Efficacy and safety of fezolinetant for moderate to severe vasomotor symptoms associated with menopause among women in East Asia: a phase 3 randomized study (MOONLIGHT I)

Abstract

Objective

To evaluate the efficacy and safety of fezolinetant for moderate to severe vasomotor symptoms (VMS) associated with menopause in East Asian women.

Methods

In this phase 3, randomized, double-blind study, postmenopausal women with moderate to severe VMS (minimum average frequency in the 10 days before randomization, ≥7/day or 50/week) received fezolinetant 30 mg/day or placebo (weeks 1–12), followed by an open-label extension phase with fezolinetant 30 mg/day (weeks 13–24). The co-primary endpoints were the mean changes in the daily frequency and severity of VMS at weeks 4 and 12.

Results

Among 301 participants, the difference in the least squares mean change (95% confidence interval) from baseline in the daily frequency of moderate to severe VMS versus placebo was −0.65 (−1.41 to 0.12) at week 4 and −0.55 (−1.35 to 0.26) at week 12. The differences in the least squares mean change from baseline in the VMS severity score versus placebo were −0.06 (−0.14 to 0.03) and −0.13 (−0.27 to 0.01) at weeks 4 and 12, respectively. Serious adverse events occurred in 0.7% of participants receiving fezolinetant in weeks 1 to 12, compared with 1.3% of those receiving placebo.

Conclusions

Fezolinetant was generally safe but did not reduce the frequency or severity of VMS versus placebo in postmenopausal women in this study.

ClinicalTrials.Gov Identifier: NCT04234204

Keywords

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

Introduction

Globally, most women aged 40 to 64 years experience vasomotor symptoms (VMS) associated with menopause, which consist of hot flashes (also called hot flushes) and night sweats.¹ A review of available data from 13 studies for the period from 2002 to 2013 reported menopausal VMS prevalence rates in Asia of 37% to 58%.¹ A later cross-sectional survey conducted in East Asia found that 83% of perimenopausal women and 78% of postmenopausal women aged 40 to 65 years had VMS.²

Additional safe and effective treatments for VMS are needed. According to international and regional guidelines, estrogen-based hormone therapy (HT) is the gold standard for treating VMS, but it is associated with increased risks of stroke, venous thromboembolism, and breast cancer (if a progestogen is included) or endometrial cancer (if given without a progestogen).^3–6 Nonhormonal therapies are options for women who desire treatment but have contraindications to HT, who prefer not to use HT, or who have not responded to or tolerated HT well.^6,7 Guideline-supported nonhormonal treatments for VMS with high-quality level 1 evidence include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), gabapentin, fezolinetant, cognitive-behavioral therapy, and clinical hypnosis.⁸ Although direct comparative trials versus HT are limited, SSRIs and SNRIs are generally perceived to have mild to moderate efficacy, and their adverse effects include dry mouth, somnolence, nausea, dizziness, and sexual dysfunction.^8–10 High doses of gabapentin (2400 mg/day) can provide similar efficacy as HT, but gabapentin use is limited by dizziness, headache, disorientation, impaired balance, and uncommon suicidal thoughts or behavior.⁸ Traditional Chinese medicine (TCM) is popular,¹¹ and it is included in regional evidence-based guidelines.^6,12 However, more clinical data are needed because the quality of available evidence is generally low.^6,12

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.^13–15 Fezolinetant directly targets the underlying mechanism responsible for VMS.^16,17 As previously reviewed by Rance et al.¹⁸ and Depypere et al.,¹⁹ body temperature is regulated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the hypothalamus, which are stimulated by neurokinin B via NK3 receptors and inhibited by estrogen. Diminished estrogen levels at menopause leave NKB signaling unopposed, resulting in hypertrophy of KNDy neurons, increased KNDy neuron signaling to the median preoptic nucleus (the thermoregulatory center of the hypothalamus), and activation of heat-dissipation effectors (e.g., skin vasodilation, sweating), leading to VMS.^18,19 By blocking NK3 receptors, fezolinetant moderates NKB signaling, suppresses the activity of KNDy neurons and neurons in the median preoptic nucleus, and reduces the frequency and severity of moderate to severe VMS associated with menopause.^19,20

In phase 3 randomized, double-blind, placebo-controlled trials (SKYLIGHT 1 and SKYLIGHT 2), fezolinetant 30 and 45 mg significantly reduced the frequency and severity of moderate to severe VMS associated with menopause at weeks 4 and 12, and the effect was maintained throughout the active treatment extension period up to week 52 in women from the United States and Europe.^16,17 SKYLIGHT 4, a randomized, double-blind, placebo-controlled study, confirmed the safety and tolerability of fezolinetant 30 and 45 mg for up to 52 weeks in postmenopausal women seeking treatment for VMS.²¹ The current phase 3 study, MOONLIGHT 1, was conducted to evaluate the efficacy and safety of fezolinetant compared with placebo for the treatment of moderate to severe VMS in East Asian women in postmenopause.

Patients and methods

Study design and participants

In MOONLIGHT 1 (NCT04234204), eligible women at multiple centers in East Asia were randomized (1:1) to receive oral fezolinetant 30 mg or an identical-looking placebo once daily for 12 weeks (Figure 1). Randomization was double-blind, with patients stratified by smoking status (current vs. former/never), and was carried out using interactive response technology. Doses occurring on study site visit days (Figure 1) were taken under supervision at the site. Intervening doses were taken at home in the morning. Women who completed the 12-week randomized period were entered into an open-label extension period in which everyone received fezolinetant 30 mg once daily through week 24. In this phase, site personnel dispensing treatment and participants remained blinded to the initial treatment given during the randomized period. Participants were then followed for 3 weeks after treatment discontinuation.

