What is Veozah (fezolinetant) and how does it work?

What is Veozah and How Does It Work

Veozah (fezolinetant) is a novel oral neurokinin 3 (NK3) receptor antagonist approved for treating moderate-to-severe vasomotor symptoms (hot flashes and night sweats) associated with menopause, working by blocking neurokinin B signaling in the hypothalamic thermoregulatory center without affecting hormones. 1

Mechanism of Action

Fezolinetant blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neurons to modulate neuronal activity in the thermoregulatory center of the hypothalamus. 1 This represents a fundamentally different approach than hormone therapy—it targets the neurological pathway that causes hot flashes rather than replacing estrogen. 2, 3

Key pharmacologic properties include:

• High affinity for NK3 receptors (Ki value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than binding affinity to NK1 or NK2 receptors 1
• Crosses the blood-brain barrier to reach the hypothalamic thermoregulatory center 2
• Does not affect sex hormone levels (follicle-stimulating hormone, testosterone, estrogen, or DHEA-sulfate) in menopausal women 1
• Causes only transient decrease in luteinizing hormone (LH) levels at peak drug concentrations 1

Clinical Efficacy

The SKYLIGHT 1 trial demonstrated robust efficacy in reducing vasomotor symptoms:

• At week 4, fezolinetant 45 mg reduced hot flash frequency by 2.07 episodes per day more than placebo (p<0.001) 4
• At week 12, fezolinetant 45 mg reduced hot flash frequency by 2.55 episodes per day more than placebo (p<0.001) 4
• Severity of vasomotor symptoms was significantly reduced at both week 4 (p=0.002) and week 12 (p=0.007) with the 45 mg dose 4
• Improvements were observed after just 1 week of treatment and maintained over 52 weeks 4

Dosing and Administration

The recommended dose is one 45 mg tablet taken orally once daily. 1, 2

Important pharmacokinetic characteristics:

• Steady-state plasma concentrations are reached after two once-daily doses, with minimal drug accumulation 1
• Median time to peak concentration is 1.5 hours (range 1-4 hours) 1
• Effective half-life is 9.6 hours in women with vasomotor symptoms 1
• Can be taken with or without food—no clinically significant differences in drug levels occur with high-fat meals 1

Safety Profile and Monitoring Requirements

Treatment-emergent adverse events occurred in 43% of women taking fezolinetant 45 mg compared to 45% taking placebo during the first 12 weeks. 4 The most common side effects are headache and gastrointestinal disturbances. 5

Critical Safety Considerations:

Liver enzyme monitoring is mandatory because fezolinetant can cause transaminase elevations: 1, 4

• Obtain baseline liver function tests before initiating treatment 1
• Repeat liver function tests at months 3,6, and 9 after starting therapy 1
• The incidence of liver enzyme elevations was low (0 cases in the 45 mg group during the first 12 weeks), and events were generally asymptomatic, transient, and resolved while on treatment or after discontinuation 4

Contraindications:

• Cirrhosis of any severity (Child-Pugh Class A, B, or C) 1
• Severe renal impairment (eGFR 15 to <30 mL/min/1.73 m²) or end-stage renal disease (eGFR <15 mL/min/1.73 m²) 1

Dose Adjustments:

• No dose adjustment needed for mild (eGFR 60 to <90) or moderate (eGFR 30 to <60) renal impairment 1
• Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19—consider potential drug interactions with strong CYP1A2 inhibitors or inducers 1

Place in Therapy

Fezolinetant represents the first FDA-approved non-hormonal neurokinin 3 receptor antagonist for vasomotor symptoms, offering an important alternative for women who cannot or do not want to use hormone therapy. 6, 5 This includes women with:

• History of breast cancer or other hormone-sensitive malignancies 3
• Cardiovascular disease or thromboembolic risk factors 3
• Personal preference to avoid hormonal treatments 2, 3

Unlike hormone therapy, fezolinetant does not prolong the QT interval to any clinically relevant extent, even at doses 20 times the maximum approved dose. 1