In this pooled analysis from the phase 3 SKYLIGHT 1 and 2 studies, none of the intrinsic and extrinsic factors identified in this study substantially reduced the response to fezolinetant at either the 30 or 45 mg doses.
Key Words: Clinical studies, Extrinsic factors, Fezolinetant, Intrinsic factors, Menopause, Vasomotor symptoms
Abstract
Objective
This study aimed to assess the efficacy of the neurokinin 3 receptor antagonist, fezolinetant, according to several intrinsic (individual related) and extrinsic (external influence) factors that may influence the frequency and severity of moderate-to-severe vasomotor symptoms (VMS) using pooled 12-week data from SKYLIGHT 1 and 2.
Methods
SKYLIGHT 1 and 2 were two phase 3, randomized, double-blind studies conducted from July 2019 to August 2021 (SKYLIGHT 1) or April 2021 (SKYLIGHT 2). Participants were initially randomized to receive daily doses of placebo, fezolinetant 30 mg, or fezolinetant 45 mg. After 12 weeks, placebo participants were rerandomized to receive fezolinetant 30 mg or 45 mg, whereas those receiving fezolinetant continued on the same dose. Change in VMS frequency from baseline to week 12 was used to assess efficacy according to several intrinsic and extrinsic factors. Overall efficacy and safety were also investigated.
Results
Overall, 1,022 individuals were included. Fezolinetant was efficacious in reducing VMS frequency across all intrinsic and extrinsic factors. Efficacy was most notable for participants who self-identify as Black (least squares mean difference for fezolinetant 45 mg versus placebo, −3.67; 95% CI, −5.32 to −2.01), current smokers (−3.48; −5.19 to −1.77), and current alcohol users (−3.48; −4.42 to −2.54). Overall efficacy was −2.51 (95% CI, −3.20 to −1.82) for fezolinetant 45 mg versus placebo. Similar findings were observed for the fezolinetant 30 mg dose. Comparable incidences of treatment-emergent adverse events were observed for placebo (132 of 342 individuals [38.6%]), fezolinetant 30 mg (132 of 340 individuals [38.8%]), and fezolinetant 45 mg (135 of 340 individuals [39.7%]).
Conclusions
None of the intrinsic and extrinsic factors analyzed substantially reduced the efficacy response to fezolinetant in SKYLIGHT 1 and 2. These data provide additional confidence for using fezolinetant in a diverse population of individuals with VMS.
Vasomotor symptoms (VMS) affect most women who are experiencing menopause and are mainly characterized by hot flashes and/or night sweats.1,2 In fact, hot flash prevalences of up to 80% have been reported in epidemiological studies.1,3 Women with VMS are known to require a significantly higher number of menopause-related physician visits and severe symptoms are associated with adverse work outcomes and increased impairment while at work.4,5
A number of studies have demonstrated that menopausal hormone therapy (HT) can effectively relieve VMS and improve quality of life.6-8 As such, several clinical guidelines consider HT as the first-line pharmacological option for treating VMS.9-11 However, a recent global survey involving 25,161 women found that more than half of the participants were averse to HT, even when they were eligible for treatment.12 Worries about side effects, the long-term risks of treatment, and the presence of risk factors in the family were among the reasons for not wanting to take HT. Therefore, there is a gap in clinical care and a practical need to identify other pharmacological agents for use in the VMS population that are effective and have high treatment acceptance rates.
Fezolinetant is a nonhormone, selective neurokinin 3 receptor (NK3R) antagonist recently approved by the US Food and Drug Administration (FDA) for the treatment of moderate-to-severe VMS due to menopause and by the European Medicines Agency (EMA) for the treatment of moderate-to-severe VMS associated with menopause.13,14 The antagonist acts by blocking neurokinin B binding to NK3Rs on kisspeptin-neurokinin B-dynorphin neurons, which moderates neuronal activity in the thermoregulatory center.15 This inhibition subsequently leads to reductions in both the frequency and severity of VMS due to menopause.16 The recent SKYLIGHT 1 and 2 phase 3 studies were conducted to comprehensively investigate the efficacy and safety of two daily doses of fezolinetant (30 mg and 45 mg).17,18 Both studies met their coprimary efficacy endpoints: mean change from baseline to weeks 4 and 12 in frequency and severity of moderate-to-severe VMS. The safety results indicated that fezolinetant was well tolerated. In the first 12 weeks of fezolinetant treatment, nine serious treatment-emergent adverse events (TEAEs) were reported, including two drug-related events in the fezolinetant 30 mg group.17,18 The long-term safety of fezolinetant has also been investigated in the phase 3, randomized, double-blind, 52-week, SKYLIGHT 4 study involving a total of 1,830 participants.19
Many earlier investigations have indicated that several intrinsic (individual related) and extrinsic (external influence) factors can influence the prevalence and severity of VMS, including race (higher risk in Black individuals and lower risk in Asian individuals), ethnicity, body size, and smoking.1,20-22 Given that certain factors influence VMS frequency and severity, it is important to ascertain the efficacy of potential therapeutics for VMS in individuals with different characteristics and demographic backgrounds. The main objective of this analysis was to assess the efficacy of fezolinetant according to several key intrinsic and extrinsic factors using pooled 12-week data from the SKYLIGHT 1 and 2 studies. This analysis predominately concentrates on VMS frequency change following fezolinetant treatment for moderate-to-severe symptoms. The VMS severity data are also presented. Secondary objectives were to explore the overall efficacy and safety of fezolinetant using data from the pooled population.
