By Lillya T. Roldan, BA, and Maria I. Rodriguez, MD, MPH
Lillya Roldan is an MD Candidate, Oregon Health & Science University, Portland, and Dr. Rodriguez is Professor, Obstetrics & Gynecology, Division of Complex Family Planning, Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland.
SYNOPSIS: In this multinational, randomized, double blind, placebo-controlled trial, 522 women with moderate to severe menopausal vasomotor symptoms received either 45 mg of fezolinetant, 30 mg fezolinetant, or placebo. Both fezolinetant doses significantly reduced the frequency and severity of menopausal symptoms at four and 12 weeks of treatment as compared with placebo.
SOURCE: Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): A phase 3 randomised controlled study. Lancet 2023;401:1091-1102.
A new nonhormonal treatment for vasomotor symptoms of menopause, fezolinetant, recently has been approved by the Food and Drug Administration (FDA). Fezolinetant decreases vasomotor symptoms by acting on the thermoregulatory center of the brain. Neurons in the thermoregulatory center of the hypothalamus are activated by the neuropeptide neurokinin B, which acts on neurokinin 3 receptors, and are inhibited by estrogen. Declining estrogen levels during the menopausal transition lead to hypertrophy of the thermoregulatory neurons and system dysfunction. As a neurokinin 3 receptor antagonist, fezolinetant potentially could serve as a nonhormonal therapy for vasomotor symptoms. Five other neurokinin 3 antagonists previously have been studied for the treatment of vasomotor symptoms. For three of the agents, studies were discontinued as a result, in part, of concerns for hepatic safety. Fezolinetant is approximately 450-fold more selective for the human neurokinin 3 receptor than these agents. A fourth medication, elinzanetant, currently is being studied in a Phase III trial. The authors of this study sought to assess the safety and efficacy of fezolinetant as a novel, nonhormonal therapy for vasomotor symptoms.
This study, SKYLIGHT 1, is a randomized, double blind, placebo-controlled, 12-week Phase III trial with a 40-week active treatment extension. The trial took place in 97 facilities across the United States, Canada, the Czech Republic, Hungary, Poland, Spain, and the United Kingdom. Study participants were women born female, aged 40-65 years, and who were experiencing an average of seven or more moderate to severe “hot flashes” per day. Participants were randomly assigned by a web-based system (1:1:1) to once-daily placebo (175 participants), fezolinetant 30 mg (173 participants), or fezolinetant 45 mg (174 participants). All investigators, project team members, clinical staff, and participants were masked to treatment assignments, with placebo and treatment appearing identical. Participants taking fezolinetant who completed the original 12-week study were able to enter a 40-week active treatment extension period and were continued on their randomized dose. Individuals in the placebo group who chose to enter the 40-week extension period were randomized to fezolinetant 30 mg or 45 mg.
The study’s primary objective was to assess the efficacy of fezolinetant against placebo on the frequency and severity of vasomotor symptoms. As such, coprimary endpoints were the mean change in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12. Participants input data daily into an electronic diary, which captured the severity of vasomotor symptoms as a categorical variable: mild symptoms (sensation of heat without sweating); moderate symptoms (sensation of heat with sweating, able to continue activity); and severe symptoms (sensation of heat with sweating, causing cessation of activity). Validated measures were used to capture secondary study outcomes, which included sleep disturbance and overall quality of life in menopause. The Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance and the Patient Global Impression of Change in Sleep Disturbance (PGI-C SD) were used to capture sleep disturbances and quality of sleep. Participants also completed the Menopause-Specific Quality of Life (MENQOL) survey, which elicits information across four domains of menopausal symptoms: vasomotor, psychosocial, physical, and sexual.
