The Lancet April 01, 2023

Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study

Lederman S, Ottery FD, Cano A, Santoro N, Shapiro M, Stute P, et al.

Bottom Line

In postmenopausal women experiencing moderate-to-severe vasomotor symptoms, the novel non-hormonal neurokinin 3 receptor antagonist fezolinetant significantly reduced the frequency and severity of hot flashes compared to placebo.

Key Findings

1. Fezolinetant 30 mg and 45 mg once daily resulted in significant and clinically meaningful reductions in the frequency and severity of moderate-to-severe vasomotor symptoms (VMS) compared with placebo at both week 4 and week 12.

2. Improvement in VMS frequency was rapid, with significant reductions observed as early as week 1 of therapy, and efficacy was sustained throughout the 52-week study period.

3. During the 12-week double-blind period, treatment-emergent adverse events (TEAEs) occurred at similar rates across groups: 45% in the placebo arm, 37% in the fezolinetant 30 mg arm, and 43% in the fezolinetant 45 mg arm.

4. The most commonly reported adverse events over the 52-week period were headache and COVID-19, with a very low incidence of generally asymptomatic, transient liver enzyme elevations.

Study Design

Design

Phase 3 RCT

Double-Blind

Sample

527

Patients

Duration

52 wk

Median

Setting

Multicenter, multinational

Population Women aged 40-65 years experiencing an average of 7 or more moderate-to-severe vasomotor symptoms (hot flashes) per day associated with menopause.

Intervention Fezolinetant 30 mg or 45 mg administered orally once daily.

Comparator Exact-matched placebo administered orally once daily.

Outcome Mean change in frequency and severity of moderate-to-severe vasomotor symptoms from baseline to weeks 4 and 12.

Study Limitations

• The trial lacked an active comparator arm (such as hormone replacement therapy, SSRIs, or SNRIs) to evaluate comparative efficacy.

• The study design evaluated safety and sustained efficacy up to 52 weeks; long-term data on safety beyond one year are lacking.

• Strict inclusion criteria excluded patients with severe comorbidities, potentially limiting generalizability to broader, medically complex populations.

• Rare cases of transaminitis necessitate routine baseline and periodic liver function monitoring in clinical practice, an element that requires real-world feasibility evaluation.

Clinical Significance

SKYLIGHT 1 demonstrated that fezolinetant is a highly effective and well-tolerated non-hormonal treatment for menopausal vasomotor symptoms. It offers a critical, targeted therapeutic alternative for women who cannot or choose not to use hormone replacement therapy (e.g., breast cancer survivors or those at risk for thromboembolism). Based on SKYLIGHT 1 and SKYLIGHT 2, the FDA approved fezolinetant (Veozah) in May 2023.

Historical Context

Vasomotor symptoms (hot flashes and night sweats) affect up to 80% of menopausal women and are a primary driver for seeking medical care. While hormone replacement therapy (HRT) is the historical gold standard, its use plummeted following the Women's Health Initiative (WHI) trials due to concerns over breast cancer and cardiovascular risks. Non-hormonal alternatives like SSRIs, SNRIs, and gabapentin have modest efficacy and variable tolerability. Discovery of the kisspeptin/neurokinin B/dynorphin (KNDy) neuronal network in the hypothalamus revealed that estrogen withdrawal leads to hypertrophy and hypersecretion of neurokinin B, disrupting the body's thermoregulatory center. Fezolinetant, a first-in-class neurokinin 3 (NK3) receptor antagonist, directly blocks this pathway, representing a paradigm shift toward targeted, non-hormonal pathophysiology-based treatment.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of fezolinetant differ from traditional hormone replacement therapy in treating vasomotor symptoms?

Key Response

Fezolinetant is a selective neurokinin 3 (NK3) receptor antagonist. In menopause, the decline of estrogen removes negative feedback on KNDy (kisspeptin, neurokinin B, dynorphin) neurons in the hypothalamus, leading to hypertrophy and overactivity of the thermoregulatory center. Fezolinetant blocks NKB signaling, directly addressing this neuroendocrine mechanism without exposing systemic tissues to exogenous hormones.

Resident

When evaluating a postmenopausal patient with severe hot flashes who has a history of estrogen-receptor positive breast cancer, how does fezolinetant fit into the management algorithm compared to SSRIs/SNRIs or gabapentin?

Key Response

Patients with ER-positive breast cancer have contraindications to systemic hormone therapy. Non-hormonal options historically included off-label SSRIs, SNRIs, or gabapentin, which often have limited efficacy or significant side effects like sexual dysfunction or sedation. Fezolinetant offers a targeted, FDA-approved non-hormonal option, though clinicians must consider cost, availability, and the requirement for baseline and periodic liver function testing due to rare transaminase elevations noted in trials.