METHODS
Ethics
At each site, an Independent Ethics Committee/Institutional Review Board reviewed the ethical, scientific, and medical appropriateness of the studies before data collection.17,18 The SKYLIGHT 1 and 2 studies were conducted in accordance with Good Clinical Practice, the Declaration of Helsinki, and International Council for Harmonisation guidelines. Each participant needed to complete signed informed consent forms before any study-related procedures were conducted.
Study design
The detailed methodologies for the SKYLIGHT 1 and 2 studies have been published previously.17,18 In summary, these were two identical, phase 3, randomized, double-blind, placebo-controlled studies (SKYLIGHT 1, NCT04003155; SKYLIGHT 2, NCT04003142) that were conducted at numerous sites in North America and Europe. The studies were conducted from July 2019 to August 2021 (SKYLIGHT 1) or April 2021 (SKYLIGHT 2). Eligible participants were born female, ≥40 to ≤65 years old, and seeking treatment or relief from moderate-to-severe VMS, defined as a minimal average of seven hot flashes per day. Individuals were required to be in good general health as determined by medical history and general physical examination. Confirmed postmenopausal status was also required, which was defined as spontaneous amenorrhea for ≥12 consecutive months; spontaneous amenorrhea for ≥6 months with biochemical criteria of menopause (follicle-stimulating hormone >40 IU/L); or a bilateral oophorectomy ≥6 weeks before the screening visit. Individuals were excluded if they were receiving a prohibited therapy (strong or moderate cytochrome P450 [CYP] 1A2 inhibitors [such as ciprofloxacin or fluvoxamine], HT, hormonal contraceptive, or any treatment for VMS); had noncontrolled hypertension; or had active liver disease, jaundice or, as defined by the protocol, elevated liver aminotransferases, or elevated bilirubin, alkaline phosphatase, or international normalized ratio. Individuals with Gilbert's syndrome were eligible for inclusion if direct bilirubin, hemoglobin, and reticulocytes were normal.
The study comprised an initial 12-week, double-blind, placebo-controlled treatment period followed by a 40-week, double-blind, uncontrolled extension period. Participants were initially randomized to receive daily doses of placebo, fezolinetant 30 mg, or fezolinetant 45 mg (1:1:1 ratio). After 12 weeks, the participants entered the uncontrolled extension period. Those who received placebo were rerandomized to receive one of the fezolinetant doses (30 mg or 45 mg), whereas those on fezolinetant continued to receive their original dose.
Efficacy assessments
Change in the VMS frequency of moderate-to-severe symptoms from baseline to week 12 was used to assess the efficacy of fezolinetant compared with placebo for the entire pooled population and for the intrinsic and extrinsic factors mentioned hereinafter. The change in VMS severity from baseline to week 12 was also assessed. Although the studies were 52 weeks in duration, only the data from the initial 12-week placebo-controlled period were used for this analysis. The VMS frequency and severity data were captured using an electronic hot flash diary. For the severity assessments, the participants were provided with a reference guide within the e-diary, which included the FDA definitions for mild (sensation of heat without sweating), moderate (sensation of heat with sweating, able to continue activity), and severe symptoms (sensation of heat with sweating, causing cessation of activity).23
Intrinsic assessments
The following intrinsic factors (related to the individual) were investigated in this study (one analysis performed per factor, unless stated otherwise): demographic characteristics (age, two different age categories [1: <55 and ≥55 years; 2: <50, ≥50 to ≤60, and >60 years]; race, two different race categories [1: White and non-White; 2: Black and non-Black]; ethnicity [Hispanic or Latina and not Hispanic or Latina]; and body mass index [BMI; ≥18.5 to <25, ≥25 to <30, and ≥30 kg/m2]) and intrinsic medical history factors (time since amenorrhea onset [<2, ≥2 to ≤10, and >10 years], VMS duration [≥1 to ≤10 and >10 years], baseline hot flash frequency [<median and ≥median], and baseline hot flash severity [<median and ≥median]).
Extrinsic assessments
The extrinsic factors (those related to the external parameters that influence the individual) investigated in this study were (one analysis performed per factor): lifestyle factors and geographical location (smoking status [current and former/never], alcohol history [current and former/never], caffeine use at baseline [0 cups of caffeinated beverage intake per day and >0 cups of caffeinated beverage intake per day], and region [Europe and North America]), extrinsic medical history factors (sleep disturbance [<1st quartile, ≥1st quartile to <median, ≥median to <3rd quartile, and ≥3rd quartile], medical history of hypertension [yes and no], oophorectomy history [yes and no], hysterectomy history [yes and no], and hysterectomy/oophorectomy history [hysterectomy without oophorectomy and hysterectomy with oophorectomy]), and use of medication (previous HT treatment [yes and no], reason for stopping HT [lack of symptomatic improvement and other], and concurrent use of selective serotonin reuptake inhibitors [SSRIs; yes and no]).
Safety assessments
The overall safety of fezolinetant and placebo were investigated using the TEAE data obtained for the entire pooled population over the initial 12-week treatment period.
Statistical analysis
The efficacy and safety data were analyzed according to the full analysis set (FAS) and safety analysis set (SAF) populations, respectively. Both populations were defined as randomized participants who received at least one dose of study drug. However, for the SAF, if any participant erroneously received a treatment different from their randomized allocation, they were summarized according to the treatment that they received at first dose. For the FAS, the randomized treatment group was used for analysis.
Descriptive statistics were used to analyze the pooled demographic data according to the intrinsic and extrinsic subgroups analyzed. For the safety data, the number and percentage of participants who experienced TEAEs were summarized by frequency for each treatment group.
