Fezolienetant Demonstrates Reduced Waist Circumference, Body Roundness and Stable Weight and BMI in 52-Week Pooled Analysis of Phase 3 SKYLIGHT Trials
Postmenopausal women taking fezolinetant experienced positive changes in body fat distribution, increases in which are known to increase risks of cardiometabolic disease.
Fezolinetant, a nonhormonal selective neurokinin-3 receptor (NK3R) antagonist approved for treating moderate to severe vasomotor symptoms (VMS) associated with menopause, demonstrated small but consistent reductions in weight, waist circumference, and body mass index (BMI) over 52 weeks according to a pooled analysis of 3 phase 3 clinical trials.
Nanette F Santoro, MD
Divisions of Reproductive Endocrinology and Infertility & Reproductive Sciences
Department of Obstetrics and Gynecology University of Colorado Anschutz Medical Campus
The findings, presented Friday afternoon, May 16, at the 2025 American College of Obstetricians and Gynecologists Annual Clinical & Scientific Meeting, reveal potential added benefits of the NK3R inhibitor for postmenopausal women, a population facing increased risk for central adiposity and cardiometabolic disease. The ACOG meeting runs through Sunday, May 18, in Minneapolis, MN.
Investigators, led by Nanette Santoro, MD, of the department of obstetrics and gynecology at the University of Colorado Anschutz Medical Campus, in Aurora, CO, conducted a pooled analysis of data from 3 randomized controlled trials in the SKYLIGHT phase 3 clinical development program—SKYLIGHT 1, SKYLIGHT 2, and SKYLIGHT 4—which together assessed the long-term safety and efficacy of fezolinetant 45 mg daily, according to the study abstract. The analysis included 1,830 postmenopausal women who received fezolinetant for up to 52 weeks. Participants in SKYLIGHT 1 and 2 were initially randomized to placebo or fezolinetant for 12 weeks and continued into an active-treatment extension. SKYLIGHT 4 was a 52-week placebo-controlled safety study. Researchers pooled data from participants who received at least 1 dose of fezolinetant 45 mg, fezolinetant 30 mg, or placebo.
At baseline, participants had a mean age of 55.3 years. Among them, 65.2% self-identified as White, 30.3% as Black or African American, 1.8% as Asian, and 2.8% as “Other.” The mean weight was 82.6 kg, mean BMI was 30.4 kg/m², and mean waist circumference was 96.3 cm. Notably, 53.3% of participants had a BMI ≥30 kg/m².
FINDINGS
After 52 weeks of treatment, mean waist circumference decreased by 0.82 cm (SE 0.25) with fezolinetant 30 mg and by 0.88 cm (SE 0.24) with fezolinetant 45 mg, compared with only 0.15 cm (SE 0.34) in the placebo group. Similarly, measures of body roundness index (BRI), which estimates visceral fat and ranges from 1 to 16 (higher scores indicating wider, rounder bodies), decreased by 0.10 (SE 0.03) with fezolinetant 30 mg and by 0.11 (SE 0.03) with fezolinetant 45 mg, versus a negligible reduction of 0.01 (SE 0.04) with placebo.
Weight remained stable across all groups, with modest mean increases of 0.47 kg (SE 0.22) with placebo, 0.23 kg (SE 0.18) with fezolinetant 30 mg, and 0.15 kg (SE 0.18) with fezolinetant 45 mg. BMI similarly showed minimal changes: +0.18 kg/m² (SE 0.08) with placebo, +0.10 kg/m² (SE 0.07) with fezolinetant 30 mg, and +0.06 kg/m² (SE 0.07) with fezolinetant 45 mg.
The safety profile of fezolinetant remained consistent with previous reports. Weight increase was reported as a treatment-emergent adverse event (TEAE) in 1.1% of participants receiving placebo, 2.0% of participants in the fezolinetant 30 mg arm, and 0.7% of those taking fezolinetant 45 mg. Santoro and colleagues reported that BMI had no discernible effect on overall safety outcomes, including TEAEs, serious adverse events, and liver biochemistry.
These findings address important clinical questions about body composition changes during menopause treatment, authors emphasized. Santoro et al cite data showing that up to 80% of women experience vasomotor symptoms during menopause, which often correlate with unfavorable body composition changes. Both weight gain and increases in and redistribution of total body fat and abdominal fat during the menopausal transition elevate risks for cardiovascular and metabolic conditions including insulin resistance, type 2 diabetes, hypertension, and hyperlipidemia, authors wrote.
Fezolinetant is currently approved at a dose of 45 mg once daily for treating moderate to severe VMS in multiple regions worldwide, including North America, Europe, Asia, and Australia. Previous analyses of the SKYLIGHT trials confirmed that fezolinetant significantly improved vasomotor symptom frequency and severity at 4 and 12 weeks compared with placebo.
This comprehensive analysis suggests fezolinetant not only effectively treats hot flashes and night sweats associated with menopause but may also be associated with favorable body composition changes, with weight stability and potential reductions in central adiposity—addressing 2 significant concerns for menopausal women simultaneously.
References
Santoro N, Blogg M, Martins K, Helbing M, Nappi RE, Iyer T. Effect of fezolinetant on weight, waist circumference, and BMI; data from phase 3, randomized, double-blind placebo-controlled studies (SKYLIGHT 1, 2 and 4) over 52 weeks. Poster presented at: 2025 Annual Meeting of the American College of Obstetricians and Gynecologists; May 16-18, 2025; Minneapolis, MN.
