What is fezolinetant (neurokinin 3 receptor antagonist) used for?

Fezolinetant: A Non-Hormonal Treatment for Menopausal Vasomotor Symptoms

Fezolinetant is a selective neurokinin-3 (NK3) receptor antagonist FDA-approved for the treatment of moderate-to-severe vasomotor symptoms (hot flashes and night sweats) associated with menopause. 1, 2

Mechanism of Action

• Fezolinetant works by blocking NK3 receptors in the hypothalamic thermoregulatory center, which prevents the neuronal signaling that triggers hot flashes and night sweats 2
• This represents a fundamentally different approach than hormonal therapy, as it directly targets the mechanistic pathway responsible for vasomotor symptoms rather than replacing hormones 2
• NK3 receptor activity plays a key role in modulating the thermoregulatory center in a manner that triggers the "hot flash" response at menopause 2

Clinical Efficacy

Reduction in Vasomotor Symptom Frequency

• Fezolinetant significantly reduces the frequency of moderate-to-severe vasomotor symptoms by approximately 2.4 episodes per day compared to placebo at 12 weeks 3
• At week 4, fezolinetant 30 mg reduced VMS frequency by 1.87 episodes/day and fezolinetant 45 mg by 2.07 episodes/day compared to placebo 1
• At week 12, fezolinetant 30 mg reduced VMS frequency by 2.39 episodes/day and fezolinetant 45 mg by 2.55 episodes/day compared to placebo 1
• Improvements in VMS frequency are observed as early as 1 week after initiation and are maintained over 52 weeks 1

Reduction in Vasomotor Symptom Severity

• Fezolinetant significantly reduces the severity of moderate-to-severe vasomotor symptoms with a mean difference of -0.40 compared to placebo 3
• At week 4, fezolinetant 30 mg reduced VMS severity by 0.15 points and fezolinetant 45 mg by 0.19 points compared to placebo 1
• At week 12, fezolinetant 30 mg reduced VMS severity by 0.24 points and fezolinetant 45 mg by 0.20 points compared to placebo 1

Quality of Life Improvements

• Fezolinetant significantly improves patient-reported outcomes including the Greene Climacteric Scale (GCS), PROMIS Sleep Disturbance Short Form 8b, and Menopause-Specific Quality of Life (MENQoL) scores 3
• Improvements in the Hot Flash-Related Daily Interference Scale (HFRDIS) demonstrate reduced impact of VMS on daily functioning 4

Dosing Recommendations

• The approved doses are fezolinetant 30 mg or 45 mg taken once daily 1
• Both doses demonstrate similar efficacy, though the 45 mg dose shows slightly greater reductions in VMS frequency 1
• No dose titration is required; patients can start at the target therapeutic dose 1

Safety Profile

Common Adverse Events

• During the first 12 weeks of treatment, treatment-emergent adverse events occurred in 37% of patients taking fezolinetant 30 mg, 43% taking fezolinetant 45 mg, and 45% taking placebo 1
• There is no significant difference in overall adverse events between fezolinetant and placebo 4
• Drug-related treatment-emergent adverse events show a slight, non-significant increase with fezolinetant (RR 1.21) 4

Hepatotoxicity Monitoring

• The incidence of liver enzyme elevations is low (1 patient on placebo, 2 on fezolinetant 30 mg, 0 on fezolinetant 45 mg in the pivotal trial) 1
• Liver enzyme elevations are generally asymptomatic, transient, and resolve while on treatment or after discontinuation 1
• Baseline liver function tests should be obtained, and periodic monitoring is recommended during treatment 4, 5

Endometrial Safety Considerations

• Endometrial events and potential hyperplasia show a statistically insignificant but increasing trend in the fezolinetant group 4
• Prospective long-term studies are needed to fully characterize endometrial safety, particularly in women with intact uteri 4, 5
• Uterine bleeding had a lower incidence in fezolinetant-treated patients 4

Drug-Related Discontinuations

• Drug-related dropout rates are similar between fezolinetant and placebo groups 4
• In the pivotal trial, 31 patients in the fezolinetant 30 mg group and 13 in the 45 mg group discontinued before week 12, mostly due to adverse events or participant withdrawal 1

Clinical Context and Positioning

Advantages Over Hormonal Therapy

• Fezolinetant provides a non-hormonal alternative for women who cannot or do not want to take menopausal hormone therapy 1, 2
• It avoids the established risks of hormone therapy including stroke, venous thromboembolism, and concerns about hormone-dependent cancers 2
• This makes it particularly valuable for breast cancer survivors and women with contraindications to estrogen therapy 2

Comparison to Other Neurokinin Antagonists

• While NK1 and NK2 receptor antagonists have been studied for various conditions including chemotherapy-induced nausea and cough, their antitussive and antiemetic effects are distinct from the thermoregulatory effects of NK3 antagonism 6
• Fezolinetant is the most advanced NK3 receptor antagonist in clinical development for menopausal VMS 2
• The specificity for NK3 receptors distinguishes fezolinetant from earlier neurokinin antagonists like aprepitant (an NK1 antagonist used for chemotherapy-induced nausea) 6

Important Clinical Caveats

• The longest follow-up data currently available extends to 52 weeks; longer-term safety data beyond one year are still being collected 1, 5
• The heterogeneity in analyzed data, relatively short follow-up periods, and small sample sizes in some trials represent limitations that require consideration 4
• Further prospective research is specifically needed to evaluate long-term endometrial safety and effects on sleep architecture 5
• The clinical trials enrolled diverse populations representative of potential fezolinetant users, enhancing generalizability 1