The Lancet MARCH 13, 2023

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

Lederman S, Ottery F, Cano A, et al.

Bottom Line

Fezolinetant, a selective neurokinin-3 receptor antagonist, demonstrated statistically significant and rapid reductions in the frequency and severity of moderate-to-severe menopausal vasomotor symptoms compared with placebo in a pivotal phase 3 trial.

Key Findings

1. Fezolinetant 30 mg and 45 mg once daily met all four co-primary endpoints, showing significant reductions in the mean frequency and severity of moderate-to-severe vasomotor symptoms (VMS) from baseline to week 4 and week 12 compared to placebo (p<0.001 for all).

2. Therapeutic effects were observed as early as week 1 and were maintained throughout the 52-week study period.

3. During the initial 12-week placebo-controlled phase, treatment-emergent adverse events (TEAEs) were reported in 37% of the 30 mg group, 43% of the 45 mg group, and 45% of the placebo group.

4. The most frequently reported TEAEs over the 52-week study duration were headache and COVID-19.

Study Design

Design

RCT

Double-Blind

Sample

501

Patients

Duration

52 wk

Median

Setting

Multicenter, North America/Europe

Population Women aged 40-65 years experiencing an average of seven or more moderate-to-severe hot flashes per day due to menopause.

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

Comparator Placebo administered once daily.

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

Study Limitations

• The study primarily focused on VMS frequency and severity, and while QoL markers improved, some analyses did not meet pre-defined minimum clinically important difference (MCID) thresholds.

• The study design, while robust for short-term efficacy, relies on a long-term open-label extension after the initial 12-week placebo-controlled period, which inherently limits comparative safety and efficacy assessments over the full 52 weeks.

• Generalizability may be impacted by strict inclusion criteria regarding VMS severity (average ≥7 hot flashes/d), which may not represent all women seeking treatment.

Clinical Significance

Fezolinetant represents a first-in-class non-hormonal treatment option for moderate-to-severe menopausal hot flashes and night sweats, providing a critical alternative for women who are candidates for whom hormone therapy is contraindicated, not preferred, or ineffective.

Historical Context

Vasomotor symptoms (VMS) have traditionally been managed with hormone replacement therapy (HRT), which carries specific risks for certain patient populations. The discovery that neurokinin B (NKB) signaling in the hypothalamic KNDy neurons is a key mediator of thermoregulation and the hot flash response led to the development of selective neurokinin-3 receptor (NK3R) antagonists as a novel, non-estrogenic mechanism to treat VMS.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of fezolinetant differ from hormone replacement therapy (HRT) in the regulation of the thermoregulatory center within the hypothalamus?

Key Response

HRT works by providing exogenous estrogen to restore negative feedback on KNDy (kisspeptin, neurokinin B, and dynorphin) neurons. In contrast, fezolinetant is a selective neurokinin-3 (NK3) receptor antagonist that directly blocks the binding of neurokinin B on these neurons, which become hypertrophied and overactive during menopause. This directly modulates the thermoregulatory center without the systemic effects of estrogen.

Resident

For a symptomatic menopausal patient with a history of deep vein thrombosis (DVT), how do the SKYLIGHT 1 results influence your choice between fezolinetant and SSRIs/SNRIs?

Key Response

Fezolinetant provides a high-efficacy, non-hormonal alternative for patients where estrogen is contraindicated (like history of DVT). While SSRIs/SNRIs are used off-label for vasomotor symptoms, SKYLIGHT 1 demonstrated statistically significant and rapid reduction in both frequency and severity of symptoms by week 4, often with a more targeted side effect profile than serotonergic agents, though liver function monitoring is required for fezolinetant.

Fellow

In analyzing the SKYLIGHT 1 data, how does the 30 mg vs. 45 mg dosing efficacy compare to the safety signal regarding transaminase elevations, and what are the implications for long-term management?

