Abstract
Introduction
Approximately 360 million women globally experience hot flashes, with varying rates influenced by cultural and racial factors. Vasomotor symptoms (VMS) impact 80% of US women during menopause, with emerging risk factors including high body mass index and African American ancestry. Fezolinetant, an oral neurokinin-3 receptor antagonist, showed promising efficacy in managing VMS. We aimed to comprehensively assess the impact of fezolinetant on VMS in postmenopausal women.
Methods
We searched PubMed, Cochrane, Web of Science, SCOPUS, and EMBASE until July 2023 for randomized controlled trials comparing fezolinetant to placebo in women with moderate to severe VMS. Primary outcomes encompassed VMS frequency and severity, and secondary outcomes included treatment effects, quality of life, and safety. Data were collected and analyzed using STATA 17 MP.
Results
We included six studies with 3657 patients. Fezolinetant significantly reduced VMS frequency at both 4 weeks (Cohen’s d = −0.56; 95% confidence interval [CI], −0.79, −0.34; P < 0.001) and 12 weeks (Cohen’s d = −0.34; 95% CI, −0.45, −0.14; P < 0.001). In terms of secondary outcomes, fezolinetant significantly improved health-related functioning and global clinical summary scores, particularly with the 90 mg twice per day dosage. Crucially, there were no statistically significant differences between fezolinetant and placebo concerning the occurrence of any treatment-emergent (odds ratio [OR] = 1.01, P = 0.81) or serious (OR = 1.57, P = 0.90) adverse events.
Conclusion
Fezolinetant effectively reduces VMS in postmenopausal women at both 4 and 12 weeks, aligning with previous research. It also improves quality of life, with a promising safety profile. Given fezolinetant’s potential for liver enzyme elevations, it is essential to monitor liver function at baseline and regularly thereafter (monthly for the first 3 months and at 6 and 9 months) to ensure patient safety. Further studies with larger sample sizes are needed to confirm these findings.
Keywords: Fezolinetant, postmenopausal, vasomotor symptoms
Globally, approximately 360 million women aged 45 and older experience hot flashes, encompassing 50% to 85% of this demographic.1 Moreover, there is considerable variability in this incidence, significantly influenced by cultural and racial factors. For instance, a Study of Women’s Health Across the Nation survey encompassing over 16,000 women in the USA revealed varying prevalence rates among ethnic groups, with African American women reporting the highest incidence (46%), followed by Hispanic (34%), White (31%), Chinese (21%), and Japanese (18%) women.2,3 China and other Asian nations exhibit notably lower rates at 10%.2,3
In the USA, vasomotor symptoms (VMS) impact roughly 80% of women navigating menopausal transitions, mainly manifesting as hot flashes or nocturnal sweats.4,5 Traditionally, certain demographic characteristics, such as low body mass index (BMI) and White ethnicity, were associated with a higher risk of VMS. However, recent research has challenged this perspective, indicating a higher risk in individuals with higher BMI and African American ancestry.6 This shift in understanding might be attributed to improved inclusivity in clinical trials, which were historically skewed toward White, middle-class women.6
The physiological mechanism underlying VMS symptoms is associated with the rhythmic release of luteinizing hormone, closely connected to the neural circuitry in the hypothalamus that regulates the secretion of gonadotropin-releasing hormone.7 Specific neurons within the arcuate nucleus, coexpressing estrogen receptor α, neurokinin 3 receptor (NK3R), kisspeptin, neurokinin B (NKB), and dynorphin, regulate the pulsatile release of gonadotropin-releasing hormone.7
Research on NK3R agonists and direct NKB administration has revealed their impact on core temperature and immediate induction of hot flushes in premenopausal women.8,9 During menopause, declining estrogen levels lead to heightened NKB signaling, excessively stimulating kisspeptin, NKB, and dynorphin neurons and triggering increased activity in the brain’s temperature control center, thereby precipitating VMS.7,10
An innovative approach targeting NK3R aims to address this mechanism, offering a nonhormonal treatment for VMS.11 Fezolinetant, an oral NK3R antagonist, holds promise in managing moderate to severe VMS associated with menopause.12,13 Clinical trials on fezolinetant demonstrated substantial reductions in VMS frequency, highlighting its potential as a therapeutic option.14 This meta-analysis investigated the effectiveness and safety of fezolinetant in postmenopausal women with moderate to severe VMS. The primary focus was the drug’s ability to provide relief and its safety profile in managing challenging menopausal symptoms.
