Efficacy and Safety of Fezolinetant for Menopausal Vasomotor Symptoms

Fezolinetant is efficacious and well-tolerated for treating moderate to severe vasomotor symptoms associated with menopause.

Vasomotor symptoms (VMS), characterized by hot flashes and night sweats, affect most women during menopause. Hormone therapy is effective for managing VMS. However, it may not be appropriate for some women, depending on underlying medical conditions and risk factors, age, time since menopause, or preference. Fezolinetant is a non-hormonal selective neurokinin-3 receptor antagonist that acts on the thermoregulatory center of the hypothalamus and is under development for treating menopausal VMS. Phase 2 trials have shown promising results. A study in The Journal of Clinical Endocrinology and Metabolism evaluated the efficacy and safety of this novel drug for managing moderate to severe menopausal VMS.

Study Design and Population

A multinational, double-blind, placebo-controlled, phase 3 trial was conducted in menopausal women aged 40 to 65 with a minimum average of seven moderate to severe VMS per day. The study comprised 500 women who were randomized to placebo (n = 167), 30 mg fezolinetant (n = 166), or 45 mg fezolinetant (n = 167) for 12 weeks.

Fezolinetant Improves Sleep and Quality of Life 

Fezolinetant was found to be efficacious for treating moderate to severe VMS at 30 and 45 mg daily doses. Both doses demonstrated statistically significant improvements in mean daily VMS frequency and severity at weeks 4 and 12 vs. placebo. Efficacy was observed within the first week of treatment and maintained through week 12, with a daily reduction of two to three VMS episodes from baseline to week 12 vs. placebo. The improvement in VMS led to improved quality of life (QOL) as measured by MENQOL, a menopause-specific patient-reported outcome tool. Moreover, both doses demonstrated sleep improvement (significant for the 45 mg dose), maintained through the extension period.

Fezolinetant Demonstrates Excellent Hepatic Safety Profile

A low incidence of serious adverse events (AEs), with no serious drug-related AEs, was reported. Fezolinetant demonstrated a generally unremarkable safety profile at both doses through week 12. A total of six participants across all treatment groups had alanine aminotransferase or aspartate aminotransferase elevations more than three times the upper limit of normal (n = 2, 30mg fezolinetant; n = 3, 45mg fezolinetant; n = 1, placebo). There were no clinical symptoms or hepatic function impairments. These results indicate the hepatic safety of fezolinetant, with no cases of Hy’s law (an indicator of drug-induced hepatic injury).

Regarding the dosage, 166 women were continued on 30 mg fezolinetant and 167 on 45 mg fezolinetant, whereas 76 women were rerandomized from placebo to 30 mg fezolinetant, and 75 were rerandomized to 45 mg fezolinetant. During the 40-week extension period, efficacy was sustained, and reductions in VMS frequency were maintained at levels consistent with the initial 12 weeks.

At least one AE was experienced by 56.6% of the participants in the placebo/30mg fezolinetant, 60.0% in the placebo/45mg fezolinetant, 64.5% in the 30mg fezolinetant, and 63.5% in the 45mg fezolinetant groups. The most common AEs were COVID-19 and headaches. 

Source

Johnson, K. A., Martin, N., Nappi, R. E., Neal-Perry, G., Shapiro, M., Stute, P., Thurston, R. C., Wolfman, W., English, M., Franklin, C., Lee, M., & Santoro, N. (2023). Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. The Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/clinem/dgad058