Figure 1.

Study design. Wk, week.

The study enrolled healthy women aged 40 to 65 years in natural or surgical postmenopause who were seeking treatment or symptom relief for VMS. All women had an average of at least seven episodes of moderate to severe VMS per day or 50 per week within 10 days prior to randomization and a body mass index of ≥16 and ≤38 kg/m². The complete inclusion and exclusion criteria are presented in Table 1.

Table 1.

Inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
• Generally healthy woman aged 40 to 65 years• Body mass index ≥16 to ≤38 kg/m²• Seeking treatment or symptom relief for VMS associated with menopause at screening• Postmenopausal status confirmed by one of the following: (1) spontaneous amenorrhea for ≥12 consecutive months, (2) spontaneous amenorrhea for ≥6 months with FSH > 40 IU/L, (3) bilateral oophorectomy (with or without hysterectomy) ≥6 weeks prior to screening, or (4) FSH > 40 IU/L in women who underwent hysterectomy without oophorectomy• Average of ≥7 episodes of moderate to severe VMS per day or ≥50 per week within 10 days prior to randomization• No clinically significant findings on mammogram or Pap smear• Negative hepatitis B and C serology at screening• Willing to undergo TVU to evaluate the uterus and ovaries at screening and at week 24 (end of treatment) or at the end of treatment in the event of early withdrawal from the trial• Willing to undergo endometrial biopsy at screening and at week 24 or at early discontinuation if endometrial thickness > 4 mm on TVU or at any time during the study in the case of uterine bleeding• Negative urine pregnancy test result	• Receipt of moderate or strong CYP450 1A2 inhibitors, hormone therapy, hormonal contraception, or any treatment for VMS (prescription, nonprescription, or herbal) and not willing to wash out and discontinue the use of such therapies for the duration of the study• History of malignancy other than nonmetastatic basal cell carcinoma of the skin• Uncontrolled hypertension (i.e., systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg based on the average of two or three readings during the screening period). Women with controlled hypertension could be enrolled at the discretion of the investigator, and women with uncontrolled hypertension could be reassessed at the investigator’s discretion after initiation or review of antihypertensive measures• Undiagnosed uterine bleeding within the past 6 months, unacceptable TVU results at screening, or endometrial biopsy confirming disordered proliferative endometrium, endometrial hyperplasia, or endometrial cancer• Active liver disease/jaundice, or ALT, AST, or ALP levels >1.5 × ULN, elevated total or direct bilirubin, or elevated INR• Creatinine >1.5 × ULN, eGFR ≤59 mL/min/1.73 m² at screening• Suicidal ideation or attempt within the past 12 months• Positive HIV test result at screening• History of any of the following: malignancy (except nonmetastatic basal cell carcinoma of the skin), substance abuse or alcohol addiction within 6 months of screening, severe drug allergy to or intolerance of drugs in general, seizures/convulsive disorders, or any medical condition or chronic disease that could confound interpretation of study outcomes or make the person unsuitable for study participation in the opinion of the investigator• Receipt of an investigational drug within 28 days or 5 half-lives prior to screening

Inclusion criteria

Exclusion criteria

• Generally healthy woman aged 40 to 65 years• Body mass index ≥16 to ≤38 kg/m²• Seeking treatment or symptom relief for VMS associated with menopause at screening• Postmenopausal status confirmed by one of the following: (1) spontaneous amenorrhea for ≥12 consecutive months, (2) spontaneous amenorrhea for ≥6 months with FSH > 40 IU/L, (3) bilateral oophorectomy (with or without hysterectomy) ≥6 weeks prior to screening, or (4) FSH > 40 IU/L in women who underwent hysterectomy without oophorectomy• Average of ≥7 episodes of moderate to severe VMS per day or ≥50 per week within 10 days prior to randomization• No clinically significant findings on mammogram or Pap smear• Negative hepatitis B and C serology at screening• Willing to undergo TVU to evaluate the uterus and ovaries at screening and at week 24 (end of treatment) or at the end of treatment in the event of early withdrawal from the trial• Willing to undergo endometrial biopsy at screening and at week 24 or at early discontinuation if endometrial thickness > 4 mm on TVU or at any time during the study in the case of uterine bleeding• Negative urine pregnancy test result

• Receipt of moderate or strong CYP450 1A2 inhibitors, hormone therapy, hormonal contraception, or any treatment for VMS (prescription, nonprescription, or herbal) and not willing to wash out and discontinue the use of such therapies for the duration of the study• History of malignancy other than nonmetastatic basal cell carcinoma of the skin• Uncontrolled hypertension (i.e., systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg based on the average of two or three readings during the screening period). Women with controlled hypertension could be enrolled at the discretion of the investigator, and women with uncontrolled hypertension could be reassessed at the investigator’s discretion after initiation or review of antihypertensive measures• Undiagnosed uterine bleeding within the past 6 months, unacceptable TVU results at screening, or endometrial biopsy confirming disordered proliferative endometrium, endometrial hyperplasia, or endometrial cancer• Active liver disease/jaundice, or ALT, AST, or ALP levels >1.5 × ULN, elevated total or direct bilirubin, or elevated INR• Creatinine >1.5 × ULN, eGFR ≤59 mL/min/1.73 m² at screening• Suicidal ideation or attempt within the past 12 months• Positive HIV test result at screening• History of any of the following: malignancy (except nonmetastatic basal cell carcinoma of the skin), substance abuse or alcohol addiction within 6 months of screening, severe drug allergy to or intolerance of drugs in general, seizures/convulsive disorders, or any medical condition or chronic disease that could confound interpretation of study outcomes or make the person unsuitable for study participation in the opinion of the investigator• Receipt of an investigational drug within 28 days or 5 half-lives prior to screening