Methods
This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines15 and the Cochrane Handbook of Systematic Reviews and Meta-Analysis.16 The study protocol was recorded in the International Prospective Register of Systematic Reviews with the registration number CRD42023473419.
Five databases (PubMed, Cochrane, Web of Science, SCOPUS, Embase) were systematically searched by three authors (M.M.A., M.T., and B.A.) until July 13, 2023. The search strategy comprised the following terms: (“vasomotor symptom*” OR “menopausal symptom*” OR “hot flash*” OR “VMS”) AND (“fezolinetant” OR “neurokinin 3 receptor antagonist” OR “neurokinin-3 receptor antagonist” OR “NK3R antagonist”). The search strategies are illustrated in Supplemental Table 1.
We included all randomized controlled trials that assessed fezolinetant compared to placebo in postmenopausal women with moderate to severe VMS and reported our primary outcomes of interest: frequency and severity of moderate to severe VMS. Other secondary endpoints were overall score changes in various tests—Menopause-Specific Quality of Life (MENQol), Hot Flash Related Daily Interference Scale (HFRDIS), Glasgow Coma Scale (GCS), Leeds Sleep Evaluation Questionnaire (LSEQ), and standard deviation score (SDS)—as well as safety: any treatment-emergent adverse event (TEAE), drug-related TEAEs, serious TEAEs, drug-related serious TEAEs, TEAEs leading to withdrawal of treatment, all-cause mortality, headache, upper respiratory infection, liver test elevations, alkaline phosphatase, depression, uterine bleeding, endometrial hyperplasia, ear and labyrinth disorders, nausea, and arthralgia.
After excluding duplicates, screening of collected studies by titles and abstracts was conducted individually using the Covidence online software by three reviewers (M.A., A.E., and R.A.). Full-text screening was performed by the same three reviewers using the previously stated eligibility criteria. Any conflicts were solved via discussion.
Data extraction
Two reviewers (M.M.A. and M.A.) pilot-tested and drafted an extraction sheet for the following data: summary characteristics (study design, country, total participants, fezolinetant dose, frequency of administration and total treatment time, menopause definition, main inclusion criteria, primary outcome, and follow-up duration), baseline characteristics (number of patients in each group, age, BMI, race, ethnicity, time since onset of hot flashes, current smoker, amenorrhea, hysterectomy, oophorectomy, total VMS score, and frequency of moderate to severe VMS), and efficacy outcomes data (VMS frequency change at 4 and 12 weeks; VMS severity change at 4 and 12 weeks; overall score change for MENQol, HFRDIS, GCS, LSEQ, and SDS; any TEAE, drug-related TEAEs, serious TEAEs, drug-related serious TEAEs, and TEAEs leading to withdrawal of treatment; all-cause mortality; and headache, upper respiratory infection, liver test elevations, alkaline phosphatase, depression, uterine bleeding, endometrial hyperplasia, ear and labyrinth disorders, nausea, and arthralgia). Three reviewers (M.A., A.E., and R.A.) separately extracted the data. Discrepancies were resolved through discussion.
Risk of bias and certainty of evidence
Four investigators (M.A., A.E., R.A., and J.S.) independently evaluated the quality of the included papers by using the updated Cochrane Collaboration’s tool for assessing the risk of bias in randomized controlled trials (RCTs; ROB 2),17 considering selection, performance, detection bias, attrition, reporting, and other potential sources of biases. Any discrepancies were resolved through discussion. To appraise the certainty of the evidence, two reviewers (M.A. and B.A.) utilized the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines,18 taking into account inconsistency, imprecision, indirectness, publication bias, and risk of bias. The assessment was performed for each outcome, and the decisions were justified and documented. Any discrepancies were resolved through discussion.
Statistical analysis and heterogeneity assessment
We combined the data as mean change and standard deviation (SD) for continuous outcomes. We analyzed it as Cohen’s d with 95% confidence intervals (CIs) using the DerSimonian-Laird random effect model. Dichotomous outcomes were expressed as events and total and analyzed as odds ratio (OR) with 95% CI using the DerSimonian-Laird random effect model. All analyses were stratified by drug dosage reported by each study.
