MON-206 The Efficacy of Fezolinetant for the Treatment of Vasomotor Symptoms due to Menopause in Individuals with and without Diabetes Mellitus: A Pooled Phase 3 Analysis

Abstract Disclosure: N.F. Santoro: study investigator, member of a scientific advisory board, and consultant for Astellas, member of a scientific advisory board for Amazon Ember, member of a scientific advisory board for MenoGeniX, consultant for Ansh Labs, past President of the Society for Reproductive Investigation. M. Blogg: employee of Astellas Pharma Europe Ltd. K. Martins: employee of Astellas Pharma Europe Ltd. M. Helbing: employee of Astellas Pharma Global Development. P. Stute: fees/consulting fees from Astellas, fees/consulting fees from Bayer, fees/consulting fees from Besins Healthcare, fees/consulting fees from Effik, fees/consulting fees from Exeltis, fees/consulting fees from Gedeon Richter, fees/consulting fees from Jenapharm, fees/consulting fees from Labatec, fees/consulting fees from Theramex. S. Palacios: member of an advisory board or a speaker for Astellas, member of an advisory board or a speaker for Bayer, member of an advisory board or a speaker for Exeltis, member of an advisory board or a speaker for Gedeon Richter, member of an advisory board or a speaker for Idorsia, member of an advisory board or a speaker for Novo Nordisk, member of an advisory board or a speaker for Procaps, member of an advisory board or a speaker for Procare Health, member of an advisory board or a speaker for Reckitt, member of an advisory board or a speaker for Serelys, member of an advisory board or a speaker for Shionogi, member of an advisory board or a speaker for Theramex. G.S. Neal-Perry: member of a scientific advisory board for Astellas, member of a scientific advisory board for Natera, Inc., member of a scientific advisory board for Novo Nordisk, research funding from the American Association of Medical Colleges, research funding from NICHD, Vice President of Diversity, Equity and Structural Change for the Society for Reproductive Investigation, Program Committee Chair for the American Society of Reproductive Medicine, Committee Membership of the Endocrine Society, Associate Editor for Frontiers in Endocrinology. Introduction Menopause is associated with an adverse metabolic profile, which may increase the risk of diabetes. Fezolinetant is an nonhormonal, neurokinin 3 receptor antagonist treatment option for individuals with moderate to severe vasomotor symptoms (VMS) due to menopause. Diabetes with complications may render some individuals ineligible for menopausal hormone therapy. Objective To explore the efficacy of fezolinetant in individuals with moderate to severe VMS with or without type 1 or 2 diabetes mellitus using pooled data from two phase 3 studies. Methods SKYLIGHT 1 and 2 (NCT04003155/NCT04003142) were double-blind, placebo-controlled studies. Both studies enrolled individuals (≥40–≤65 years) who were assigned female at birth and seeking treatment/relief from moderate to severe VMS. Participants were randomized to placebo, or fezolinetant 30 or 45 mg for 12 weeks. Fezolinetant-treated participants then continued their dose and placebo participants were re-randomized to fezolinetant 30 or 45 mg for 40 weeks. Efficacy was assessed in terms of the change from baseline difference vs placebo in VMS frequency and severity at weeks 4 and 12 for the diabetic and non-diabetic populations. Change from baseline at week 52 was evaluated. A mixed model repeated measurements analysis of covariance model was used to calculate adjusted means; associated 95% confidence intervals (CIs) are for descriptive purposes. Safety was assessed in terms of liver biochemistry for the entire 52-week, phase 3 population. Results Of 1022 participants, 78 had been diagnosed with diabetes (placebo: 22/342 [6.4%], fezolinetant 30 mg: 29/339 [8.6%], fezolinetant 45 mg: 27/341 [7.9%]). Improvements in VMS frequency were noted with fezolinetant 45 mg vs placebo in both the diabetic and non-diabetic populations at week 4 (least squares mean difference in change from baseline data vs placebo [95% CI] – diabetic: –0.40 [–2.75, 1.94]; non-diabetic: –2.43 [–3.08, –1.78]). Similar findings were noted with fezolinetant 45 mg at week 12 (diabetic: –2.70 [–5.27, –0.14]; non-diabetic: –2.49 [–3.21, –1.77]). For VMS frequency, diabetic status did not impact improvements from baseline to week 52 with fezolinetant 45 mg (diabetic: –9.19 [–10.87, –7.50]; non-diabetic: –8.43 [–8.94, –7.92]). Similar trends were noted in the VMS severity data for all timepoints, although improvements were not noted with fezolinetant 45 mg at week 4 in the diabetic population (0.13 [–0.19, 0.45]). Elevations in liver transaminases were infrequently observed and there were no meaningful differences in the number of participants with elevated liver enzymes according to diabetic status. Comparable results were achieved for fezolinetant 30 mg. Conclusions Fezolinetant can be regarded as an effective treatment for moderate to severe VMS in individuals with and without diabetes mellitus. Further investigations are warranted in this population. Presentation: Monday, July 14, 2025