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CYP450, cytochrome P450; eGFR, estimated glomerular filtration rate; FSH, follicle-stimulating hormone; HIV, human immunodeficiency virus; INR, international normalized ratio; TVU, transvaginal ultrasound; ULN, upper limit of normal; VMS, vasomotor symptoms.

Ethical considerations

The study protocol, informed consent form, and other study documents were approved by the Institutional Review Board at each study site, as listed in Supplemental Table S1. All participants provided written informed consent prior to the initiation of any study procedures. The study was conducted in accordance with the 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. The reporting of this study conforms to the CONSORT 2010 Statement.²²

Study endpoints and assessments

Participants recorded the frequency and severity of VMS each day in an electronic diary from screening through follow-up. Night sweats were recorded in the morning upon awakening at the start of each day. The electronic diary was a validated, interactive, real-time, vendor-hosted, handheld system available for use 24 hours per day for data entry, and it contained a reference guide with definitions of mild, moderate, and severe hot flashes. All study site visits, scheduled as presented in Figure 1, included laboratory testing (biochemistry, coagulation, and hematology panels) and physical examinations, with the exception of weeks 2 and 14, when no physical examination was conducted and only liver biochemistry and international normalized ratio testing were performed. Although every attempt was made to conduct protocol-specified visits, telemedicine visits and the use of local laboratories were permitted when necessary because of COVID-19-related site closures for all visits excluding the screening, day 1, and end-of-treatment visits. Bone marker concentrations, including bone-specific alkaline phosphatase (BSAP), procollagen type 1 amino-terminal propeptide (P1NP), and carboxy-terminal telopeptide of type I collagen (CTX), were measured on day 1, at the end of treatment, and at the end of follow-up. Transvaginal ultrasound (TVU) was performed at screening and the end of treatment. Women who had not undergone full or supracervical hysterectomy underwent endometrial biopsy at screening. Biopsy was repeated at the end of treatment if endometrial thickness exceeded 4 mm on TVU or uterine bleeding occurred during treatment.

The co-primary efficacy endpoints were the mean changes from baseline in the frequency and severity of moderate to severe VMS at weeks 4 and 12. These time points are in accordance with US Food and Drug Administration guidelines for the conduct of clinical trials of interventions for VMS associated with menopause.²³ Secondary efficacy endpoints included the mean changes from baseline in the frequency and severity of moderate to severe VMS in each week up to week 12, the mean percent reduction from baseline in the frequency of moderate to severe VMS in each week up to week 12, the proportion of women with ≥50% and 100% reductions from baseline in the frequency of moderate to severe VMS in each week up to week 12, and the mean change from baseline in the frequency and severity of moderate to severe VMS at week 24.

Secondary safety endpoints included treatment-emergent adverse events (TEAEs), TVU and endometrial biopsy findings, vital signs, electrocardiographic (ECG) parameters, laboratory test results, and bone marker concentrations. Safety was analyzed for each treatment arm during the randomized period (weeks 1–12) and over the entire period of fezolinetant exposure (i.e., weeks 13–24 for those who switched from placebo and weeks 1–24 for those who received continuous fezolinetant). Adverse events of special interest included uterine bleeding, endometrial hyperplasia/cancer or disordered proliferative endometrium, reported TEAEs of liver test elevations or elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3 × the upper limit of normal (ULN), thrombocytopenia or platelet count <150,000/µL, and bone fractures. An independent Liver Safety Monitoring Panel of three liver experts reviewed unblinded aggregate liver safety data every 3 to 6 months, as well as blinded individual cases of ALT or AST > 3 × ULN or total bilirubin > 2 × ULN for potential drug-induced liver injury (DILI).

Statistical analyses

The target enrollment was 300 women (150 per treatment group). Based on positive results from a previous phase 2b dose-finding study conducted in the United States,²⁴ a cohort of 100 women per treatment group was estimated to provide ≥80% power to detect a reduction of 2/day in the frequency of moderate to severe VMS, assuming a standard deviation (SD) of 5, and a reduction of 0.40 per day in the severity score, assuming an SD of 1, using a two-sample t-test at a two-sided alpha of 5%. The number of participants was increased from 100 to 150 per treatment group to allow up to 32% of participants to withdraw prematurely. All four co-primary endpoints had to be statistically significant for treatment to be considered successful. Although the combined power for testing all four co-primary endpoints was lower than that for each individual endpoint, these endpoints were correlated (especially the same endpoint at different time points), which was expected to limit the potential reduction in power.