Fellow

Given the KNDy neuron role in the broader hypothalamic-pituitary-gonadal axis, what theoretical impacts might NK3 antagonism have on other neuroendocrine functions, and how does the SKYLIGHT 1 safety data address these concerns?

Key Response

KNDy neurons also regulate GnRH pulsatility. NK3 antagonism could theoretically alter LH/FSH dynamics or affect bone metabolism and mood. Fellows should understand how the trial monitored for off-target central nervous system effects, bone density, and hormonal panels, evaluating whether selectively blocking NKB spares other critical endocrine axes in menopausal populations while specifically targeting the thermoregulatory center.

Attending

How do we balance the robust efficacy of fezolinetant seen in the SKYLIGHT trials against its high cost and the need for serial hepatic monitoring when counseling patients who have failed standard non-hormonal therapies?

Key Response

Attendings must weigh clinical efficacy against real-world barriers. While fezolinetant represents a paradigm shift, the requirement for baseline and follow-up transaminase testing (at months 3, 6, and 9) adds a logistical burden. The discussion should center on shared decision-making, patient selection such as those failing SSRIs with severe quality-of-life impairment, and navigating insurance step-therapy protocols.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The SKYLIGHT 1 trial utilized a placebo-controlled design relying on patient-reported diaries. What are the methodological limitations of assessing subjective vasomotor symptom severity, and how could future study designs better incorporate objective measures of thermoregulatory dysfunction?

Key Response

VMS trials are heavily affected by a strong placebo response, often showing a 30 to 50 percent reduction in symptoms in the control arm. While patient-reported outcomes are clinically relevant, they introduce recall and subjective biases. Future studies could integrate ambulatory skin conductance monitors to objectively quantify hot flashes, allowing researchers to differentiate true physiological treatment effects from psychological placebo responses more precisely.

Journal Editor

In evaluating the SKYLIGHT 1 manuscript, how does the high placebo response rate typical of VMS trials impact the statistical power and the clinical interpretation of the minimal clinically important difference (MCID) reported for fezolinetant?

Key Response

A seasoned reviewer would scrutinize the effect size relative to the placebo arm. Even if the p-value is significant, the absolute difference in hot flash frequency (often just 2 to 3 fewer flushes per day compared to placebo) must be evaluated against the MCID. Editors must ensure the authors do not overstate the clinical impact, emphasizing the absolute reduction and quality of life improvements rather than just relative percentages.

Guideline Committee

Based on the SKYLIGHT 1 results, how should the North American Menopause Society (NAMS) update their position statement on non-hormonal management of VMS to incorporate NK3 receptor antagonists, and what level of evidence grade should be assigned?

Key Response

Current NAMS guidelines recommend CBT, SSRIs/SNRIs, and gabapentinoids for women with contraindications to hormone therapy. SKYLIGHT 1 provides Level I evidence supporting the addition of fezolinetant as a non-hormonal pharmacological option. Committees must debate its placement in the treatment algorithm, determining whether it should supersede SSRIs given its targeted mechanism, or follow them due to cost and hepatic monitoring requirements.

Clinical Landscape

Noteworthy Related Trials

2002

Women's Health Initiative (WHI) Estrogen plus Progestin Trial

n = 16,608 · JAMA

Tested

Conjugated equine estrogens plus medroxyprogesterone acetate

Population

Healthy postmenopausal women with an intact uterus

Comparator

Placebo

Endpoint

Coronary heart disease and invasive breast cancer

Key result: The trial was stopped early due to increased risks of cardiovascular events and breast cancer, fundamentally altering menopausal symptom management.

2020

Fezolinetant Phase 2b Dose-Ranging Study

n = 352 · Menopause

Tested

Fezolinetant at various once-daily and twice-daily doses

Population

Postmenopausal women experiencing moderate-to-severe vasomotor symptoms

Comparator

Placebo

Endpoint

Mean change in frequency and severity of moderate-to-severe VMS at weeks 4 and 12

Key result: The study demonstrated rapid and significant reductions in VMS frequency and severity, with an acceptable safety profile across multiple doses.

2023

SKYLIGHT 2 Trial

n = 501 · J Clin Endocrinol Metab

Tested

Fezolinetant 30mg or 45mg daily

Population

Postmenopausal women with moderate-to-severe vasomotor symptoms

Comparator

Placebo

Endpoint

Frequency and severity of moderate-to-severe vasomotor symptoms at weeks 4 and 12

Key result: Fezolinetant 30mg and 45mg daily significantly reduced the frequency and severity of vasomotor symptoms compared to placebo.

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