023; 30: 573–590. doi: 10.1097/gme.0000000000002200.

18.

Zhu

Yang

Wang

, et al. Assessment of knowledge, understanding and awareness of Chinese women clinical staff towards menopause hormone therapy: a survey study. J Obstet Gynaecol 2023; 43: 2171779. doi: 10.1080/01443615.2023.2171779.

19.

Lin

Feng

Attitude and knowledge for menopause management among health professionals in mainland China. Climacteric 2020; 23: 614–621. doi: 10.1080/13697137.2020.1775809.

20.

Veoza [summary of product characteristics]. Leiden, Netherlands Astellas Pharma Europe B.V.; 2023.

21.

Veozah™ [package. insert]. Northbrook, IL: Astellas Pharma US, Inc.; 2023.

22.

Australian Product information - Veoza™ (fezolinetant). Macquarie Park, NSW, Australia: Astellas Pharma Australia; 2024.

23.

Lederman

Ottery

Cano

, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised study. Lancet 2023; 401: 1091–1102. doi: 10.1016/S0140-6736(23)00085-5.

24.

Johnson

Martin

Nappi

, et al. Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: a phase 3 RCT. J Clin Endocrinol Metab 2023; 108: 1981–1997. doi: 10.1210/clinem/dgad058.

25.

Neal-Perry

Cano

Lederman

, et al. Safety of fezolinetant for vasomotor symptoms associated with menopause: a randomized controlled trial. Obstet Gynecol 2023; 141: 737–747. doi: 10.1097/aog.0000000000005114.

26.

Schulz

Altman

Moher

, CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c332. doi: 10.1136/bmj.c332.

27.

U.S. Food and Drug Administration. Guidance for Industry – Drug-induced liver injury: premarketing clinical evaluation. 2009. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf. Accessed: August 12, 2019.

28.

ICH Expert Working Group. E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 1995. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e1a-extent-population-exposure-assess-clinical-safety-drugs-intended-long-term-treatment-non-life. Accessed: February 5, 2024.

29.

U.S. Food and Drug Administration. Guidance for Industry – Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms: recommendations for clinical evaluation. 2003. Available at: https://www.fda.gov/media/71359/download. Accessed: February 28, 2023.

30.

Ruan

Bai

Ren

, et al. Efficacy and safety of fezolinetant for moderate to severe vasomotor symptoms among women in East Asia: a phase 3 randomized study (MOONLIGHT 1). J Int Med Res 2024; in press.

31.

Fraser

Lederman

Waldbaum

, et al. A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause. Menopause 2020; 27: 382–392. doi: 10.1097/GME.0000000000001510.

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