Efficacy analyses were conducted using the full analysis set (FAS), which consisted of all participants who completed randomization and received at least one dose of the study drug, with women classified according to their assigned treatment regardless of the treatment they actually received. Safety was analyzed in all women who received at least one dose, with women classified according to the treatment actually received at the first dose irrespective of treatment assignment. The primary endpoints were also analyzed in a per-protocol population in which women were excluded if they had no data available for the primary efficacy endpoint or if they had <85% compliance with either the interactive diary or treatment.

VMS severity was calculated using the weighted average as follows: ([number of mild hot flashes/day × 1] + [number of moderate hot flashes/day × 2] + [number of severe hot flashes/day × 3])/total number of daily (or weekly) mild/moderate/severe hot flashes. For each of the co-primary efficacy endpoints, a mixed model repeated measures (MMRM) analysis of covariance was used with treatment group, week, region, and smoking status (current vs. former/never) as factors; baseline weight and baseline VMS frequency or severity as covariates; and interactions of treatment by week and baseline measurement by week. An unstructured covariance structure shared across treatment groups was used to model the within-person errors (and then Toeplitz if the model did not converge). The Kenward–Roger approximation was used to estimate denominator degrees of freedom and adjust standard errors. Comparisons between fezolinetant and placebo were calculated by the least squares (LS) mean difference using a two-tailed 95% confidence interval (CI) and P-values. LS means were estimated using weights proportional to the percent of women randomized as current smokers. A sensitivity analysis was performed using a simplified MMRM model with treatment group and week as factors, baseline measurement as a covariate, and interactions of treatment by week and baseline by week.

Secondary efficacy endpoints analyzing changes in the frequency and severity of VMS from baseline in each week and percent reductions at weeks 4 and 12 used the same model described for the primary endpoints. For the responder analyses of the proportion of participants with ≥50% and 100% reductions in VMS frequency, logistic regression was used for each week with treatment group and smoking status as factors and baseline VMS frequency as a covariate. The Kaplan–Meier estimate was used to estimate the time to response. Fezolinetant and placebo were compared using odds ratios (ORs) with two-tailed 95% CIs and P-values.

Results

Study population

MOONLIGHT 1 was conducted in East Asia from 17 March 2020 to 20 April 2022. Of an initial 60 study sites, 55 screened potential participants, and 48 ultimately randomized 302 women to either fezolinetant 30 mg (n = 150) or placebo (n = 152; Figure 2). Thirty-eight women (12.6%) had protocol violations, including the wrong treatment/dose (n = 17 [5.6%]; nine receiving fezolinetant and eight receiving placebo), receipt of prohibited therapy (n = 13 [4.3%]), failure to satisfy the inclusion criteria (n = 10 [3.3%]), and continuation in the study despite meeting the withdrawal criteria (n = 1 [0.3%]). For the 12-week analyses, the efficacy (FAS) and safety analysis populations each included 150 women in the fezolinetant group and 151 women in the placebo group who received at least one dose of the study intervention in the randomized period (Table 2). For the 24-week analyses, the FAS and safety populations comprised 150 women initially allocated to fezolinetant and 133 women who switched to fezolinetant from placebo.

Figure 2.

Participant flow.

Table 2.

Demographics and baseline characteristics (safety analysis population).

Characteristic	Placebo (n = 151)	Fezolinetant 30 mg (n = 150)	Total (N = 301)
Age, mean (SD), years	54.8 (4.4)	54.7 (4.5)	54.7 (4.4)
Weight, mean (SD), kg	61.6 (8.6)	61.4 (9.1)	61.5 (8.8)
BMI, mean (SD), kg/m²	24.2 (2.9)	24.2 (3.2)	24.2 (3.0)
Current smoker, n (%)^a	3 (2.0)	4 (2.7)	7 (2.3)
Time since onset of VMS, mean (range), months	39.9 (1‒259)	40.7 (0‒258)	40.3 (0‒259)
Prior HT use for VMS, n (%)	21 (13.9)	25 (16.7)	46 (15.3)
History of hysterectomy, n (%)	20 (13.2)	13 (8.7)	33 (11.0)
History of oophorectomy, n (%)	10 (6.6)	9 (6.0)	19 (6.3)

Current smoker versus former or never-smoker was a stratification factor for randomization.

BMI, body mass index; HT, hormone therapy; SD, standard deviation; VMS, vasomotor symptoms.

Efficacy

For the co-primary endpoints, the LS mean reductions from baseline in VMS frequency (Figure 3a) and severity (Figure 3b) at weeks 4 and 12 were all larger for fezolinetant than for placebo, but these differences did not reach significance. The results of the per-protocol analysis and the sensitivity analysis using the simplified MMRM model were consistent with those of the primary analysis for all co-primary endpoints (data not shown).

Figure 3.

Co-primary endpoints: Reduction from baseline in the frequency and severity of moderate to severe VMS at weeks 4 and 12 (full analysis set). (a) Frequency of VMS at weeks 4 and 12 and (b) Severity of VMS at weeks 4 and 12. CI, confidence interval; LS, least squares; VMS, vasomotor symptoms.

The unadjusted mean (SD) daily frequency of VMS was reduced from 10.46 (3.78) at baseline to 5.82 (4.11) and 3.98 (3.89) at weeks 4 and 12, respectively, in the fezolinetant group, whereas the value declined from 9.67 (2.97) at baseline to 5.98 (3.78) and 4.29 (3.57) at weeks 4 and 12, respectively, in the placebo group. The unadjusted mean (SD) daily severity of VMS decreased from 2.15 (0.25) at baseline to 1.82 (0.45) at week 4 and 1.55 (0.66) at week 12 in the fezolinetant group, whereas the value fell from 2.16 (0.25) to 1.86 (0.45) at week 4 and 1.69 (0.58) at week 12 in the placebo group.