Both fezolinetant doses were shown to significantly reduce the frequency and severity of vasomotor symptoms as compared to placebo. Among the 173 individuals assigned to the fezolinetant 30 mg group, the mean frequency of daily moderate to severe vasomotor symptoms decreased from 10.7 events daily (4.7) at baseline to 5.4 events per day at week 4 and 4.5 events per day (3.7) at week 12. This represented a mean percentage change from baseline of -48% (35.0) at week 4 and -56% (35.9) at week 12. A similar effect was seen among people in the group receiving fezolinetant 45 mg. The mean frequency of daily moderate to severe vasomotor symptoms decreased from 10.4 daily (3.9) at baseline to 5.2 daily (4.5) at week 4, and 4.1 events daily (3.9) at week 12 (mean percentage change, -51% [35.4] at week 4; -61% [32.7] at week 12). It is important to note that a strong placebo effect also was observed. People randomized to placebo experienced a 30% reduction in symptoms by week 12. Previous research has indicated that a 50% reduction in vasomotor symptoms is clinically significant; this was achieved by both doses of fezolinetant.1
For the secondary outcome of sleep disturbances, neither dose of fezolinetant resulted in significant improvements by week 12 as compared to placebo. However, the MENQOL total score and vasomotor domain independently both improved significantly at weeks 4 and 12 among individuals treated with either dose of fezolinetant as compared with placebo (P < 0.02). Overall, the medication was well tolerated with few adverse events. The most common adverse event reported was headache; there was no significant difference in occurrence among all three groups. A total of five treatment-related serious adverse events were reported, with four occurring in the treatment groups. Two individuals experienced increases in liver function and transaminase tests that resolved after treatment discontinuation. One case of paresthesia and an instance of varicose vein occurrence also were reported. No clinically relevant changes in hematology, biochemistry, coagulation, or urinalysis parameters occurred across the treatment groups.
COMMENTARY
Natural menopause is a retrospective diagnosis. It is defined as the end of menstruation, after a person has not had menses for 12 months. Menopausal transition typically occurs over several years and is characterized by menstrual irregularity and marked hormone changes. This physiologic transition can cause hot flashes (vasomotor symptoms), mood and sleep disturbances, and vaginal dryness.
Vasomotor symptoms are a common and bothersome symptom of menopause, with a prevalence of 50% to 82% among women experiencing natural menopause. Of those who reported vasomotor symptoms, a majority (87%) reported daily symptoms, with approximately 33% experiencing more than 10 “hot flashes” per day.2 The frequency and intensity of vasomotor symptoms contribute to poor sleep, mood, and concentration, and reduced overall quality of life.
For mild vasomotor symptoms, behavioral measures, such as lowering the room temperature, dressing in layers, and avoiding triggers (e.g., spicy foods), is adequate. Nonhormonal medication options include selective serotonin reuptake inhibitors, gabapentin, and selective norepinephrine reuptake inhibitors. For women with moderate or severe symptoms, the mainstay of menopausal vasomotor symptom treatment is systemic hormone therapy (HT) with estrogen alone, or in combination with progestin.2 However, many menopausal individuals are unable to take HT because of underlying medical conditions, past medical history, or they simply are unwilling to do so.3 A 2021 global cross-sectional survey of post-menopausal women determined that HT was contraindicated in one in 10 women, and, of those who were eligible, a high proportion were HT-cautious.4
This study presents the first evidence of the safety and efficacy of a novel nonhormonal agent for vasomotor symptom relief, with significant reduction in hot flashes during the first four weeks of use. The FDA now has approved fezolinetant 45 mg for use among menopausal women experiencing moderate to severe symptoms. The 45-mg dose was found to reduce the severity and frequency of vasomotor symptoms more effectively than the 30-mg dose, with comparable side effects. Clinicians should consider fezolinetant for individuals for whom hormones are contraindicated or for those who decline to use them. Insurance coverage may present a barrier to use of this new medication; Medicare does not routinely cover the costs of the medication, and without a coupon, the copay may exceed $600.
REFERENCES
- Newton KM, Carpenter JS, Guthrie KA, et al. Methods for the design of vasomotor symptom trials: The menopausal strategies: Finding lasting answers to symptoms and health network. Menopause 2014;21:45-58.
- [No authors listed]. ACOG Practice Bulletin No. 141: Management of menopausal symptoms. Obstet Gynecol 2014;123:202-216.
- Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): A phase 3 randomised controlled study. Lancet 2023;401:1091-1102.
- Nappi RE, Kroll R, Siddiqui E, et al. Global cross-sectional survey of women with vasomotor symptoms associated with menopause: Prevalence and quality of life burden. Menopause 2021;28:875-882.
In this multinational, randomized, double blind, placebo-controlled trial, 522 women with moderate to severe menopausal vasomotor symptoms received either 45 mg of fezolinetant, 30 mg fezolinetant, or placebo. Both fezolinetant doses significantly reduced the frequency and severity of menopausal symptoms at four and 12 weeks of treatment as compared with placebo.
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