Quantitative assessment of neurokinin receptor antagonists in menopausal hot flashes: a model-based meta-analysis.

Abstract

Importance: Neurokinin 3 receptor antagonists (NK3-RAs) represent a novel class of nonhormone agents for the treatment of hot flashes in women with menopause.

Objective: This study aims to quantitatively evaluate treatment efficacy by developing a pharmacodynamic model and to assess the clinical value of the intervention by indirect comparisons with hormone and nonhormone therapies using previously published model-based meta-analysis data.

Evidence review: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were systematically searched through October 30, 2025, for placebo-controlled randomized trials evaluating NK3-RAs in menopausal women with hot flashes. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Data were analyzed using a maximum drug effect model. Develop a time-effect model to characterize the changes in the pure effect of the drug over time after accounting for the placebo response.

Findings: These studies evaluated two NK3-RAs: fezolinetant and elinzanetant. Both agents demonstrated a rapid onset of action, with efficacy reaching a plateau shortly after initiation, and exhibited clear dose-response relationships. When the dose of fezolinetant was increased from 15 to 180 mg, the reduction in hot flash frequency increased from 10.2% to 33.4%; similarly, increasing the dose of elinzanetant from 40 to 300 mg also demonstrated a dose-dependent reduction in hot flash symptoms. At the recommended doses, fezolinetant (45 mg) and elinzanetant (120 mg) achieved reductions of 20.6% and 19.6%, respectively. Model-based indirect comparisons using previously published efficacy estimates suggested that these effects were greater than those reported for paroxetine (14.8%) and corresponded to ∼52% and 49% of the effect observed with estradiol at 12 weeks. Placebo responses in NK3-RA trials were higher than those reported in other non-hormone therapy studies and were comparable to those observed in hormone therapy trials. The larger overall treatment effects observed in NK3-RA studies may have been influenced, in part, by the elevated placebo responses reported in these trials.

Conclusions and relevance: Fezolinetant (45 mg) and elinzanetant (120 mg) demonstrated comparable efficacy for menopausal hot flashes. Model-based indirect comparisons provided clinical context for interpreting their efficacy relative to other hormone and nonhormone therapies. This study provides quantitative evidence to inform medication selection and pharmacoeconomic evaluations in women with menopausal hot flashes.