A mixed-model repeated measurements analysis of covariance model was used to estimate the least squares (LS) mean differences between the fezolinetant groups and placebo, as well as the 95% CIs, for the overall pooled data and according to the specific intrinsic and extrinsic factors. Changes from baseline in VMS frequency or VMS severity available at week 1 through week 12 were the dependent variables in all models. The model for the overall pooled data included treatment group, study, week, and smoking status (current versus former/never) as fixed effects; baseline weight and baseline measurement as covariates; and treatment by week and baseline by week as interaction effects. The model for the assessment of intrinsic and extrinsic factors included treatment group, study, subgroup, and week as fixed effects; baseline measurement as a covariate; and treatment by week, baseline by week, subgroup by treatment, subgroup by week, and subgroup by treatment by week as interaction effects. Therefore, the models were adjusted for baseline VMS frequency or baseline VMS severity to control for potential baseline imbalance between the groups. The interaction effect of subgroup by treatment at week 12 was evaluated using t test.
SKYLIGHT 1 and SKYLIGHT 2 were designed so that the family-wise type I error rate (the probability of making one or more false discoveries) was controlled for all the comparisons of active dose groups with placebo for the coprimary efficacy endpoints, namely, mean change from baseline to weeks 4 and 12 in frequency and severity of moderate-to-severe VMS. The current pooled analyses of the intrinsic and extrinsic factors do not control the type I error rate (ie, without multiplicity adjustment), so P values do not confer statistical significance. Rather, the P values included in the results should be considered indicative, not confirmatory, and have been used for the purposes of hypothesis generation.
RESULTS
Study population
In total, 1,022 individuals were included in both the FAS and SAF for the overall pooled data (522 participants from SKYLIGHT 1 and 500 participants from SKYLIGHT 2).
The demographic data were generally well balanced across the fezolinetant and placebo groups (Tables 1 and 2). Slight differences were observed across groups in some of the intrinsic or extrinsic factors. For example, a slightly greater proportion of the individuals in the fezolinetant 45 mg group (152 participants [44.7%]) were overweight (BMI, ≥25 to <30 kg/m2) compared with the placebo group (133 participants [38.9%]) and fezolinetant 30 mg group (118 participants [34.8%]). Furthermore, a marginally lower proportion of the fezolinetant 45 mg group had stopped HT because of a lack of improvement in symptoms compared with the placebo and fezolinetant 30 mg groups. A slightly higher proportion of the individuals in the fezolinetant 30 mg group had undergone hysterectomy without oophorectomy compared with the placebo and fezolinetant 45 mg groups. However, it is important to note that only small proportions of the overall population were included in these extrinsic factor subpopulations.
TABLE 1.
Demographics: intrinsic factors
| Parameter, n (%) | Placebo n = 342 | Fezolinetant 30 mg n = 339 | Fezolinetant 45 mg n = 341 | Total N = 1,022 |
|---|---|---|---|---|
| Age group 1 | ||||
| <55 years | 180 (52.6) | 186 (54.9) | 179 (52.5) | 545 (53.3) |
| ≥55 years | 162 (47.4) | 153 (45.1) | 162 (47.5) | 477 (46.7) |
| Age group 2 | ||||
| <50 years | 47 (13.7) | 61 (18.0) | 55 (16.1) | 163 (15.9) |
| ≥50 to ≤60 years | 253 (74.0) | 243 (71.7) | 242 (71.0) | 738 (72.2) |
| >60 years | 42 (12.3) | 35 (10.3) | 44 (12.9) | 121 (11.8) |
| Race 1a | ||||
| White | 276 (80.9) | 278 (82.5) | 274 (80.8) | 828 (81.4) |
| Non-White | 65 (19.1) | 59 (17.5) | 65 (19.2) | 189 (18.6) |
| Race 2b | ||||
| Black | 59 (17.3) | 56 (16.6) | 59 (17.3) | 174 (17.0) |
| Non-Black | 283 (82.7) | 282 (83.4) | 282 (82.7) | 847 (83.0) |
| Ethnicityc | ||||
| Hispanic or Latina | 78 (22.9) | 76 (22.4) | 89 (26.1) | 243 (23.8) |
| Not Hispanic or Latina | 262 (77.1) | 263 (77.6) | 252 (73.9) | 777 (76.2) |
| BMI groupd | ||||
| <18.5 kg/m2 | 0 | 2 (0.6) | 2 (0.6) | 4 (0.4) |
| ≥18.5 to <25 kg/m2 | 97 (28.4) | 104 (30.7) | 85 (25.0) | 286 (28.0) |
| ≥25 to <30 kg/m2 | 133 (38.9) | 118 (34.8) | 152 (44.7) | 403 (39.5) |
| ≥30 kg/m2 | 112 (32.7) | 115 (33.9) | 101 (29.7) | 328 (32.1) |
| Time since amenorrhea onsete | ||||
| <2 years | 65 (19.8) | 54 (16.3) | 59 (17.7) | 178 (17.9) |
| ≥2 to ≤10 years | 180 (54.7) | 183 (55.1) | 177 (53.0) | 540 (54.3) |
| >10 years | 84 (25.5) | 95 (28.6) | 98 (29.3) | 277 (27.8) |
| VMS duration | ||||
| <1 year | 14 (4.1) | 12 (3.5) | 10 (2.9) | 36 (3.5) |
| ≥1 to ≤10 years | 239 (69.9) | 250 (73.7) | 254 (74.5) | 743 (72.7) |
| >10 years | 89 (26.0) | 77 (22.7) | 77 (22.6) | 243 (23.8) |
| Baseline hot flash frequency | ||||
| <median | 171 (50.0) | 163 (48.1) | 177 (51.9) | 511 (50.0) |
| ≥median | 171 (50.0) | 176 (51.9) | 164 (48.1) | 511 (50.0) |
| Baseline hot flash severity | ||||
| <median | 172 (50.3) | 163 (48.1) | 176 (51.6) | 511 (50.0) |
| ≥median | 170 (49.7) | 176 (51.9) | 165 (48.4) | 511 (50.0) |
Data are shown for the FAS.
