Fezolinetant: The NK3 Antagonist for Hot Flashes
Menopause Peptides
50%+ VMS reduction
Fezolinetant reduced the frequency of moderate-to-severe hot flashes by more than 50% at 12 weeks in Phase 3 trials, the first non-hormonal peptide-targeted treatment for vasomotor symptoms.
Johnson et al., The Lancet, 2023 (SKYLIGHT 1)
Johnson et al., The Lancet, 2023 (SKYLIGHT 1)
View as imageFezolinetant (brand name Veozah) became the first neurokinin 3 (NK3) receptor antagonist approved by the FDA when it received approval on May 12, 2023, for moderate-to-severe vasomotor symptoms (VMS) due to menopause. It represents a fundamentally different approach to hot flash treatment: rather than replacing estrogen, fezolinetant blocks the peptide signaling pathway that goes haywire when estrogen declines. The target is neurokinin B (NKB), a tachykinin peptide that helps regulate body temperature in the hypothalamus. When peptide hormone levels shift during menopause, NKB signaling becomes overactive in the thermoregulatory center, triggering the vasomotor episodes that affect up to 80% of menopausal women. Fezolinetant silences that signal without touching the hormonal axis.
Key Takeaways
- Fezolinetant is the first FDA-approved NK3 receptor antagonist, blocking neurokinin B signaling in hypothalamic KNDy (kisspeptin/neurokinin B/dynorphin) neurons that regulate body temperature
- SKYLIGHT 1 Phase 3 trial: fezolinetant 45 mg reduced moderate-to-severe hot flash frequency by more than 50% at week 12, with significant improvement by week 4 (Johnson et al., The Lancet, 2023)
- SKYLIGHT 2 Phase 3 trial confirmed results, with both 30 mg and 45 mg doses significantly reducing VMS frequency and severity versus placebo (Lederman et al., JCEM, 2023)
- Over 3,000 women enrolled across three Phase 3 trials (SKYLIGHT 1, 2, and 4) in the BRIGHT SKY program
- The mechanism originates from the discovery of KNDy neurons, which co-express kisspeptin, neurokinin B, and dynorphin and serve as the hypothalamic thermostat affected by estrogen withdrawal (Lehman et al., 2010)
- The FDA added a boxed warning for rare serious liver injury; liver function monitoring is required before and during treatment
The Problem: Why Menopause Causes Hot Flashes
Hot flashes (vasomotor symptoms) are the hallmark complaint of menopause, affecting 50-80% of women during the menopausal transition. A hot flash is a sudden sensation of heat, typically centered on the face, neck, and chest, lasting 1-5 minutes and often accompanied by sweating, flushing, and anxiety. Severe hot flashes disrupt sleep, reduce quality of life, and can persist for years.
The mechanism was poorly understood until the discovery of KNDy neurons in the hypothalamic arcuate nucleus. These specialized neurons co-express three peptides: kisspeptin, neurokinin B (NKB), and dynorphin.[1] KNDy neurons function as a critical node controlling gonadotropin-releasing hormone (GnRH) secretion and, crucially, they also interact with thermoregulatory neurons in the nearby median preoptic nucleus.
In premenopausal women, estrogen acts as a brake on NKB expression in KNDy neurons. When estrogen declines during menopause, NKB expression increases dramatically, and NKB signaling through NK3 receptors on thermoregulatory neurons becomes overactive. This shifts the thermoneutral zone, the range of body temperatures the brain considers "normal," to an abnormally narrow band. Small fluctuations in core temperature that would previously go unnoticed now trigger the heat-dissipation response: vasodilation, sweating, and the subjective sensation of a hot flash.
This peptide-level understanding created a clear drug target. Block NKB at the NK3 receptor, and the thermoneutral zone should widen back to normal, reducing hot flash frequency without altering estrogen levels.
How Fezolinetant Works
Fezolinetant is an oral, selective NK3 receptor antagonist. It crosses the blood-brain barrier and binds to NK3 receptors in the hypothalamus, preventing NKB from activating thermoregulatory signaling cascades. By blocking only the NK3 receptor (not NK1 or NK2, which mediate different tachykinin functions including pain and inflammation), fezolinetant targets the specific peptide pathway responsible for vasomotor symptoms.
The kisspeptin system is integral to this pathway. Kisspeptin is the master regulator of GnRH pulsatility and reproductive function.[2] Within KNDy neurons, NKB acts as an autocrine/paracrine stimulator (increasing KNDy neuron firing) while dynorphin acts as an inhibitor. Fezolinetant interrupts the NKB stimulatory arm without affecting dynorphin inhibition or kisspeptin's downstream effects on GnRH secretion. This selectivity means fezolinetant reduces hot flashes without significantly altering LH, FSH, or estradiol levels, a critical advantage over hormonal approaches.
For the broader kisspeptin-based approach to vasomotor symptoms, the KNDy neuron circuit offers multiple potential intervention points beyond the NK3 receptor alone.
The Phase 3 Evidence: BRIGHT SKY Program
Fezolinetant's approval rested on the BRIGHT SKY clinical development program comprising three Phase 3 randomized controlled trials enrolling over 3,000 women with moderate-to-severe VMS.
