Fezolinetant reduces menopause-related vasomotor symptoms

Treatment with fezolinetant 30 and 45 mg daily provides relief from moderate-to-severe vasomotor symptoms (VSM) associated with menopause, suggests a study.

Women aged 40 to 65 years with minimum average of seven moderate-to-severe VMS/day were enrolled in this double-blind, placebo-controlled, 12-week phase III trial with a 40-week active treatment extension (SKYLIGHT 1). They were randomly assigned to receive once-daily fezolinetant 30 mg, 45 mg, or placebo. Completers were rerandomized to fezolinetant 30/45 mg for 40 additional weeks.

Mean daily change in VMS frequency and severity from baseline to weeks 4 and 12 was the primary endpoint. Safety was also evaluated.

Both doses of fezolinetant significantly reduced VMS frequency and severity at weeks 4 and 12 when compared with placebo. [J Clin Endocrinol Metab 2023;108:1981-1997]

Least squares mean reductions in VMS frequency relative to placebo were as follows: week 4: fezolinetant 30 mg, ‒1.84 (p<0.001); 45 mg, ‒2.55 (p<0.001); week 12: 30 mg, ‒1.86 (p<0.001); 45 mg, ‒2.53 (p<0.001). For VMS severity, mean reductions were as follows: week 4: fezolinetant 30 mg, ‒0.15 (p<0.05); 45 mg, ‒0.29 (p<0.001); week 12: 30 mg, ‒0.16 (p<0.05); 45 mg, ‒0.29 (p<0.001).

The investigators observed improvements in VMS frequency and severity as early as week 1, which persisted through week 52.

Serious treatment-emergent adverse events were rare, occurring in 2 percent of patients receiving fezolinetant 30 mg, 1 percent of those on fezolinetant 45 mg, none with placebo.

These results support those from phase II trials, demonstrating significant reductions in total VMS score and mean frequency of moderate-to-severe VMS, as well as improvements in quality-of-life measures at week 12 as compared with placebo. [Menopause 2020;27:382‐392; J Clin Endocrinol Metab 2019;104:5893‐5905]

Placebo effect

Notably, the LS mean reduction in VMS at week 12 was greater than 50 percent in both fezolinetant doses. A 50-percent decrease is considered clinically significant. [Menopause 2014;21:45‐58]

“Reductions in VMS frequency and severity in this study were also seen in the placebo group, replicating the well-documented placebo effect in studies investigating potential treatments for VMS,” the investigators said. [Endocr Pract 2011;17:949‐954; Menopause 2021;29:239‐246]

In an earlier study, treatment of menopausal women with placebo alone resulted in a 33-percent decrease in hot flash frequency. [Psychosom Med 2015;77:167‐175]

“SKYLIGHT 2 was designed to conform to the US Food and Drug Administration Draft Guidance on clinical studies of VMS, with a placebo group and requirement for four coprimary endpoints,” the investigators said. [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/estrogen-and-estrogenprogestin-drug-products-treat-vasomotor-symptoms-and-vulvar-and-vaginal-atrophy]

“Despite the placebo effect, statistically significant differences were observed for both fezolinetant doses vs placebo at weeks 4 and 12 and continued during the extension period,” they added.

The current study is limited by the absence of placebo beyond 12 weeks. In addition, the investigators did not examine other menopause symptoms, such as mood changes and sexual function.