BMI, body mass index; FAS, full analysis set; VMS, vasomotor symptoms.
aOne, two, and two participants in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, were not included in the White/non-White race analysis. In total, four participants identified as having more than one race. Because these four individuals were partially White, but not Black, they were excluded from the White/non-White race analysis and included in the Black/non-Black analysis. Race data were missing for one participant in the fezolinetant 30 mg group.
bRace data were missing for one participant in the fezolinetant 30 mg group.
cEthnicity data were missing for two participants in the placebo group.
dBMI data were missing for one participant in the fezolinetant 45 mg group.
eThirteen, seven, and seven participants in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, had not experienced amenorrhea.
TABLE 2.
Demographics: extrinsic factors
| Parameter, n (%) | Placebo n = 342 | Fezolinetant 30 mg n = 339 | Fezolinetant 45 mg n = 341 | Total N = 1,022 |
|---|---|---|---|---|
| Smoking status | ||||
| Current | 57 (16.7) | 55 (16.2) | 57 (16.7) | 169 (16.5) |
| Former/never | 285 (83.3) | 284 (83.8) | 284 (83.3) | 853 (83.5) |
| Alcohol history | ||||
| Current | 180 (52.6) | 190 (56.0) | 184 (54.0) | 554 (54.2) |
| Former/never | 162 (47.4) | 149 (44.0) | 157 (46.0) | 468 (45.8) |
| Caffeinated beverage intake at baselinea | ||||
| 0 cups per day | 52 (16.0) | 61 (18.9) | 53 (16.1) | 166 (17.0) |
| >0 cups per day | 273 (84.0) | 261 (81.1) | 277 (83.9) | 811 (83.0) |
| Region | ||||
| Europe | 108 (31.6) | 104 (30.7) | 108 (31.7) | 320 (31.3) |
| North America | 234 (68.4) | 235 (69.3) | 233 (68.3) | 702 (68.7) |
| Sleep disturbanceb,c | ||||
| <1st quartile | 78 (22.9) | 84 (24.9) | 84 (24.6) | 246 (24.1) |
| ≥1st quartile to <median | 83 (24.3) | 69 (20.5) | 80 (23.5) | 232 (22.8) |
| ≥median to <3rd quartile | 82 (24.0) | 89 (26.4) | 96 (28.2) | 267 (26.2) |
| ≥3rd quartile | 98 (28.7) | 95 (28.2) | 81 (23.8) | 274 (26.9) |
| Medical history of hypertension | ||||
| Yes | 73 (21.3) | 76 (22.4) | 71 (20.8) | 220 (21.5) |
| No | 269 (78.7) | 263 (77.6) | 270 (79.2) | 802 (78.5) |
| Oophorectomy history | ||||
| Yes | 75 (21.9) | 70 (20.6) | 76 (22.3) | 221 (21.6) |
| No | 267 (78.1) | 269 (79.4) | 265 (77.7) | 801 (78.4) |
| Hysterectomy history | ||||
| Yes | 102 (29.8) | 113 (33.3) | 113 (33.1) | 328 (32.1) |
| No | 240 (70.2) | 226 (66.7) | 228 (66.9) | 694 (67.9) |
| Hysterectomy/oophorectomy historyd | ||||
| Hysterectomy without oophorectomy | 33 (32.4) | 47 (41.6) | 41 (36.3) | 121 (36.9) |
| Hysterectomy with oophorectomy | 69 (67.6) | 66 (58.4) | 72 (63.7) | 207 (63.1) |
| Previous HT treatmente | ||||
| Yes | 64 (19.0) | 68 (20.3) | 68 (20.5) | 200 (19.9) |
| No | 273 (81.0) | 267 (79.7) | 264 (79.5) | 804 (80.1) |
| Reason for stopping HTf | ||||
| Lack of symptomatic improvement | 23 (35.9) | 24 (35.3) | 17 (25.0) | 64 (32.0) |
| Other | 41 (64.1) | 44 (64.7) | 51 (75.0) | 136 (68.0) |
| Concurrent use of SSRIs | ||||
| Yes | 18 (5.3) | 21 (6.2) | 15 (4.4) | 54 (5.3) |
| No | 324 (94.7) | 318 (93.8) | 326 (95.6) | 968 (94.7) |
Data are shown for the FAS.
FAS, full analysis set; HT, hormone therapy; PROMIS SD SF 8b, Patient-Reported Outcomes Measurement Information System Sleep Disturbance — Short Form 8b; SSRI, selective serotonin reuptake inhibitor.
aA total of 17, 17, and 11 participants in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, had no caffeinated beverage intake data at baseline or any of the visits. If baseline caffeinated beverage intake was missing, but there was at least one caffeinated beverage intake result at any visit, then the missing baseline data were imputed in accordance with the study visit data.
bSleep disturbance was measured using the PROMIS SD SF 8b.
cOne and two participants in the placebo and fezolinetant 30 mg groups, respectively, had no baseline sleep disturbance data.
dIndividuals with a history of hysterectomy were used as the denominator.
eFive, four, and nine participants in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, had no baseline HT data.
fIndividuals who received previous HT treatment were used as the denominator.
