Fezolinetant Did Not Increase Body Weight or BMI

Medscape

21-05-2025

MINNEAPOLIS — Women taking fezolinetant for menopausal vasomotor symptoms did not experience any significant change in weight or body mass index (BMI) after a year of taking the medication, according to a pooled analysis of previous trial data.
'The most important findings are that fezolinetant does not seem to be associated with any weight gain,' said Nanette F. Santoro, MD, University of Colorado Anschutz Medical Campus in Aurora, Colorado, who presented the data in a poster at the American College of Obstetricians and Gynecologists (ACOG) 2025 Annual Meeting.
'It looks like it is weight neutral, and if anything, we're seeing a signal that your waist and your body roundness will actually go down in association with the drug because the placebo group didn't have that change in waist circumference,' Santoro told Medscape Medical News . 'And, both doses of fezolinetant, 30 mg and 45 mg, showed a decrease in waist [circumference] and a decrease in body roundness.'
Santoro speculated that the modest reduction in waist circumference and body roundness may have been related to better sleep.
'Outside of hot flashes and night sweats, weight gain is the next most common and bothersome complaint in menopausal women,' Chrisandra L. Shufelt, MD, professor of internal medicine and associate director of the Women's Health Research Center for Mayo Clinic in Jacksonville, Florida, told Medscape Medical News .
'This data is reassuring that there's no associated weight gain with fezolinetant, as some of the other nonhormonal medication options come with a side effect of weight gain,' said Shufelt, who was not involved in the research.
Greater BMI, body fat, and waist circumference are also associated with greater severity of vasomotor symptoms, the authors noted in their poster.
The researchers analyzed data on weight, waist circumference, body roundness, and BMI in women who received fezolinetant for vasomotor symptoms in the phase 3 SKYLIGHT 1, 2, and 4 studies. Since body fat cannot be determined based on BMI, the researchers included the body roundness index (BRI), derived from the ratio of waist circumference to height. The BRI can estimate visceral fat and ranges from 1 to 16, with higher scores indicating wider, rounder bodies with presumably more visceral fat.
'BRI has been found to be superior in estimating risk for clinical endpoints including cardiometabolic disease, kidney disease, and cancer,' the researchers noted. 'Longitudinal studies also show that high BRI was linked to increased risk of all-cause mortality and cardiovascular disease–specific mortality.'
The average BRI among US women is 5.86, based on an estimate from the 2018 National Health and Nutrition Examination Survey. The average was 5.87 for people aged 45-65 years and 6.03 for people older than 65 years.
The SKYLIGHT 1 and 2 studies were identical randomized controlled studies that ran for 12 weeks, comparing 30 mg and 45 mg of fezolinetant with placebo, plus a 40-week active treatment open-label extension. SKYLIGHT 1 enrolled 522 women, and SKYLIGHT 2 enrolled 500 women. SKYLIGHT 4 enrolled 1830 women who received either 30 mg fezolinetant, 45 mg fezolinetant, or placebo in a double-blind randomized controlled trial lasting 52 weeks.
This analysis pooled the results from 2852 total participants, including 2203 women who received fezolinetant (1103 receiving 30 mg and 1100 receiving 45 mg). The placebo group initially included 952 women, but those enrolled in the SKYLIGHT 1 and 2 trials then switched to fezolinetant at 12 weeks for the 40-week extension, so the analysis included their data initially as placebo participants and then in the fezolinetant numbers after 12 weeks.
The participants were an average 54 years old and included 15.8%-18.2% Black women and 20.9%-22.2% Latino/Hispanic women across the three groups. At baseline across the groups, their average weight was 75.1-75.7 kg, average BMI was 28.2-28.3, average waist circumference was 90.8-90.9 cm, and average BRI was 4.60-4.63.
Average weight remained stable through 52 weeks for those receiving placebo (+0.47 kg), 30 mg fezolinetant (+0.23 kg), and 45 mg fezolinetant (+0.15 kg). Average BMI was similarly stable for the three groups through 52 weeks, but average waist circumference decreased 0.82 cm in the 30-mg fezolinetant group and 0.88 cm in the 45-mg fezolinetant group compared with a 0.15 cm decrease in the placebo group.
Similarly, BRI decreased from baseline to 52 weeks by 0.10 in the 30-mg fezolinetant group and by 0.11 in the 45-mg fezolinetant group compared with a 0.01 decrease in the placebo group.
If better sleep is potentially involved in the decrease in body roundness and waist circumference, it may also provide more opportunity for increased exercise, Santoro suggested, although that remains speculative since this analysis did not include data on sleep or physical activity.
Weight increase was reported as an adverse event in 1.1% of those taking placebo, 2% of those taking 30 mg fezolinetant, and 0.7% of those taking 45 mg fezolinetant.
'BMI has no discernible difference on safety in the pooled SKYLIGHT analysis as measured by overall treatment-emergent adverse events, treatment-emergent adverse events related to study intervention, serious adverse events, serious adverse events related to study intervention, treatment-emergent adverse events of special interest, and liver biochemistry,' the authors reported.
The research was funded by Astellas Pharma. Santoro reported financial disclosures involving Astellas Pharma, Ember, MenoGeniX, and Ansa Labs. Three authors are employees of Astellas Pharma. Other authors reported disclosures with Exeltis, HRA Pharma, Novo Nordisk, Pfizer, Abbott, Astellas Pharma, Bayer Pharmaceutical, Besins Healthcare, Fidia Farmaceutici S.P.A., Gedeon Richter, Merck, Scynexis, Shionogi, Theramex, Viatris, and Vichy Laboratories. Shufelt is an adviser for Bayer Pharmaceutical.