Statistical heterogeneity among the included studies was assessed using the I2 model using the equation I2 = Q − dfQ × 100%. A P value <0.1 was considered significant for possible heterogeneity, and I2 values ≥50% indicated high heterogeneity. We performed a certainty assessment called leave-one-out sensitivity analysis in various scenarios by excluding each study at a time and observing the potential changes to the overall effect estimate to ensure that the effect estimate was not driven heavily by a certain study. We created Doi plots that present the relation between effect estimates and standard error using Egger’s regression test to investigate the potential of publication bias among the included studies.
Results
Our search yielded results across the different databases, with 386 records remaining for abstract screening after omitting 133 duplicates. Title and abstract screening was conducted on 253 studies, of which 216 records were excluded, leaving 29 studies retrieved for full-text review. Out of these, 23 were excluded and 6 were incorporated into our review.11–13,19–21 The flow diagram illustrating the search and selection process is presented in Figure 1.
Figure 1.
PRISMA flowchart of the screening process.
The six trials included 3657 patients randomized to receive either fezolinetant or a placebo. The comprehensive characteristics of the trials are outlined in Table 1. All trials had a follow-up duration of 12 weeks, except those of Lederman et al (SKYLIGHT-1)13 and Johnson et al (SKYLIGHT-2),12 which had a rerandomization phase of women treated with placebo to 30 or 45 mg fezolinetant and followed up to 52 weeks total time. The mean ages of the fezolinetant and control groups were 54.1 ± 4.1 and 54.4 ± 4.3 years, respectively. In the fezolinetant group, the mean number of months since the onset of hot flashes was 76.3 ± 146.5, whereas in the placebo group, it was 81.9 ± 73.6. Additional baseline characteristics of the patients are depicted in Table 2.
Table 1.
Characteristics of included studies
| Study ID | Study design | Country | Total participants | Fezolinetant |
Menopause definition | Primary outcome | Follow-up duration | |
|---|---|---|---|---|---|---|---|---|
| Dose (mg) | TTT | |||||||
| Depypere et al19 | Randomized placebo-controlled double-blind | Belgium | 87 | 90 BID | 12 weeks | 12+ consecutive months of spontaneous amenorrhea or 6+ months with FSH > 40 IU/L or 3+ months with FSH > 40 IU/L and E2 < 0.21 nmol/L or bilateral oophorectomy > 6 weeks before screening | Baseline to week 12: Weekly average of daily VMS scores | 2–3 weeks after the end of treatment |
| Fraser et al11 | Randomized placebo-controlled double-blind | USA | 356 | 15, 30, 60, 90 BID; 30, 60 120 QD | 12 weeks | 12+ months of spontaneous amenorrhea or 6+ months amenorrhea with FSH > 40 IU/L or bilateral oophorectomy (with/without hysterectomy) 6 weeks before screening | Mean frequency and severity change of moderate/severe VMS at baseline, week 4, and week 12 | 3 weeks after the last dose of study drug |
| Johnson et al (SKYLIGHT-2)12 | Randomized placebo-controlled double-blind | USA, Canada, Czechia, Latvia, Poland, Spain, UK | 500 | 30, 45 QD | 12 weeks; extension period of 40 weeks | FSH > 40 IU/L or bilateral oophorectomy ≥ 6 weeks before screening (with or without hysterectomy) | Mean daily change in VMS frequency and severity from baseline to weeks 4 and 12 | 43 weeks |
| Lederman et al (SKYLIGHT-1)13 | Randomized placebo-controlled double-blind | USA, Canada, Czechia, Hungary, Poland, Spain, UK | 527 | 30, 45 QD | 12 weeks; extension period of 40 weeks | FSH > 40 IU/L or bilateral oophorectomy for at least 6 weeks before the screening visit (with or without hysterectomy) and a BMI of 18–38 kg/m² | Mean change in frequency of moderate to severe VMS from baseline to weeks 4 and 12 | 3 weeks after the last dose of study drug |
| Neal-Perry et al (SKYLIGHT-4)20 | Phase 3, randomized, double-blind | Spain, Italy, Canada | 1831 | 30, 45 QD | 12 weeks; extension period of 40 weeks | 12+ consecutive months of spontaneous amenorrhea or 6+ months amenorrhea with FSH > 40 IU/L or bilateral oophorectomy 6 or more weeks before screening | Frequency and severity of treatment-emergent adverse events; percentages of participants with endometrial hyperplasia; percentages of participants with endometrial malignancy | 3 weeks |
| Santoro et al (VESTA)21 | Phase 2b, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group study | USA and UK | 356 | 15, 30, 60, 90 BID; 30, 60, 120 QD | 12 weeks | NA | Frequency of VMS episodes, MENQoL, HFRDIS, and GCS | 3 weeks |
BID indicates twice a day; BMI, body mass index; E2, estradiol; FSH, follicle-stimulating hormone; GCS, Glasgow Coma Scale; HFRDIS, Hot Flash Related Daily Interference Scale; MENQoL, Menopause-Specific Quality of Life; QD, once a day; TTT, total treatment time; VMS, vasomotor symptoms.
