Results from a phase 3 randomised controlled trial of the non-hormonal drug Fezolinetant (45mg once daily) found the treatment to be efficacious and well tolerated for moderate-severe vasomotor symptoms in women considered unsuitable candidates for hormone therapy, said the researchers.
Improvements in moderate-severe vasomotor symptoms were observed as early as week one, with sustained benefit throughout the 24-week treatment period, and no safety signals of concern, including drug induced liver injury, were observed.
Vasomotor symptoms – hot flushes and night sweats – are the most common and bothersome symptoms associated with menopause, endured by up to 80% of women during menopause.
Moderate-severe symptoms occur in 11%-46% of women over 40, with a median total duration around 7.4 years, whereas the severity of vasomotor symptoms associated with menopause varies throughout the course of menopause and among women.
Although vasomotor symptoms are common and often severe enough to warrant medical treatment, approved and effective non-hormonal treatments are limited.
Hormone therapy is effective but not appropriate for everyone. Treatment is contraindicated in women with a history of breast cancer, uterine cancer, active liver disease, or thromboembolic diseases, and caution is advised in those with comorbidities such as cardiovascular disease, diabetes and raised triglyceride levels.
Fezolinetant, an oral, non-hormonal, neurokinin 3 receptor antagonist, is a treatment option for moderate-severe vasomotor symptoms, approved in many countries, at a dose of 45mg once daily.
Fezolinetant blocks neurokinin B signalling, normalising kisspeptin, neurokinin B, and dynorphin neuron activity in the thermoregulatory centre of the brain to reduce the frequency and severity of vasomotor symptoms.
Well tolerated
The drug was shown to be efficacious and well tolerated for treating moderate-severe vasomotor symptoms associated with menopause in phase 3 studies SKYLIGHT 1 and SKYLIGHT 2, which both included a 12-week placebo control period followed by active treatment extension to 52 weeks.
To further investigate the clinical benefits of fezolinetant for the treatment of moderate-severe vasomotor symptoms, a phase 3b trial (DAYLIGHT) was conducted, which included a 24 week placebo control period and enrolled a population considered unsuitable for hormone therapy.
Individuals aged 40-65 with moderate-severe vasomotor symptoms associated with menopause and considered unsuitable candidates for hormone therapy were randomised 1:1 using interactive response technology to fezolinetant 45 mg or placebo once daily and stratified by smoking status (current and non-smoker (former or never).
Categories for hormone unsuitability were defined based on contraindicated; caution (based on medical history); stoppers (previous discontinuation of hormone therapy owing to lack of efficacy, side effects, or medical advice); or averse (informed choice not to use hormone therapy after discussion with a clinician).
Global
The study, published in The BMJ, was conducted between 8 November 2021 and 20 April 2023 at 69 centres in 16 countries. Overall, the centres randomised 453 participants (fezolinetant n=227, placebo n=226), with 370 (81.7%) completing the study (195 and 175, respectively).
The safety analysis and full analysis sets, defined as all participants who were randomised and received at least one dose of study drug, comprised 452 participants (fezolinetant n=226, placebo n=226), as one participant randomised to the fezolinetant group did not receive study drug. Of these, 387 (85.6%) participants completed the 24-week treatment period.
Eighty two (18.1%) participants discontinued treatment owing to adverse events (n=25, 5.5%), loss to follow-up (n=5, 1.1%), protocol deviation (n=2, 0.4%), withdrawal from study (n=47, 10.4%), and other reasons (n=3, 0.7%). Of the 47 (10%) participants who withdrew from treatment, 17 (8%) were assigned to fezolinetant and 30 (13%) to placebo.
All five participants lost to follow-up were in the placebo group; one participant completed treatment with the last dose in week 24 but did not return for the safety follow-up, and the other four participants discontinued early but no reason was provided. Mean (SD) age was 54.5 (4.7) years, and most of the participants were white (n=435, 96.7%).
Most participants were categorised as either hormone therapy averse (n=168, 37.2%) or caution (n=165, 36.5%); the remainder were contraindicated (n=50, 11.1%) or stoppers (n=69, 15.3%). Mean (SD) overall drug use was 150.8 (44.6) days. Baseline personal characteristics were generally similar between the two treatment groups.
