Systematic review and network meta-analysis comparing the efficacy of fezolinetant with hormone and nonhormone therapies for treatment of vasomotor symptoms due to menopause

Abstract

Importance: The neurokinin 3 receptor antagonist fezolinetant 45 mg/d significantly reduced frequency/severity of moderate to severe vasomotor symptoms (VMS) of menopause compared with placebo in two phase 3 randomized controlled trials. Its efficacy relative to available therapies is unknown.

Objective: We conducted a systematic review and Bayesian network meta-analysis to compare efficacy with fezolinetant 45 mg and hormone therapy (HT) and non-HT for VMS in postmenopausal women.

Evidence review: Using OvidSP, we systematically searched multiple databases for phase 3 or 4 randomized controlled trials in postmenopausal women with ≥7 moderate to severe VMS per day or ≥50 VMS per week published/presented in English through June 25, 2021. Mean change in frequency and severity of moderate to severe VMS from baseline to week 12 and proportion of women with ≥75% reduction in VMS frequency at week 12 were assessed using fixed-effect models.

Findings: The network meta-analysis included data from the pooled phase 3 fezolinetant trials plus 23 comparator publications across the outcomes analyzed (frequency, 19 [34 regimens]; severity, 6 [7 regimens]; ≥75% response, 9 [15 regimens]). Changes in VMS frequency did not differ significantly between fezolinetant 45 mg and any of the 27 HT regimens studied. Fezolinetant 45 mg reduced the frequency of moderate to severe VMS events per day significantly more than all non-HTs evaluated: paroxetine 7.5 mg (mean difference [95% credible interval {CrI}], 1.66 [0.63-2.71]), desvenlafaxine 50 to 200 mg (mean differences [95% CrI], 1.12 [0.10-2.13] to 2.16 [0.90-3.40]), and gabapentin ER 1800 mg (mean difference [95% CrI], 1.63 [0.48-2.81]), and significantly more than placebo (mean difference, 2.78 [95% CrI], 1.93-3.62]). Tibolone 2.5 mg (the only HT regimen evaluable for severity) significantly reduced VMS severity compared with fezolinetant 45 mg. Fezolinetant 45 mg significantly reduced VMS severity compared with desvenlafaxine 50 mg and placebo and did not differ significantly from higher desvenlafaxine doses or gabapentin ER 1800 mg. For ≥75% responder rates, fezolinetant 45 mg was less effective than tibolone 2.5 mg (not available in the United States) and conjugated estrogens 0.625 mg/bazedoxifene 20 mg (available only as 0.45 mg/20 mg in the United States), did not differ significantly from other non-HT regimens studied and was superior to desvenlafaxine 50 mg and placebo.

Conclusions: The only HT regimens that showed significantly greater efficacy than fezolinetant 45 mg on any of the outcomes analyzed are not available in the United States. Fezolinetant 45 mg once daily was statistically significantly more effective than other non-HTs in reducing the frequency of moderate to severe VMS.

Relevance: These findings may inform decision making with regard to the individualized management of bothersome VMS due to menopause.

FIG. 1

Search results. PICOS, population-intervention/comparators-outcomes-study design (eligibility criteria by which studies were screened for inclusion); VMS, vasomotor symptoms.

FIG. 2

Change from baseline in daily frequency of moderate to severe VMS versus placebo and versus fezolinetant 45 mg at 12 weeks.^{,-,-,-,-,- a}Data for synthetic CE were derived from a study of plant-based synthetic conjugated estrogens, which is discontinued in the United States. ^bEstradiol acetate 0.9 mg is a prodrug that delivers 0.78 mg E2. ^cThere was a high degree of heterogeneity among two trials of placebo versus tibolone 2.5 mg. ^dThere was a high degree of heterogeneity among six trials of placebo versus desvenlafaxine 100 mg. CE, conjugated estrogens; CrI, credible interval; E2, estradiol; ER, extended release; HT, hormone therapy; NMA, network meta-analysis; non-HT, nonhormone therapy; TDS, transdermal delivery system; VMS, vasomotor symptoms.

FIG. 3

Change from baseline in severity of moderate to severe VMS versus placebo and versus fezolinetant 45 mg at 12 weeks.^{,,-, a}There was a high degree of heterogeneity among trials comparing desvenlafaxine 150 mg with either placebo (two trials) or desvenlafaxine 100 mg (two trials). CrI, credible interval; ER, extended release; HT, hormone therapy; NMA, network meta-analysis; non-HT, nonhormone therapy; VMS, vasomotor symptoms.

FIG. 4

Odds of response^a at 12 weeks versus placebo and versus fezolinetant: fixed-effect model.^{,,,,,,,, a}A reduction of ≥75% from baseline in frequency of moderate to severe VMS at week 12. ^bProdrug that provides 0.39 mg E2. ^cThere was a high degree of heterogeneity among five trials comparing placebo with desvenlafaxine 100 mg. BZA, bazedoxifene; CE, conjugated estrogens; CrI, credible interval; E2, estradiol; HT, hormone therapy; non-HT, nonhormone therapy; P4, progesterone; TDS, transdermal delivery system.