Table 2.
Baseline characteristics of the patients
| Study ID | Dose (mg) |
N
|
Age (years): Mean (SD) |
BMI: Mean (SD) |
Current smoker, n (%) |
Amenorrhea, n (%) |
Hysterectomy, n (%) |
Oophorectomy, n (%) |
Frequency of moderate/ severe VMS, mean (SD) |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Fez | Plac | Fez | Plac | Fez | Plac | Fezolinetant |
Placebo |
Fez | Plac | Fez | Plac | Fez | Plac | Fez | Plac | ||||
| Yes | No | Yes | No | ||||||||||||||||
| Depypere et al | 90 BID | 43 | 44 | 53.3 (4.03) | 53.7 (4.25) | 25.1 (4.71) | 26.5 (6.15) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 80.7 (32.81) | 72.0 (26.64) |
| Fraser et al | 15 BID | 45 | 43 | 53.7 (5.0) | 54.8 (5.5) | 29.3 (4.3) | 27.3 (4.8) | 10 (22.2) | 35 (77.7) | 3 (7.0) | 40 (83.1) | 27 (60.0) | 25 (58.1) | NA | NA | NA | NA | 11.1 (7.1) | 9.7 (3.5) |
| 30 BID | 44 | 53.9 (3.8) | 28.3 (4.0) | 5 (11.6) | 38 (86.3) | 35 (81.4) | NA | NA | 9.9 (4.6) | ||||||||||
| 60 BID | 45 | 54.6 (5.0) | 29.1 (5.2) | 8 (17.8) | 37 (82.2) | 28 (62.2) | NA | NA | 9.5 (4.0) | ||||||||||
| 90 BID | 44 | 54.9 (4.0) | 27.3 (4.6) | 4 (9.1) | 40 (90.9) | 32 (72.7) | NA | NA | 9.3 (3.6) | ||||||||||
| 30 QD | 45 | 52.7 (3.8) | 28.8 (4.0) | 3 (7.0) | 40 (88.9) | 27 (62.8) | NA | NA | 11.2 (6.4) | ||||||||||
| 60 QD | 45 | 55.0 (4.9) | 28.3 (4.4) | 11 (24.4) | 34 (75.5) | 36 (80.0) | NA | NA | 9.4 (2.7) | ||||||||||
| 120 QD | 44 | 56.8 (4.4) | 28.8 (4.9) | 3 (6.8) | 41 (93.1) | 35 (79.5) | NA | NA | 9.7 (3.7) | ||||||||||
| Johnson et al (SKYLIGHT-2) | 30 | 166 | 167 | 53.9 (4.9) | 54.7 (4.6) | 27.94 (18.1–37.6)a | 28.16 (18.6–38.0)a | 34 (20.5) | 132 (79.5) | 35 (21.0) | 132 (79) | 163 (98.2) | 159 (95.2) | 53 (31.9) | 51 (30.5) | 34 (20.5) | 37 (22.2) | NA | NA |
| 45 | 167 | 54.3 (5.4) | 27.91 (18.0–37.5)a | 34 (20.4) | 133 (97.6) | 162 (97.0) | 56 (33.5) | 38 (22.8) | NA | ||||||||||
| Lederman et al (SKYLIGHT-1) | 30 | 174 | 175 | 54.2 (4.9) | 54.7 (4.8) | 28.14 (4.83) | 28.19 (4.28) | 22 (13%) | 152 (87%) | 22 (13%) | 153 (87%) | 170 (98%) | 170 (97%) | 61 (35%) | 51 (29%) | 37 (21%) | 38 (22%) | NA | NA |
| 45 | 173 | 54.2 (5.1) | 28.28 (4.35) | 22 (13%) | 151 (87%) | 171 (99%) | 56 (32%) | 37 (21%) | NA | ||||||||||
| Neal-Perry et al (SKYLIGHT-4) | 30 | 611 | 610 | 54.7 (64.7) | 54.9 (64.8) | 28.46 (4.5) | 28.26 (4.6) | 116 (19.0) | 495 (81) | 117 (19.2) | 494 (80.9) | NA | NA | 100 (16.4) | 127 (20.8) | 75 (12.3) | 86 (14.1) | NA | NA |
| 45 | 609 | 54.7 (64.8) | 28.46 (4.7) | 116 (19.0) | 493 (60.7) | NA | 114 (18.7) | 86 (14.1) | NA | ||||||||||
| Santoro et al (VESTA) | 15 BID | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 30 BID | NA | NA | NA | NA | NA | NA | NA | NA | |||||||||||
| 60 BID | NA | NA | NA | NA | NA | NA | NA | NA | |||||||||||
| 90 BID | NA | NA | NA | NA | NA | NA | NA | NA | |||||||||||
| 30 QD | NA | NA | NA | NA | NA | NA | NA | NA | |||||||||||
| 60 QD | NA | NA | NA | NA | NA | NA | NA | NA | |||||||||||
| 120 QD | NA | NA | NA | NA | NA | NA | NA | NA | |||||||||||
BID indicates twice a day; BMI, body mass index; Fez, fezolinetant; Plac, placebo; QD, once a day; VMS, vasomotor symptoms.