At week 4, the LS mean (95% CI) percent change from baseline in VMS frequency was −45.93% (−51.14% to −40.73%) for fezolinetant, compared with −38.08% (−43.30% to −32.85%) for placebo, giving a difference of −7.86% (−15.25% to −0.46%; P = 0.037). At week 12, the LS mean (95% CI) percent change was −63.41% (−68.91% to −57.90%) for fezolinetant, versus −56.47% (−62.09% to −50.86%) for placebo, giving a difference of −6.93% (−14.82% to 0.95%; P = 0.085).

In the analyses of the results for each week, larger reductions in VMS frequency and severity were observed for fezolinetant than for placebo in the first week, and these differences were maintained for every week through week 12. The fezolinetant group had significantly (P < 0.05) larger reductions in VMS frequency than the placebo group in 6 of the 12 weeks (weeks 1, 2, 3, 6, 8, and 10) and significantly (P < 0.05) larger reductions in VMS severity at weeks 3 and 8. In addition, fezolinetant was associated with significantly greater percentage reductions from baseline in the frequency of moderate to severe VMS in all weeks excluding week 12 (all P < 0.05, Figure 4).

Figure 4.

Percentage reduction from baseline in the VMS frequency by week during the 12-week randomized period (full analysis set). CI, confidence interval; LS, least squares; VMS, vasomotor symptoms; Wk, week.

For the responder analysis, a significantly (P < 0.05) larger proportion of women in the fezolinetant group experienced ≥50% reductions in the frequency of moderate to severe VMS at weeks 1, 5, and 12 (Figure 5a). The median time to ≥50% reduction was 16 days for fezolinetant, versus 27 days for placebo. A significantly larger proportion of women in the fezolinetant group had 100% reductions from baseline in the frequency of moderate to severe VMS at weeks 9, 10, and 12 (all P < 0.05, Figure 5b). The median time to 100% reduction could not be calculated.

Figure 5.

Proportion of women with reductions from baseline in the frequency of moderate to severe VMS by week during the 12-week randomized period (full analysis set). (a) ≥50% reduction and (b) 100% reduction. CI, confidence interval; NC, not calculated; VMS, vasomotor symptoms; Wk, week.

Over the entire treatment period (weeks 1–24), women who received fezolinetant 30 mg continuously for 24 weeks exhibited sustained reductions in VMS frequency (Figure 6a) and severity (Figure 6b). Women initially randomized to placebo experienced further reductions in VMS frequency (Figure 6a) and severity (Figure 6b) once they switched to fezolinetant 30 mg in the extension.

Figure 6.

Mean frequency per day and severity of moderate to severe VMS by visit during the 12-week randomized period and 12-week extension period (full analysis set). (a) Mean frequency and (b) Mean severity. SE, standard error; VMS, vasomotor symptoms.

Safety

The overall safety profiles of fezolinetant and placebo in the first 12-week period of MOONLIGHT 1 are summarized in Table 3. Approximately half of the women in each group experienced TEAEs, and the frequency of individual TEAEs was low and similar between the groups. All TEAEs in the randomized period were mild or moderate in severity. Two women (1.3%) in the placebo group each experienced one serious TEAE (intervertebral disc protrusion and fibroadenoma of the breast). One woman (0.7%) in the fezolinetant group experienced three serious TEAEs, namely gastric polyps, a large intestine polyp, and pneumonia. These events were not considered to be related to the study intervention. One woman (0.7%) in the fezolinetant group and two women (1.3%) in the placebo group experienced TEAEs leading to treatment discontinuation.

Table 3.

Overview of TEAEs (safety analysis population).

	Weeks 1 to 12 (randomized period)		Weeks 1 to 24 (fezolinetant exposure only)
TEAE, n (%)	Placebo (n = 151)	Fezolinetant 30 mg (n = 150)	Placebo→fezolinetant 30 mg (n = 133)	Continuous fezolinetant 30 mg (n = 150)
Any TEAE	74 (49.0)	75 (50.0)	69 (51.9)	103 (68.7)
Drug-related TEAE^a	21 (13.9)	41 (27.3)	15 (11.3)	51 (34.0)
Serious TEAE^b	2 (1.3)	1 (0.7)	1 (0.8)	3 (2.0)
Drug-related^a serious TEAE^b	0	0	0	0
Severe TEAE	0	0	1 (0.8)	1 (0.7)
Deaths	0	0	0	0
TEAE leading to treatment discontinuation^c	2 (1.3)	1 (0.7)	0	5 (3.3)
Drug-related TEAE leading to treatment discontinuation	2 (1.3)	1 (0.7)	0	4 (2.7)
TEAEs in ≥3% of either treatment group in either time period
Headache	6 (4.0)	10 (6.7)	2 (1.5)	11 (7.3)
Platelet count decreased	12 (7.9)	9 (6.0)	6 (4.5)	11 (7.3)
Dizziness	8 (5.3)	5 (3.3)	2 (1.5)	6 (4.0)
Fatigue	1 (0.7)	5 (3.3)	0	5 (3.3)
URTI	4 (2.6)	5 (3.3)	5 (3.8)	7 (4.7)
ALT increase	2 (1.3)	4 (2.7)	0	10 (6.7)
AST increase	2 (1.3)	4 (2.7)	0	7 (4.7)
Blood glucose increase	3 (2.0)	4 (2.7)	3 (2.3)	6 (4.0)
Insomnia	5 (3.3)	3 (2.0)	3 (2.3)	7 (4.7)
Arthralgia	4 (2.6)	3 (2.0)	3 (2.3)	4 (2.7)
Vaginal hemorrhage	1 (0.7)	1 (0.7)	2 (1.5)	5 (3.3)
Palpitations	0	3 (2.0)	0	6 (4.0)
AEs of special interest
Liver test elevation^d or elevation of ALT and/or AST to >3 × ULN	6 (4.0)	9 (6.0)	0	14 (9.3)
Uterine bleeding	2 (1.3)	2 (1.3)	3 (2.3)	9 (6.0)
Endometrial hyperplasia/cancer or disordered proliferative endometrium	0	0	3 (2.3)	4 (2.7)
Thrombocytopenia or platelet count < 150 × 10⁹/L	12 (7.9)	9 (6.0)	6 (4.5)	11 (7.3)
Bone fractures	0	0	1 (0.8)	1 (0.7)