Key Response

Both doses showed efficacy, but the 45 mg dose (the eventual FDA-approved dose) demonstrated a robust and consistent reduction in symptoms. Regarding safety, a small percentage of patients experienced transient elevations in ALT/AST (>3x ULN). Fellows must integrate this by ensuring baseline liver testing and periodic monitoring, distinguishing this drug-induced liver injury risk from other common menopausal comorbidities.

Attending

How does the emergence of NK3 receptor antagonists like fezolinetant challenge the traditional 'estrogen-first' paradigm in treating vasomotor symptoms (VMS), particularly regarding patient autonomy and the legacy of the Women's Health Initiative (WHI)?

Key Response

Fezolinetant allows clinicians to decouple the treatment of VMS from the complex risk-benefit discussion of systemic hormone therapy. It offers an 'estrogen-level' efficacy for VMS without the associated concerns of breast cancer or cardiovascular events highlighted by the WHI, potentially making it the preferred choice for a broader range of patients regardless of their contraindications.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The SKYLIGHT 1 trial used patient-reported daily diaries as a primary endpoint. What are the limitations of relying on subjective VMS reporting in Phase 3 trials, and how might the incorporation of objective measures like sternal skin conductance affect the interpreted effect size of NK3 antagonists?

Key Response

Subjective reporting is prone to high placebo response rates (often 30-50% in VMS trials) and recall bias. Objective measures like skin conductance (measuring sweat) provide physiological verification of hot flashes. While SKYLIGHT 1 showed significant separation from placebo, using objective triggers would help determine if fezolinetant is primarily modulating the perception of heat or the physiological trigger itself.

Journal Editor

Given that SKYLIGHT 1 only reports data through 12 weeks of double-blind treatment, what specific data from the 40-week safety extension (SKYLIGHT 2 or 4) would be critical to establish the durability and safety profile necessary for a practice-changing publication?

Key Response

As an editor, I would look for the 'rebound effect' after cessation, the long-term stability of the liver enzyme signals, and any evidence of endometrial hyperplasia (though not expected via NK3 mechanism). Short-term efficacy is common in VMS; long-term safety is the primary barrier for new non-hormonal classes entering a market dominated by inexpensive, off-label generics.

Guideline Committee

Should the North American Menopause Society (NAMS) elevate fezolinetant to a 'Level A' recommendation alongside hormone therapy, and how does its cost-effectiveness influence its position relative to low-dose paroxetine?

Key Response

The SKYLIGHT 1 data provides Level 1 evidence for efficacy. However, current NAMS and ACOG guidelines emphasize cost-effectiveness. While paroxetine 7.5mg is the only other FDA-approved non-hormonal therapy, its efficacy is generally considered modest compared to HRT. Fezolinetant fills the gap of 'high-efficacy non-hormonal,' but its high cost may relegate it to second-line therapy behind HRT or generics unless specifically contraindicated.

Clinical Landscape

Noteworthy Related Trials

2002

Women's Health Initiative (WHI)

n = 16,608 · JAMA

Tested

Conjugated equine estrogens plus medroxyprogesterone acetate

Population

Postmenopausal women

Comparator

Placebo

Endpoint

Incidence of coronary heart disease and invasive breast cancer

Key result: The trial found an increased risk of breast cancer, cardiovascular disease, and stroke with hormone replacement therapy, shifting the clinical landscape for vasomotor symptom management.

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

Mean change from baseline in frequency and severity of vasomotor symptoms

Key result: Fezolinetant significantly reduced the frequency and severity of moderate-to-severe vasomotor symptoms compared to placebo at weeks 4 and 12.

2023

MOTIVATE Trial

n = 1,073 · Menopause

Tested

Fezolinetant 30mg or 45mg daily

Population

Postmenopausal women with vasomotor symptoms

Comparator

Placebo

Endpoint

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

Key result: Both doses of fezolinetant demonstrated significant reductions in the frequency of moderate-to-severe vasomotor symptoms compared to placebo.

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