Mean and range.
Risk of bias and quality of evidence
Our included RCTs exhibited a low risk of bias, except for the study by Santoro et al, which evidenced some concerns because of the lack of data about the randomization method. More information is presented in Figure 2. The confidence level of the evidence is summarized in a GRADE evidence profile (Table 3). Detailed information regarding the assessment of each study is provided in Supplemental Table 2.
Figure 2.
Quality assessment of the risk of bias in the included trials.
Table 3.
GRADE evidence profile
| Certainty assessment |
Summary of findings |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Participants (studies) Follow-up |
Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | Overall certainty of evidence | Study event rates (%) |
Relative effect (95% CI) | Anticipated absolute effects |
||
| With placebo | With fezolinetant | Risk with placebo | Risk difference with fezolinetant | ||||||||
| VMS frequency at 4 weeks | |||||||||||
| 1267 (4 RCTs) | Not serious | Very seriousa | Not serious | Not serious | None | ⨁⨁◯◯ Low |
386 | 881 | — | The mean VMS frequency at 4 weeks was 0 | MD 0.56 lower (0.34 lower to 0.79 lower) |
| VMS frequency at 12 weeks | |||||||||||
| 1278 (3 RCTs) | Not serious | Very seriousa | Not serious | Not serious | None | ⨁⨁◯◯ Low |
423 | 855 | — | The mean VMS frequency at 12 weeks was 0 | MD 0.54 lower (0.33 lower to 0.74 lower) |
| VMS severity at 4 weeks | |||||||||||
| 1266 (4 RCTs) | Not serious | Very seriousa | Not serious | Not serious | None | ⨁⨁◯◯ Low |
385 | 881 | — | The mean VMS severity at 4 weeks was 0 | MD 0.54 lower (0.33 lower to 0.74 lower) |
| VMS frequency at 12 weeks | |||||||||||
| 1241 (4 RCTs) | Not serious | Not serious | Not serious | Not serious | None | ⨁⨁⨁⨁ High |
386 | 855 | — | The mean VMS frequency at 12 weeks was 0 | MD 0.34 lower (0.21 lower to 0.48 lower) |
| Any TEAEs | |||||||||||
| 3153 (5 RCTs) | Not serious | Not serious | Not serious | Not serious | None | ⨁⨁⨁⨁ High |
579/1035 (55.9%) | 1181/2118 (55.8%) | OR 1.01 (0.91 to 1.12) | 559 per 1000 | 2 more per 1000 (from 23 fewer to 28 more) |
| Any serious TEAEs | |||||||||||
| 3153 (5 RCTs) | Not serious | Not serious | Not serious | Very seriousb | None | ⨁⨁◯◯ Low |
16/1035 (1.5%) | 52/2118 (2.5%) | OR 1.57 (1.01 to 2.44) | 15 per 1000 | 9 more per 1000 (from 0 fewer to 21 more) |
| TEAEs leading to withdrawal of treatment | |||||||||||
| 3153 (5 RCTs) | Not serious | Not serious | Not serious | Very seriousb | None | ⨁⨁◯◯ Low |
37/1035 (3.6%) | 99/2118 (4.7%) | OR 1.26 (0.92 to 1.73) | 36 per 1000 | 9 more per 1000 (from 3 fewer to 25 more) |
CI, confidence interval; MD, mean difference; OR, odds ratio; TEAE, treatment-emergent adverse event; VMS, vasomotor symptoms.
aConsiderable heterogeneity is noted (I2 > 75%).
bA wide confidence interval that does not exclude the risk of appreciable benefit/harm.