TEAEs were coded using the MedDRA v23.0 preferred terms.

Women with TEAEs considered to have a reasonable possibility of being caused by the study intervention as assessed by the investigator. If a relationship was missing, it was considered drug-related.

Includes serious adverse events upgraded by the sponsor based on review of the sponsor’s list of “always serious” terms.

TEAEs leading to treatment discontinuation: hepatic enzyme elevation and headache/tinnitus in one woman each during placebo treatment; liver enzyme elevation (ALT, AST, and GGT); peripheral swelling, arthralgia, and hypoesthesia; platelet count decrease; insomnia; and somnolence among five women during treatment with fezolinetant.

Liver test elevation as part of adverse events of special interest was based on TEAE reports related to elevations in ALT, AST, ALP, or total bilirubin levels.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event; ULN, upper limit of normal; URTI, upper respiratory tract infection; VMS, vasomotor symptoms.

The safety profile of fezolinetant for up to 24 weeks of exposure was generally consistent with that observed in the first 12 weeks (Table 3). Two women experienced TEAEs that were considered severe during the extension period, including insomnia in a woman who had received continuous fezolinetant and back pain in a woman who had switched from placebo to fezolinetant. During weeks 1 to 24, three women (2.0%) in the continuous fezolinetant group experienced eight serious TEAEs, including the three aforementioned events occurring during the first 12 weeks and the following additional events in the extension phase: ALT increase, AST increase, gamma-glutamyl transferase increase, malignant neoplasm of thymus, and dyspnea. None of these events was considered related to treatment by the investigator. One (0.8%) woman who switched from placebo to fezolinetant experienced vertigo as a serious TEAE during fezolinetant treatment. During weeks 1 to 24, five women (3.3%) experienced TEAEs leading to fezolinetant discontinuation, including the woman who discontinued during the randomized period. None of the women who switched from placebo discontinued fezolinetant because of TEAEs during the extension period.

The mean (SD) change in endometrial thickness on TVU from baseline to week 24 was 0.24 (1.52) mm among women who received continuous fezolinetant, compared with 0.10 (1.54) mm among women who switched from placebo to fezolinetant. Three women had endometrial hyperplasia on biopsy, including one woman who switched from placebo to fezolinetant and two women who received continuous fezolinetant. In addition, one woman in the placebo group was diagnosed with disordered proliferative pattern at week 12, and she did not transition to active treatment.

Nineteen TEAEs associated with blood glucose elevation (preferred terms: hyperglycemia, blood glucose increase, diabetes mellitus, type 2 diabetes mellitus, and impaired fasting glucose) were reported in 14 women. This included five women with events during fezolinetant therapy in the first 12 weeks, five women with events during placebo treatment, and eight women with events during the extension phase (two women in each treatment group had events in both periods). It should be noted that the study protocol did not specify any timing or fasting requirement for blood collection. TEAEs related to glucose elevation occurred independent of the medical history of diabetes. Eight of the women had recovered or were recovering by the end of the study.

During the first 12 weeks, ALT or AST elevation >3 × ULN was observed on laboratory testing in one woman in the placebo group (0.7%) but none in the fezolinetant group (Table 4). Across the 24-week treatment period, one woman displayed aminotransaminase elevation > 3 × ULN during fezolinetant treatment (Table 4). Her case was reviewed by the Liver Safety Monitoring Panel and considered to be possibly related to fezolinetant. This transient event was considered serious and moderate in severity by the investigator, and it resolved after treatment discontinuation. No participant had bilirubin levels > 2 ×ULN, and no cases met Hy’s Law criteria for severe DILI.

Table 4.

Liver enzyme and total bilirubin elevation based on the maximum values recorded during laboratory testing (safety analysis population).

	Weeks 1 to 12 (randomized period)		Weeks 1 to 24 (fezolinetant exposure only)
	Placebo (n = 151)	Fezolinetant 30 mg (n = 150)	Placebo→fezolinetant 30 mg (n = 133)	Continuous fezolinetant 30 mg (n = 150)
Number with nonmissing data	147	148	133	148
ALT or AST, n (%)
>3 × ULN	1 (0.7)	0	0	1 (0.7)
>5 × ULN	0	0	0	1 (0.7)
>10 × ULN	0	0	0	1 (0.7)
>20 × ULN	0	0	0	1 (0.7)
ALP > 1.5 × ULN, n (%)	1 (0.7)	0	1 (0.8)	1 (0.7)
Total bilirubin > 2 × ULN, n (%)	0	0	0	0
ALT/AST > 3 × ULN + total bilirubin >2 × ULN^a^,b, n (%)	0	0	0	0

Measured within 1 day of each other.