Comparison with other studies
Improvements in frequency of moderate-severe vasomotor symptoms in the fezolinetant group compared with placebo were observed as early as day 1, consistent with efficacy results in phase 3 studies SKYLIGHT 1 and SKYLIGHT 2.
The available safety data appeared generally consistent with the known safety profile for fezolinetant, including data from phase 3 placebo controlled trials showing that fezolinetant is well tolerated for as much as 52 weeks.
The incidence of serious TEAEs from baseline to week 24 was low. No safety signals of concern were observed, including liver safety, in the fezolinetant group, and no drug induced liver injury was observed in any study participants.
Some participants experienced an increase in transaminase levels, which overall were not serious, and asymptomatic liver test abnormalities, captured through protocol specified routine testing.
Three participants in the fezolinetant group had raised ALT levels three times the ULN; none of them was accompanied by bilirubin levels twice the ULN. The liver safety monitoring panel concluded that a causal association was possible in one participant and unlikely in the other two participants.
Strengths, weaknesses of study
The findings add to a large body of data showing a positive benefit-risk profile for fezolinetant and the potential of this drug to address an important unmet need for individuals with moderate-severe vasomotor symptoms associated with menopause.
The study included a longer placebo control period (24 weeks) than previous phase 3 studies, and a large defined patient population unsuitable for current hormone therapy (ie, hormone therapy contraindicated, caution, stoppers, and averse). A potential limitation of this study was that participants were from 16 countries, with most self-identifying as white. Further studies of fezolinetant in global populations with diverse ethnicity or races would be of interest.
Findings
The study support the utility of fezolinetant as an effective non-hormonal treatment option for individuals who cannot or choose not to use hormone therapy for the management of moderate-severe vasomotor symptoms associated with menopause.
Study details
Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial
Katrin Schaudig, Xuegong Wang, Céline Bouchard et al.
Published in The BMJ on 18 November 2024
Abstract
Objectives
To assess the efficacy and safety of the non-hormonal, neurokinin 3 receptor antagonist, fezolinetant, to treat moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy.
Design
Phase 3b randomised controlled trial.
Setting
16 countries.
Participants
453 individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause who were considered unsuitable candidates for hormone therapy (contraindicated, caution (based on medical history), stoppers (previous discontinuation of hormone therapy), or averse (informed choice not to use hormone therapy)) were randomised to receive fezolinetant (n=227) or placebo (n=226).
Intervention
Fezolinetant 45 mg or placebo once daily for 24 weeks.
Main outcome measures
The primary endpoint was mean change in daily frequency of moderate-severe vasomotor symptoms from baseline to week 24. Secondary endpoints were mean change in symptom severity, sleep disturbance using the Patient-Reported Outcome Measurement Information System Sleep Disturbance Short Form (PROMIS SD-SF) 8b total score, and safety.
Results
370 (81.7%) participants completed the study (fezolinetant=195, placebo group=175). The safety and full analysis sets comprised 452 participants who received at least one dose of study drug. Mean age was 54.5 (standard deviation 4.7) years and most of the participants (435 (96.7%) were white and categorised as either hormone therapy averse (168 (37.2%)) or caution (165 (36.5%)). At week 24, fezolinetant significantly reduced the frequency (least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001) and severity of vasomotor symptoms (–0.39, –0.57 to –0.21; P<0.001). At week 24, the fezolinetant group had a greater reduction in sleep disturbance (PROMIS SD-SF 8b total score) compared with placebo (–2.5, –3.9 to –1.1; P<0.001). Improvements over placebo were observed as early as week 1. Both groups showed similar incidences of treatment emergent adverse events (TEAEs, 147 (65.0%) in the fezolinetant group, 138 (61.1%) in the placebo group) and serious TEAEs (10 (4.4%) and 8 (3.5%), respectively). The most common TEAEs in the fezolinetant group were covid-19 (30 (13.3%)), headache (20 (8.8%)), and fatigue (13 (5.8%)).
Conclusions
Fezolinetant was efficacious and well tolerated over a six month period for treating moderate-severe vasomotor symptoms in individuals considered unsuitable for hormone therapy. These results highlight the utility of fezolinetant as an effective treatment option for those who have contraindications to or choose not to use hormone therapy.
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