Efficacy and safety results
The pooled effect estimates showed that fezolinetant was favored to decrease VMS frequency at 4 weeks compared to placebo (Cohen’s d = −0.56; 95% CI, −0.79 to −0.34; P < 0.001); the pooled studies were heterogeneous (I2 = 79.60%, P < 0.001). Subgroup analysis was conducted based on the dosage of fezolinetant; the most frequent dosage form was 30 mg once daily. The pooled analysis favored fezolinetant 30 mg once daily compared to placebo to decrease VMS frequency at 4 weeks (Cohen’s d = −0.32; 95% CI, −0.46 to −0.18; P < 0.001). The pooled studies for 30 mg once daily of fezolinetant were homogenous (I2 = 0.00%; P = 0.55; Figure 3).
Figure 3.
Forest plot for the outcome of VMS frequency after (a) 4 weeks and (b) 12 weeks. BID indicates twice a day; CI, confidence interval; Q/D, once a day; SD, standard deviation; VMS, vasomotor symptoms.
We tested statistical heterogeneity using the Galbraith plot. By inspection, all studies of fezolinetant 30 mg once daily were in the 95% CI of precision area, indicating no heterogeneity across studies (Figure 3).
We used the Doi plot to detect possible publication bias, and there was a minor asymmetry across studies, with an LFK of −1.21. Further studies are needed to achieve stability (Figure 3).
We also assessed VMS frequency at 12 weeks, in which the pooled effect estimates favored fezolinetant compared to placebo with an overall Cohen’s d of −0.54 (95% CI, −0.74 to −0.33; P < 0.001). The pooled results were maintained across subgroup analyses on different dosage forms of fezolinetant. The most frequent dosage of fezolinetant was 30 mg once daily and showed a statistically significant reduction in VMS frequency at 12 weeks (Cohen’s d = −0.34; 95% CI, −0.45 to −0.14; P < 0.001); moreover, the pooled studies were homogenous (I2 = 0.00%; P = 0.22; Figure 3).
VMS severity
The pooled studies showed that fezolinetant was favored compared to placebo to decrease VMS severity at both 4 weeks (Cohen’s d = −0.54; 95% CI, −0.75 to −0.33; P < 0.001) and 12 weeks (Cohen’s d = −0.34; 95% CI, −0.48 to −0.21; P < 0.001). Subgroup analysis was conducted based on different dosage forms of fezolinetant. Fezolinetant 30 mg once daily was the most consistent dosage form across studies and was superior to placebo in decreasing VMS severity at 4 weeks (Cohen’s d = −0.27; 95% CI, −0.41 to −0.13; P < 0.001) and 12 weeks (Cohen’s d = −0.22; 95% CI, −0.36 to −0.07; P < 0.001; Figure 4).
Figure 4.
Forest plot for the outcome of VMS severity after (a) 4 weeks and (b) 12 weeks. BID indicates twice a day; CI, confidence interval; Q/D, once a day; SD, standard deviation; VMS, vasomotor symptoms.
Compared with placebo, fezolinetant significantly decreased HFRDIS scores and GCS scores (Cohen’s d = −0.35; P = 0.03 and −0.35, P < 0.001, respectively). However, subgroup analysis on dosage showed that only fezolinetant 90 mg twice per day was superior to placebo in decreasing HFRDIS and GCS scores (Cohen’s d = −0.66; P = 0.02 and −0.54, P < 0.001, respectively; Supplemental Figures 1 and 2).
Moreover, the pooled analysis showed that fezolinetant at doses of 30 and 45 mg once daily significantly reduced the MENQoL (Cohen’s d = −0.15; P = 0.04 and −0.3, P < 0.001, respectively), whereas other doses were not associated with a significant difference (Supplemental Figure 3).
