Fezolinetant

Menopause / Vasomotor

Also known as: Veozah, ESN364

NK3 Receptor AntagonistsResearch phase: FDA-approvedRegulatory: FDA-approved (2023) for moderate to severe vasomotor symptoms due to menopause (Veozah). Once-daily oral, 45mg.

Mechanism

Fezolinetant is the first non-hormonal prescription drug specifically approved for menopausal hot flashes. It works by blocking NK3 receptors in the brain's thermoregulatory center. During menopause, overactive NKB (neurokinin B) signaling disrupts the body's thermostat, triggering hot flashes. Fezolinetant calms this signaling without using estrogen, making it an option for women who cannot or prefer not to take hormone therapy.

Technical detail

Fezolinetant is a selective NK3 receptor (TACR3) antagonist targeting KNDy neurons in the hypothalamic arcuate/infundibular nucleus. In menopause, estrogen withdrawal disinhibits NKB signaling, causing tonic NK3R activation on KNDy neurons which project to the preoptic/anterior hypothalamic thermoregulatory center, narrowing the thermoneutral zone and triggering inappropriate heat dissipation responses (vasodilation, sweating = hot flashes). Fezolinetant blocks NKB-NK3R Gq-PLC signaling, widening the thermoneutral zone. It does not affect estrogen levels or reproductive hormone axes. Hepatic metabolism via CYP1A2; liver monitoring recommended.

Evidence

Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study
Lederman S et al. (2023) — Lancet — PMID: 36924778
In a randomized double-blind placebo-controlled phase 3 trial, fezolinetant 30 mg and 45 mg significantly reduced hot flash frequency and severity versus placebo at weeks 4 and 12 in menopausal women with moderate-to-severe vasomotor symptoms.
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