Of the participants who had previously received HT treatment, 23 (35.9%), 24 (35.3%), and 17 (25.0%) of the individuals in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, had discontinued because of a lack of symptomatic improvement. In addition, 18 (5.3%), 21 (6.2%), and 15 individuals (4.4%) from the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, were concurrently receiving SSRIs.
Efficacy analysis
In terms of the overall pooled data, fezolinetant was efficacious in reducing VMS frequency compared with placebo in terms of moderate-to-severe symptoms (Fig. 1). At 12 weeks, the LS mean difference for the 45 mg dose versus placebo was −2.51 (95% CI, −3.20 to −1.82). A similar finding was noted for the fezolinetant 30 mg group where an LS mean difference of −2.15 (95% CI, −2.84 to −1.45) was noted.
FIG. 1.
Difference in change from baseline to week 12 in VMS frequency between the fezolinetant groups and placebo: overall pooled data. Data are shown for the FAS. The number of participants with baseline data is shown. P values were calculated without multiplicity adjustment. FAS, full analysis set; LS, least squares; VMS, vasomotor symptoms.
Reductions in VMS severity were also observed with fezolinetant versus placebo (Supplemental Fig. 1, http://links.lww.com/MENO/B255). For the 45 mg dose at 12 weeks, the LS mean difference versus placebo was −0.24 (95% CI, −0.35 to −0.13). A similar finding was apparent for the fezolinetant 30 mg group (LS mean difference, –0.20; 95% CI, −0.31 to −0.08).
Intrinsic factor analysis
Based on reductions in VMS frequency, fezolinetant was efficacious in treating moderate-to-severe VMS due to menopause across all intrinsic factors investigated (Fig. 2). This finding was observed for all demographic factors (age, race, ethnicity, and BMI) and intrinsic medical history factors (time since amenorrhea onset, VMS duration, hot flash frequency, and hot flash severity). The VMS severity results were consistent with the observed VMS frequency results (Supplemental Fig. 2, http://links.lww.com/MENO/B256).
FIG. 2.
Difference in change from baseline to week 12 in VMS frequency between the fezolinetant groups and placebo: intrinsic factors. (A) Demographic characteristics and (B) intrinsic medical history factors. Data are shown for the FAS. The number of participants with baseline data is shown. P values were calculated without multiplicity adjustment. aTotal numbers of participants — placebo, 342; fezolinetant 30 mg, 339; fezolinetant 45 mg, 341. bOne, two, and two participants in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, were not included in the White/non-White race analysis. In total, four participants identified as having more than one race. Because these four individuals were partially White, but not Black, they were excluded from the White/non-White race analysis and included in the Black/non-Black analysis. Race data were missing for one participant in the fezolinetant 30 mg group. cData were missing for one participant in the fezolinetant 30 mg group. dData were missing for two participants in the placebo group. eTwo participants in each of the fezolinetant 30 mg and fezolinetant 45 mg groups had a BMI of <18.5 kg/m2. Data were missing for one participant in the fezolinetant 45 mg group. fThirteen, seven, and seven participants in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, had not experienced amenorrhea. gIn total, 14, 12, and 10 participants from the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, had a VMS duration of <1 year. BMI, body mass index; FAS, full analysis set; HF, hot flash; LS, least squares; TSAO, time since amenorrhea onset; VMS, vasomotor symptoms.
The efficacy of fezolinetant was apparent across races, with improvement particularly notable in participants who self-identify as Black. For participants who self-identify as White, an LS mean difference in VMS frequency of −2.17 (95% CI, −2.93 to −1.41) was obtained for fezolinetant 45 mg versus placebo. Comparatively, for participants who identify as Black, an LS mean difference of −3.67 (95% CI, −5.32 to −2.01) was noted for fezolinetant 45 mg versus placebo. Fezolinetant was also markedly efficacious in participants who had a ≥median baseline hot flash frequency. For these individuals, an LS mean difference in VMS frequency of −3.66 (95% CI, −4.64 to −2.69) was obtained for fezolinetant 45 mg versus placebo. Similar findings were noted for the 30 mg group in comparison with placebo.
A wide 95% CI (≥3.7) was noted for the VMS frequency analysis that compared both doses of fezolinetant with placebo for individuals who were >60 years old.
Extrinsic factor analysis
In terms of the extrinsic factors investigated, fezolinetant was efficacious in treating moderate-to-severe VMS due to menopause, based on reductions in VMS frequency (Fig. 3). This finding was observed for all lifestyle factors and geographical locations (smoking status, alcohol history, caffeine use, and region), extrinsic medical history factors (sleep disturbance, hypertension, oophorectomy, hysterectomy, and hysterectomy/oophorectomy), and use of medication (previous HT, reason for stopping HT, and use of SSRIs). Similar findings were noted for the VMS severity results (Supplemental Fig. 3, http://links.lww.com/MENO/B257). The only exception was for the subgroup who consumed 0 cups of caffeinated beverage per day where no difference was noted between the fezolinetant 30 mg and placebo groups (LS mean difference, 0.00; 95% CI, −0.28 to 0.27).
FIG. 3.