The pooled analysis did not detect any significant difference between fezolinetant and placebo in terms of any TEAE (OR = 1.01, P = 0.81) and any serious TEAE (OR = 1.57, P = 0.90; Figure 5). In addition, there were no significant differences between fezolinetant and placebo in drug-related TEAEs (OR = 1.31, P = 0.12), drug-related serious TEAEs (OR = 1.61, P = 0.47), TEAEs leading to the withdrawal of treatment (OR = 1.26, P = 0.15), headache (OR = 0.96, P = 0.76), upper respiratory tract infection (OR = 0.87, P = 0.69), liver enzyme elevation (OR = 1.23, P = 0.19), depression (OR = 1.06, P = 0.78), uterine bleeding (OR = 0.69, P = 0.06), endometrial hyperplasia (OR = 0.81, P = 0.76), or nausea and vomiting (OR = 2.2, P = 0.19; Supplemental Figures 4 to 12).
Figure 5.
Forest plot for the safety outcomes of (a) any treatment-emergent adverse event and (b) any serious treatment-emergent adverse event. BID indicates twice a day; CI, confidence interval; Q/D, once a day.
Discussion
This study sought to evaluate the influence of fezolinetant on VMS. We evaluated VMS frequency and severity at 4 and 12 weeks, as well as outcomes such as HFRDIS and GCS scores. Fezolinetant, particularly when administered once daily at 30 mg, significantly reduced VMS frequency and severity at 4 and 12 weeks. It is important to note that a reduction of over two VMS occurrences per day compared to placebo is typically considered clinically significant by the Food and Drug Administration.22 It also significantly decreased HFRDIS and GCS scores, with the 90 mg twice per day dosage showing superiority. Although SKYLIGHT-1 showed that that MENQoL score, specifically the vasomotor domain, significantly improved from baseline to weeks 4 and 12 in participants treated with fezolinetant 30 and 45 mg, our meta-analysis showed no significant difference regarding the MENQoL score. The results support fezolinetant as a potential treatment option for managing VMS in postmenopausal women.
The importance of targeting NK3R signaling for nonhormonal management of hot flashes is underscored by the neural circuits in the hypothalamus responsible for the disruption of thermoregulatory control in VMS.23,24 Studies conducted by Fraser et al, Depypere et al, and Prague et al affirm that NK3R antagonists can successfully alleviate VMS in menopausal women without affecting the levels of ovarian hormones, such as estradiol.11,14,19 Notably, no changes were observed in estradiol levels throughout the trial, and the initial levels of gonadotropins and estradiol in our study participants closely resembled those of healthy menopausal women.19,23 Although there was a dose-dependent reduction in luteinizing hormone, this effect was not associated with alterations in estradiol levels and aligned with the recognized centrally acting mechanisms of NK3 receptor antagonists.14,23
SKYLIGHT-1 and SKYLIGHT-2 studies, designed with a replicative approach, offer comprehensive insights into the effectiveness of fezolinetant, encompassing a collective sample of over 1000 women. The data extracted from SKYLIGHT-2 not only corroborate the findings of SKYLIGHT-1 but also strengthen the accumulating body of evidence regarding the promising potential of fezolinetant as an innovative and nonhormonal therapeutic solution for alleviating moderate to severe VMS in menopausal women.12,13
The combined analysis did not reveal any noteworthy difference in liver enzyme elevation between the group treated with fezolinetant and the group receiving a placebo. In a prior investigation conducted by Fraser et al, nine participants were documented to encounter temporary elevations in alanine aminotransferase or aspartate aminotransferase levels, surpassing three times the upper limit of normal. This typically occurred between the fourth and eighth weeks of treatment.11,25 Notably, the observed increases in alanine aminotransferase/aspartate aminotransferase were temporary, irrespective of the treatment duration; these enzyme levels returned to their baseline values once the treatment was discontinued and demonstrated a trend toward baseline values for those participants who continued with the treatment.11,26 Notably, none of these elevations was associated with any evidence of impaired liver function or symptoms related to liver issues. Although women in the investigation carried out by Prague et al showed temporary increases in liver transaminase levels, there were no indications of liver toxicity.14 It is noteworthy that the increase in liver markers could be a distinctive and unrelated effect associated with the chemical structure of NK3 receptor antagonists. This phenomenon appears to be unique to this class of medications and is not associated with the broader category of drugs under examination.24–27 Moreover, we observed no significant difference between the two groups concerning the reporting of endometrial increased thickness, which was also pointed out in a previous study conducted by Fraser and colleagues in 2020, which reported that the intervention did not result in alterations to endometrial lining thickness and did not induce endometrial hyperplasia—both of which are independent risk factors for endometrial cancer.11