Severe drug-induced liver injury (Hy’s Law) is defined as ALT or AST > 3 × ULN with active treatment versus placebo plus total bilirubin >2 × ULN without an alternative explanation (e.g., viral hepatitis, preexisting or acute liver disease, other hepatotoxic drug).

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

Platelet counts < 150 × 10⁹/L were reported in 27 women during the randomized period (fezolinetant: n = 12 [8.3%]; placebo: n = 15 [10.6%]), and 22 women had platelet counts < 150 × 10⁹/L while taking fezolinetant during the entire 24-week study period. Of these, 10 women in the continuous fezolinetant group and 15 who switched from placebo to fezolinetant had platelet counts < 150 × 10⁹/L more than once in the 24-week period. Of the cases in which platelet counts < 150 × 10⁹/L resulted in clinical consequences, one case (considered nonserious) in the fezolinetant group resulted in treatment withdrawal during the active treatment extension period.

On the bone turnover marker assessment, no meaningful changes were found from baseline to week 24 in BSAP or P1NP levels. The mean (SD) change in CTX levels was −2.4 (190.7) ng/L in women who switched from placebo to fezolinetant, versus −22.3 (177.2) ng/L in the continuous fezolinetant group. There were two bone fractures, including one in each treatment group, during the extension period.

There were no trends regarding changes in vital signs or body weight in either period. Four women in the placebo group and seven women in the fezolinetant group had ECG changes from normal at baseline to abnormal (e.g., T-waves flat, first degree atrioventricular block) at week 12, and five women in each group shifted from normal at baseline to abnormal at week 24.

Discussion

In the MOONLIGHT 1 study, reductions in the frequency and severity of VMS at weeks 4 and 12 (the co-primary endpoints) were numerically greater for fezolinetant than for placebo in postmenopausal women in East Asia. However, these differences were not statistically significant, potentially owing to a higher-than-expected placebo response. Fezolinetant was associated with numerically greater reductions in VMS frequency and severity than placebo in every week of the 12-week double-blind treatment period, and the differences in frequency were statistically significant in half of the assessments during the first 12 weeks, albeit not at weeks 4 and 12. The reductions were sustained during the next 12 weeks with no evidence of a reduced effect size suggestive of tachyphylaxis. Women who started on placebo demonstrated additional and sustained reductions in VMS frequency and severity after switching to fezolinetant.

In the preceding global phase 3 SKYLIGHT 1 and SKYLIGHT 2 trials, fezolinetant 30 and 45 mg produced statistically significant reductions in the same four co-primary endpoints among women in North America and Europe using otherwise similar inclusion criteria and assessments.^16,17 Although there are limitations to cross-trial comparisons, fezolinetant 30 mg produced similar reductions in VMS frequency in the MOONLIGHT 1, SKYLIGHT 1,¹⁶ and SKYLIGHT 2 trials,¹⁷ whereas the placebo effect was greater in MOONLIGHT 1.

A strong and sustained placebo effect is common in studies of pharmacologic treatments for VMS,^25–27 and this effect was possibly amplified by the close medical attention that participants received in this trial. A meta-analysis of six randomized controlled trials (RCTs) of HT found that placebo was associated with a reduction of 25.37 (95% CI = 13.19–37.55) hot flashes per week, representing a 58% reduction (95% CI = 45.1–67.7) in frequency.²⁸ A subsequent meta-analysis that pooled 45 RCTs of any pharmacologic intervention for VMS similarly reported that placebo was associated with a reduction of 24.38 (95% CI = 19.88–28.88) VMS episodes per week, although individual trials included reductions of up to 56.30 per week.²⁵ In MOONLIGHT 1, the reduction in the mean VMS frequency in the placebo arm was 5.71 per day at week 12 (equivalent to approximately 40 per week). The corresponding reductions in the placebo arms of SKYLIGHT 1 and SKYLIGHT 2 were 3.90 and 4.97 per day, respectively.^16,17

There might be regional differences in how women experience or perceive VMS and its treatment. Reported VMS prevalence rates skewed lower in Asia (37%–58%) than in North America (41%–77%) and Europe (56%–97%) among women aged 40 to 64 years in a 2014 review of data available at that time.¹ However, the prevalence was much higher in a cross-sectional survey of East Asian women published in 2022. Specifically, 83% of perimenopausal women and 78% of postmenopausal women reported VMS, including rates of moderate to severe VMS in 56% and 55% of such women, respectively. In that survey, more than half of those with moderate to severe VMS were not treating their symptoms. Furthermore, only 15% of those in perimenopause and fewer than 9% of those in postmenopause had ever used prescription treatments, although 44% and 36%, respectively, had used nonprescription therapies (e.g., mind-body alternatives, diet/supplements, botanical therapies, TCM).² In another survey of postmenopausal women from East Asia, nearly half of the women interviewed had no prior knowledge of HT. Nearly two-thirds were unaware that HT could alleviate menopausal symptoms, but nearly one-quarter were aware of the associated breast cancer risk.²⁸ It is unclear how these perceptions of VMS treatment would translate into a greater placebo response in MOONLIGHT 1. We could not find any factors clearly associated with the high placebo response in MOONLIGHT 1.