SKYLIGHT 1
This randomized, double-blind, placebo-controlled trial enrolled women aged 40-65 with an average of seven or more moderate-to-severe hot flashes per day at 97 sites across the US, Canada, and Europe. Participants received once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg for 12 weeks, followed by a 40-week active treatment extension (Johnson et al., The Lancet, 2023).
Both fezolinetant doses significantly reduced VMS frequency at week 4 and week 12 compared to placebo. At week 12, the reduction in hot flash frequency exceeded 50% in both treatment groups. VMS severity also improved significantly. Treatment-emergent adverse events occurred in 37% of the 30 mg group and 43% of the 45 mg group, compared to 45% in the placebo group, indicating that fezolinetant did not increase overall adverse event rates above placebo.
SKYLIGHT 2
The second confirmatory trial (Lederman et al., JCEM, 2023) replicated SKYLIGHT 1's findings. Both 30 mg and 45 mg doses produced statistically significant and clinically meaningful reductions in VMS frequency and severity at weeks 4 and 12. The response was rapid: women reported improvement within the first week of treatment.
SKYLIGHT 4
This 52-week safety study evaluated fezolinetant's long-term tolerability. The extended safety data supported continued use without new safety signals, with the exception of hepatic transaminase elevations that led to the liver monitoring requirements.
Safety Profile and the Liver Warning
The most common adverse effects in clinical trials were abdominal pain (4.5%), diarrhea (3.8%), insomnia (3.5%), back pain (2.9%), and hepatic transaminase elevation (2.3%). Most adverse events were mild to moderate in severity.
The FDA initially approved fezolinetant with a standard liver function monitoring requirement. In March 2025, the FDA added a boxed warning, the most prominent safety warning, after post-marketing reports of rare but serious liver injury, including cases requiring hospitalization. The updated labeling requires liver function tests before starting treatment, at 3 months, 6 months, 9 months, and then periodically as clinically indicated. Fezolinetant should not be used in patients with known hepatic impairment, cirrhosis, or unexplained transaminase elevation.
This safety concern is real but contextually proportionate. The boxed warning describes a rare event (estimated occurrence less than 1 in 1,000 treated patients) and the monitoring protocol can detect liver enzyme changes before they become clinically significant. For women unable or unwilling to use hormone therapy, the risk-benefit calculation may still favor fezolinetant, particularly given the substantial impact severe VMS has on quality of life.
How It Compares to Hormone Therapy
Hormone replacement therapy (HRT) remains the most effective treatment for menopausal VMS, reducing hot flash frequency by 75-90%. Fezolinetant's efficacy is lower: approximately 50-60% reduction in VMS frequency. This gap is real and should be acknowledged.
However, fezolinetant fills a specific clinical need. Approximately 20-30% of menopausal women have contraindications to estrogen therapy, including history of breast cancer, venous thromboembolism, or cardiovascular disease. Others decline HRT due to personal preference or concern about cancer risk. Before fezolinetant, non-hormonal options were limited to off-label use of SSRIs/SNRIs, gabapentin, and clonidine, all of which have modest efficacy and their own side effect profiles.
Fezolinetant is the first treatment designed specifically for hot flashes based on understanding the peptide mechanism that causes them. Peptide alternatives to HRT represent a growing therapeutic category as the molecular biology of menopausal symptoms becomes clearer.
The Broader Significance for Peptide Medicine
Fezolinetant's approval illustrates a pattern in peptide drug development: understanding an endogenous peptide signaling pathway leads to a targeted therapeutic. NKB was identified as a key thermoregulatory peptide through basic neuroscience research on KNDy neurons. The drug does not replace a missing peptide or mimic one; it blocks a peptide signal that has become dysregulated.
This "antagonist" approach to peptide therapeutics differs from the "agonist" approach exemplified by GLP-1 receptor agonists (which mimic an endogenous peptide). Both strategies depend on the same foundational science: mapping which peptides signal through which receptors to produce which physiological effects, then engineering molecules that modulate those specific nodes.
Elinzanetant, a dual NK1/NK3 receptor antagonist, is in late-stage clinical development and may offer additional efficacy by blocking both neurokinin B and substance P signaling simultaneously. The NK3 antagonist class is likely to expand as post-marketing data clarifies fezolinetant's long-term safety profile.
The Bottom Line
Fezolinetant (Veozah), approved by the FDA in May 2023, is the first NK3 receptor antagonist for menopausal hot flashes. It blocks neurokinin B signaling in hypothalamic KNDy neurons, the specific peptide pathway that becomes overactive when estrogen declines during menopause. Phase 3 trials enrolling over 3,000 women showed greater than 50% reduction in moderate-to-severe hot flash frequency at 12 weeks. The FDA added a boxed warning for rare serious liver injury in 2025, requiring periodic liver function monitoring. Fezolinetant provides a non-hormonal option for the 20-30% of menopausal women who cannot use estrogen therapy, with lower efficacy than HRT but a targeted mechanism based on peptide neuroscience.