Difference in change from baseline to week 12 in VMS frequency between the fezolinetant groups and placebo: extrinsic factors. (A) Lifestyle factors and geographical location, (B) extrinsic medical history factors, and (C) use of medication. Data are shown for the FAS. The number of participants with baseline data is shown. P values were calculated without multiplicity adjustment. aTotal numbers of participants — placebo, 342; fezolinetant 30 mg, 339; fezolinetant 45 mg, 341. bA total of 17, 17, and 11 participants in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, had no caffeinated beverage intake data at baseline or any of the visits. If baseline caffeinated beverage intake was missing, but there was at least one caffeinated beverage intake result at any visit, then the missing baseline data were imputed in accordance with the study visit data. cData were missing for one and two participants in the placebo and fezolinetant 30 mg groups, respectively. dThe population comprised individuals with a history of hysterectomy. eData were missing for five, four, and nine participants in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively. fThe population comprised individuals who received previous HT treatment. CBI, caffeinated beverage intake; FAS, full analysis set; HT, hormone therapy; Hyst, hysterectomy; LOSI, lack of symptomatic improvement; LS, least squares; Ooph, oophorectomy; SSRI, selective serotonin reuptake inhibitor; VMS, vasomotor symptoms.
Fezolinetant was an effective treatment in former/never smokers and notably in current smokers. For current smokers, an LS mean difference in VMS frequency of −3.48 (95% CI, −5.19 to −1.77) was obtained for fezolinetant 45 mg versus placebo. For the former/never smokers, an LS mean difference of −2.32 (95% CI, −3.08 to −1.57) was obtained for the same comparison between groups. The efficacy of fezolinetant was also demonstrated in participants who were former/never users of alcohol and particularly in current users of alcohol. For these current users, an LS mean difference in VMS frequency of −3.48 (95% CI, −4.42 to −2.54) was obtained when fezolinetant 45 mg was compared with placebo. Comparatively, for the former/never users of alcohol, an LS mean difference of −1.42 (95% CI, −2.42 to −0.42) was obtained for fezolinetant 45 mg versus placebo. Furthermore, fezolinetant seemed to be particularly effective in individuals who had received previous HT treatment (LS mean difference in VMS frequency, –3.92; 95% CI, −5.48 to −2.36) compared with individuals who had not received HT (LS mean difference in VMS frequency, –2.20; 95% CI, −2.98 to −1.42). The results for the 30 mg group supported those obtained with the 45 mg group.
A wide 95% CI (≥3.7) was noted for the VMS frequency analysis that compared both doses of fezolinetant with placebo for individuals who had experienced a hysterectomy with or without oophorectomy, previously used SSRIs, and stated that their reason for stopping HT was a lack of improvement in symptoms.
Safety analysis
The pooled safety TEAE data revealed that fezolinetant was safe and well tolerated (Table 3). The proportions of participants who reported a TEAE were 132 individuals (38.6%), 132 individuals (38.8%), and 135 individuals (39.7%) for the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively. In total, one individual (0.3%), five individuals (1.5%), and four individuals (1.2%) in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively, experienced a serious TEAE. The specific events recorded were cholelithiasis (placebo); atrial fibrillation, coronavirus disease 2019, tooth infection, transaminases increased, and liver function test increased (fezolinetant 30 mg); and biliary dyskinesia, posterior tibial nerve injury, paresthesia, and varicose vein (fezolinetant 45 mg). The only drug-related serious TEAEs in either study were experienced by two individuals from the fezolinetant 30 mg group, which were transaminases increased and liver function test increased. For the latter event, the participant had alanine aminotransferase and aspartate aminotransferase results that were 16.0 and 37.9 times the upper limit of normal, respectively, after 85 days of treatment with fezolinetant 30 mg. Levels returned to normal by study day 106 following study drug discontinuation.
TABLE 3.
TEAE overview
| Parameter, n (%) | Placebo n = 342 | Fezolinetant 30 mg n = 340 | Fezolinetant 45 mg n = 340 |
|---|---|---|---|
| Any TEAE | 132 (38.6) | 132 (38.8) | 135 (39.7) |
| Drug-related TEAEs | 33 (9.6) | 41 (12.1) | 38 (11.2) |
| Serious TEAEs | 1 (0.3) | 5 (1.5) | 4 (1.2) |
| Drug-related serious TEAEs | 0 | 2 (0.6) | 0 |
| TEAEs causing permanent discontinuation of study drug | 10 (2.9) | 12 (3.5) | 9 (2.6) |
| Drug-related TEAEs causing permanent discontinuation of study drug | 7 (2.0) | 7 (2.1) | 8 (2.4) |
| Deaths | 0 | 0 | 0 |
Data are shown for the SAF (12-week data only). The SAF and the FAS differ in the number of participants in the fezolinetant 30 mg and fezolinetant 45 mg groups, as one participant was randomly assigned to fezolinetant 45 mg but in error received fezolinetant 30 mg.
FAS, full analysis set; SAF, safety analysis set; TEAE, treatment-emergent adverse event.
DISCUSSION
Summary
All individuals who are born with ovaries will go through menopause provided that they live long enough. Consequently, a vastly diverse population of individuals may experience bothersome VMS due to menopause. It is, therefore, vital to demonstrate the effectiveness of any potential pharmacological agent for treating VMS in individuals who have a wide range of lifestyles and phenotypic characteristics. The NK3R antagonist, fezolinetant, is a novel nonhormone treatment option, and the 45 mg dose received FDA approval in May 2023 for the treatment of moderate-to-severe VMS due to menopause and EMA approval in December 2023 for the treatment of moderate-to-severe VMS associated with menopause.13,14 This study demonstrated that this dose of fezolinetant effectively reduced VMS frequency compared with placebo after the analysis of a range of intrinsic and extrinsic factors that potentially exacerbate VMS in a population who were experiencing moderate-to-severe symptoms. Over a 12-week interval, comparable changes in VMS frequency obtained with fezolinetant 45 mg were observed with 30 mg, and similar findings were observed for the VMS severity results.
