Fezolinetant: promising treatment for menopausal vasomotor symptoms (SKYLIGHT 1)

Reference

Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associate with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet 2023;401(10382);1091-1102.

Synopsis

This study was a phase 3 clinical trial, designed and sponsored by the pharmaceutical company that developed the drug. The paper was written by its employees. The new drug, fezolinetant was recently approved by the FDA. It is a selective receptor agonist that binds in the thermoregulatory center of the hypothalamus. It blocks the stimulation that triggers vasomotor symptoms in the absence of estrogen, which is also inhibitory. The investigators conducted a randomized, double-blind, placebo-controlled trial (N = 522) of 2 drug doses (30 mg and 45 mg) and placebo, each taken once daily. Participants were patients in menopause, 40 to 65 years old, with an average of at least 7 moderate-to-severe hot flashes daily. The main study period was 12 weeks in duration, followed by continuation for 40 more weeks with the same dose in the active medication groups, and randomization of the control group to the 2 active groups for an additional 40 weeks. Both doses of fezolinetant significantly reduced the frequency and severity of hot flashes compared with placebo at week 4 and week 12, with little difference between them. At week 4, frequency decreased (least squares mean vs placebo) by -1.87 (standard error [SE] 0.42; P < .001) for 30 mg dose, and -2.07 (SE 0.42; P < .001) for 45 mg. At week 12, similarly, decreases were -2.39 (SE 0.44; P < .001) and -2.55 (SE 0.43; P < .001), for 30 mg and 45 mg doses, respectively. Results for a reduction in severity of symptoms were similar. Improvements were maintained over the 40-week extension period. Adverse events were minor and not significantly different between groups. The study was not powered to detect rare serious adverse effects.