It is unclear whether past TCM use for VMS affected the results of this study. The use of any concurrent pharmacologic treatments for VMS (including herbal TCM) was prohibited in this study, and the use of nonpharmacologic methods (e.g., acupuncture, diet, other nonpharmacologic forms of TCM) was not captured. It could not be determined whether concomitant pharmacologic treatments taken for non–VMS-related indications or nonpharmacologic therapies affected VMS or contributed to any placebo effects.

The fezolinetant dose of 30 mg was originally selected as potentially the lowest effective dose based on results of a phase 2 study conducted in the United States.²⁴ Recently, the US Food and Drug Administration, European Commission, and Australian Therapeutic Goods Administration approved fezolinetant 45 mg once daily based on data from the SKYLIGHT trials in which fezolinetant 45 mg was associated with a generally more robust and more consistent reduction in VMS associated with menopause compared with fezolinetant 30 mg with a similar safety profile.^13–17 Given the outcomes of the SKYLIGHT trials, a fezolinetant dose of 45 mg once daily would be of interest for future investigations, including in Asian populations.

Despite the lack of statistical significance in the co-primary endpoints, fezolinetant 30 mg demonstrated significant efficacy in the secondary responder analyses. At week 12, significantly larger proportions of women in the fezolinetant group experienced ≥50% and 100% (complete relief) reductions in VMS frequency than observed in the placebo group. Similarly, in the SKYLIGHT trials, fezolinetant was associated with larger proportions of women experiencing ≥50% and ≥75% reductions in VMS frequency than placebo.^16,17

Fezolinetant 30 mg for up to 24 weeks was generally well tolerated, including a low rate of treatment discontinuation and low rates of individual and serious TEAEs. Only one participant experienced of AST or ALT > 3 × ULN during 24 weeks of fezolinetant treatment. Her liver enzyme elevations were transient, resolving after treatment discontinuation. No cases of Hy’s Law or severe liver injury were observed. Endometrial changes on TVU were largely unremarkable and not clinically relevant. The overall safety profile was consistent with that observed in the phase 3 SKYLIGHT 1 and SKYLIGHT 2 trials and two long-term safety studies (SKYLIGHT 4 and MOONLIGHT 3), and no new safety signals were noted.^16,17,21,29 In MOONLIGHT 3, an open-label 52-week safety study conducted in China, 88.7% of women treated with fezolinetant 30 mg experienced TEAEs, most commonly upper respiratory tract infection, dizziness, headache, proteinuria, and insomnia.²⁹ As observed in MOONLIGHT 1, the longer MOONLIGHT 3 trial found that fezolinetant had minimal effects on the endometrium, liver, or bone.

A key limitation of this study was that only one dose (30 mg) was evaluated, which did not allow opportunities to identify the optimal or most effective dose of fezolinetant for women in this regional population. Other limitations included the short duration (12 weeks) of the placebo-controlled period relative to the expected use of the drug in clinical practice, although this duration is standard for efficacy trials of VMS therapies. The lack of an active control group did not permit direct comparison of efficacy between fezolinetant and current standards of care. This study was also not designed to evaluate any potential benefit of fezolinetant regarding other menopausal symptoms (e.g., changes in mood, sexual function).

Conclusions

Although fezolinetant 30 mg once daily did not significantly reduce the frequency or severity of moderate to severe VMS at weeks 4 and 12 in East Asian women versus placebo, participants treated with fezolinetant had numerically greater reductions from baseline in the mean frequency of moderate to severe VMS relative to placebo. In addition, significantly larger proportions of women who received fezolinetant 30 mg achieved ≥50% or 100% reductions in VMS frequency than observed for placebo. The sensitivity of Asian women to fezolinetant and the optimal dose for this subgroup require further investigation. Fezolinetant 30 mg was generally safe and well tolerated when administered for up to 24 weeks in women from East Asia.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241247684 - Supplemental material for Efficacy and safety of fezolinetant for moderate to severe vasomotor symptoms associated with menopause among women in East Asia: a phase 3 randomized study (MOONLIGHT I)

Supplemental material, sj-pdf-1-imr-10.1177_03000605241247684 for Efficacy and safety of fezolinetant for moderate to severe vasomotor symptoms associated with menopause among women in East Asia: a phase 3 randomized study (MOONLIGHT I) by Xiangyan Ruan, Wenpei Bai, Mulan Ren, Tak Kim, Ji Young Lee, Fei-Chi Chuang, Peng-Hui Wang, Weizhong He, Xiao Ma, Kentaro Miyazaki, Nan Song, Xuegong Wang and Qi Yu in Journal of International Medical Research

Footnotes

Acknowledgments

The authors thank the study investigators and staff, and all women who participated in the study. The authors also thank Tianyu Zhou for his valuable contributions to the study design as well as data acquisition, analysis, and interpretation.

Author contributions

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

Study principal investigator: QY

Data acquisition: all authors

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

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 from 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 and Nan Song are employees 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 Lauren A. Cerruto and Jessica D. Herr, PharmD, of Echelon Brand Communications, LLC, an OPEN Health company, and funded by Astellas Pharma Inc.

Supplemental material

Supplemental material for this article is available online.

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