Demographic data
In this pooled analysis, the placebo and fezolinetant groups were well balanced with regard to the baseline demographic data. Interestingly, approximately 30% of participants who had previously used HT discontinued treatment because of a lack of symptomatic improvement. Given the population under analysis, this proportion might be expected to be higher, as the individuals who enrolled in this study may be seeking treatment because of a lack of symptomatic relief after hormone treatment. Furthermore, approximately 5% of the study population were receiving a concurrent SSRI at baseline. A higher prevalence of SSRI use was expected, as indicated by a United States/European survey study, which showed that 20.0% of individuals with VMS were prescribed an SSRI or a serotonin-norepinephrine reuptake inhibitor.24 However, as eligible participants had to experience a minimal average of seven hot flashes per day, it could have been possible that SSRI use lowered the number of hot flashes per day25 to fewer than the required number for inclusion. The observed prevalence may also have been low because any participant who used any treatment for VMS (prescription, over the counter, or herbal) was excluded from the study.
Intrinsic and extrinsic factors
Several studies have investigated the influence of distinct characteristics on the occurrence of VMS and the effect of pharmacological interventions in these subpopulations.
Age
Epidemiological investigations have indicated that, rather than the actual age of the individual, time since amenorrhea onset seems to affect VMS frequency. For example, the Penn Ovarian Aging Study found that the prevalence of hot flashes typically increased each year before menopause and reached a peak in the first 2 years after amenorrhea onset.26 The frequency of hot flashes subsequently decreased after menopause, returning to premenopausal levels after 9 years.
Although HT is regarded as the first-line pharmacological approach for treating VMS, safety concerns can restrict its use and treatment duration according to the individual's age. In support of this statement, The Menopause Society recommends carefully considering the relative benefits and risks in individuals who are due to initiate HT and are >60 years old or those with >10 years since menopausal onset.11 Although the results achieved in this study have explored the effect of these factors on efficacy outcomes, rather than safety, fezolinetant effectively reduced VMS frequency in individuals who were >60 years old and those with >10 years from amenorrhea onset.
Recent studies have estimated that VMS last a median of 7.4 years.27 Therefore, as women age they may be diagnosed with a medical condition that potentially contraindicates the use of HT, such as breast cancer or venous thromboembolism.11 Within the clinic, these particular individuals may therefore need to stop taking HT, even if it has been an effective treatment for their VMS.
Race
Analyses from both the Penn Ovarian Aging Study and the Study of Women's Health Across the Nation (SWAN) have found that women who identify as Black or African American experience a higher frequency of VMS.1,26 In addition, women who identify as Black seem to experience VMS for a longer duration, as demonstrated by SWAN investigators who reported that Black women experienced VMS for >10 years on average compared with just 6.5 years for White women.27 The severity of symptoms also seems to covary by race, with a greater proportion of women who identify as Black stating that they had experienced VMS for ≥6 days compared with women who identify as White, Chinese, or Japanese.1 In addition, a cross-sectional survey investigation found that women who identify as Native American or Black were more likely to have ever experienced VMS compared with other ethnic groups in a population of premenopausal individuals.20
Despite the aforementioned epidemiological findings, women who identify as Black may receive less pharmacological intervention to address menopausal symptoms compared with other ethnic groups. A pilot study involving 113 participants showed that 49% of White individuals accepted HT compared with only 24% of Black individuals, despite having similar clinical criteria.28 In support of this finding, a SWAN analysis found that White individuals were approximately twice as likely to receive HT as African American individuals.29 Some studies have also indicated that HT may not be as effective in Black women with a recent SWAN study showing that HT improved self-reported quality of life in White women in comparison with complementary alternative medicine or no treatment, whereas the opposite finding was observed in Black participants.30
Genetic polymorphism studies have shown that Black or African individuals display distinct CYP2C19 and CYP2D6 alleles compared with their White counterparts.31,32 Because some SSRIs are predominately metabolized by these enzymes,33,34 it is possible that the race of the individual could affect the efficacy of these drugs. However, a randomized, placebo-controlled study found that race did not significantly modify the treatment effect achieved with escitalopram.35
Overall, these findings suggest that there is an unmet treatment need in Black individuals with bothersome VMS and fezolinetant may offer an effective treatment alternative in this subpopulation.
Smoking
Cigarette smoking substantially increases the risk of experiencing frequent or severe VMS, as demonstrated by the results of a pooled analysis from eight cohort studies.22 In addition, a comprehensive epidemiological investigation found that both current and former smokers are more likely than never smokers to experience early menopause, although these are slightly different categories to the subgroups used in this investigation.36 Owing to the association between smoking and lung cancer risk, The Menopause Society encourages smoking cessation in current or past users of HT.11 This recommendation is based on a possible association between HT and lung cancer because of the presence of estrogen receptors and aromatase in healthy lung tissue and lung cancers.37,38 Fezolinetant effectively attenuates VMS in smokers and may reflect a potential alternative for this subpopulation.