As our results showed, there were notable distinctions in adverse side effects between the two groups. In the SKYLIGHT-1 trial,13 a relatively high number of side effects was reported within the placebo group, which can likely be attributed to the nocebo effect. This phenomenon applies to instances where patients encounter adverse side effects or symptoms due to anticipating potential harm from treatment, even when receiving a placebo containing no active substances. It is important to highlight that adverse events may not always be directly associated with the intervention or the placebo, because they can sometimes be ascribed to other factors or concurrent medical conditions. Crucially, it is important to highlight that the increased occurrence of adverse events in the placebo group does not automatically imply that fezolinetant is entirely risk free. The primary objective of the trial was to assess the effectiveness of fezolinetant. However, to definitively establish its safety profile, a more extensive study with longer follow-up periods is essential. Notably, the trial conducted by Neal-Perry et al20 achieved a larger population size, thereby addressing the need for a broader participant base, leaving the focus on the necessity for extended follow-up periods. Additionally, any differences in adverse events between the treatment and placebo groups should be approached with caution, taking into consideration the potential impact of the nocebo effect or random variability.28
This study fills a critical gap by investigating fezolinetant, an NK3R antagonist, as a potential nonhormonal treatment for managing VMS in postmenopausal women. Building on prior research demonstrating its effectiveness without impacting ovarian hormones, the study systematically evaluated fezolinetant’s impact on VMS frequency, severity, and associated outcomes. With a robust sample size across SKYLIGHT-1 and SKYLIGHT-2 trials, the study highlights fezolinetant’s promising role in alleviating VMS. Addressing safety concerns, it notes transient liver enzyme elevations and no significant endometrial thickness changes.
Fezolinentant could offer potential benefits in managing VMS in individuals with estrogen-sensitive cancers, such as breast cancer. These symptoms may worsen due to the hormone deprivation therapy commonly employed in breast cancer treatment or in survivors for whom hormonal replacement therapy is not advisable.28,29 Thus, we advocate for further clinical trials to explore fezolinetant’s efficacy in addressing VMS among patients with estrogen-sensitive cancers.
The strengths of this meta-analysis encompass an exhaustive literature review sourced from various databases, a clear research objective focusing on fezolinetant’s impact on postmenopausal VMS, compliance with PRISMA and Cochrane guidelines to ensure a systematic meta-analysis, a detailed methods sections enhancing reproducibility, subgroup analyses providing insights into dose-dependent effects, and a risk of bias assessment using Cochrane Collaboration’s tool for critical evaluation and GRADE assessment. However, several limitations faced this meta-analysis, including a minor publication bias; limited data on fezolinetant, which is a potential limitation to comprehensive meta-analysis; heterogeneity in study duration due to variable follow-up durations, which may introduce heterogeneity, impacting result synthesis; concerns about Santoro et al’s study due to unclear randomization that might affect the reliability of this study’s results; and the nocebo effect highlighting the complexity in interpreting adverse events.
Future studies should focus on long-term safety assessment considering larger and more diverse populations. The inclusion of more diverse study populations would ensure generalizability, and investigation of mechanisms in future research could delve deeper into understanding specific pathways in fezolinetant’s efficacy in reducing VMS. Therefore, these implications suggest a direction for future research to adopt more standardized methodologies, investigate specific treatments, prioritize transparency in study design, and conduct more comprehensive safety evaluations to enhance the quality and reliability of findings in the field of menopausal symptom management.
In conclusion, fezolinetant, especially at a 30 mg daily dose, effectively reduced the frequency and severity of VMS in postmenopausal women. These results align with prior research, showcasing its potential as a nonhormonal VMS treatment. Additionally, fezolinetant improves women’s quality of life by decreasing HFRDIS and GCS scores. The 90 mg twice-daily dosage has proven particularly effective in this regard. Importantly, significant differences in adverse events were found between fezolinetant and the placebo group, with the placebo group’s higher rate likely attributed to the nocebo effect. Though the findings suggest a promising safety profile and a representative sample size similar to SKYLIGHT-4,20 additional research with extended follow-up periods is necessary to validate fezolinetant’s safety. Fezolinetant shows promise as a groundbreaking nonhormonal treatment for menopausal VMS, offering hope to women seeking symptom relief during this life stage.
Supplementary Material
Disclosure statement/Funding
The authors report no funding or conflicts of interest.
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