Alcohol use
The influence of alcohol on VMS frequency remains equivocal. A Midlife Women's Health Study found that higher alcohol intake was associated with a decreased incidence of hot flashes, whereas a population-based prospective cohort study noted that alcohol use was a significant predictor for VMS occurrence.39,40 A small crossover study reported that alcohol ingestion contributed to substantial increases in circulating estradiol levels in women receiving HT, although no increase was noted in control women who were not receiving treatment.41 In addition, regular alcohol consumption could obviously affect the liver metabolism of any oral therapeutic administered to treat VMS, including HT components.42
Specific subpopulations
Some of the VMS frequency analyses that compared fezolinetant with placebo had wide 95% CIs. This finding was predominately because of the low proportions of the pooled population analyzed. Furthermore, it is important to consider the fact that a large placebo effect can be observed in individuals with VMS, even in those who have recently started experiencing symptoms.43 In addition, VMS are associated with an increased risk of certain psychosocial factors,44 and estradiol levels can still fluctuate in this population, particularly in women who have only recently experienced their final menstrual period.45
Safety analysis
The pooled safety results showed that fezolinetant was well tolerated. Similar incidences of TEAEs were noted in the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, and nine individuals reported a serious TEAE after fezolinetant treatment. Further details about the safety results from these studies can be found in the primary publications.17,18 The safety findings from this pooled analysis are in alignment with the results from SKYLIGHT 4.19 Similar incidences of TEAEs were also observed in all three groups from SKYLIGHT 4 (391 participants [64.1%], 415 participants [67.9%], and 389 participants [63.9%] from the placebo, fezolinetant 30 mg, and fezolinetant 45 mg groups, respectively). A low incidence of serious TEAEs (43 participants [3.5%] in the fezolinetant groups) was also reported in SKYLIGHT 4.
Limitations
Although a spectrum of novel data was obtained in this intrinsic/extrinsic analysis, this study has a few limitations. Owing to the 12-week duration of the placebo-controlled period in the original studies, this analysis was restricted to this timescale. Additional data of interest may have been uncovered if a longer placebo-controlled period had been used. Grouping the participants according to the various intrinsic or extrinsic factors led to small subgroup numbers for some of the analyses, rendering the data less precise for some of the relationships. Because the principal objective was to analyze the efficacy of fezolinetant according to the intrinsic and extrinsic factors identified, the safety of fezolinetant was not explored in terms of these factors. Other useful information could have been acquired if additional factors were included in the efficacy investigations, for example, analyzing individuals who had and did not have anxiety, diabetes, or depression.
CONCLUSIONS
In this pooled analysis from the phase 3 SKYLIGHT 1 and 2 studies, none of the intrinsic and extrinsic factors identified in this study substantially reduced the response to fezolinetant at either the 30 or 45 mg doses. This finding implies that fezolinetant can be regarded as an effective treatment for moderate-to-severe VMS in individuals who present with a range of lifestyle and phenotypic characteristics that may affect the frequency and severity of their VMS. This analysis also showed that fezolinetant was a well-tolerated treatment with comparable incidences of TEAEs in the placebo and fezolinetant groups.
Footnotes
The results of this study have been previously presented in e-poster format at the 2023 ACOG Annual Clinical and Scientific Meeting, Baltimore, MD, May 19-21, 2023.
Funding/support: This study was funded by Astellas Pharma Inc. Medical writing support was provided by Michael Parsons from Envision Pharma, Inc and funded by the study sponsor.
Clinical trial registration: SKYLIGHT 1, NCT04003155 (https://classic.clinicaltrials.gov/ct2/show/NCT04003155); SKYLIGHT 2, NCT04003142 (https://classic.clinicaltrials.gov/ct2/show/NCT04003142).
Financial disclosure/conflicts of interest: N.S. is a study investigator, member of a scientific advisory board, and consultant for Astellas; a member of a medical advisory board for Amazon (Project Ember); a member of a scientific advisory board for MenoGeniX and QUE Oncology; a consultant for Ansh Labs; an associate editor for Menopause; and a past president of the Society for Reproductive Investigation. R.E.N. has past financial relationships (lecturer, member of advisory boards, and/or consultant) with Boehringer Ingelheim, Eli Lilly, Endoceutics, Exeltis, Novo Nordisk, Palatin Technologies, Pfizer, Procter & Gamble, Teva Women's Health, and Zambon; has ongoing relationships with Abbott, Astellas, Bayer HealthCare, Fidia, Gedeon Richter, HRA Pharma, Merck & Co, Organon, Shionogi, and Theramex; and serves as president elect of the International Menopause Society. G.N-.P. is a member of a scientific advisory board for Astellas and Ferring Pharmaceuticals; has received research funding from the American Association of Medical Colleges, Merck, and NICHD; is the vice president of Diversity, Equity and Structural Change for the Society for Reproductive Investigation; is the program committee chair for the American Society of Reproductive Medicine; holds committee membership of the Endocrine Society; and is an associate editor for Frontiers in Endocrinology. M.E., D.D.K., Y.Y., and F.D.O. are employees of Astellas Pharma Inc.
Data sharing: 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 https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.
Supplemental digital content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s Website (www.menopause.org).
Contributor Information
Rossella E. Nappi, Email: nappi@rossellanappi.com.
Genevieve Neal-Perry, Email: genevieve_nealperry@med.unc.edu.
Marci English, Email: marci.english@astellas.com.
Deanna D. King, Email: Deanna.King@astellas.com.
Yusuke Yamaguchi, Email: yusuke-yamaguchi@astellas.com.
Faith D. Ottery, Email: faith.ottery@astellas.com.
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