Research in context
Evidence before this study
Women face a substantial burden of vasomotor symptoms (hot flashes, also called hot flushes or night sweats) during menopausal transition, impacting quality of life, sleep, mood, concentration, and sexual wellbeing. Vasomotor symptoms can start before menopause, continue for more than 10 years, and have been associated with a decline in physical health. Available treatments, such as menopausal hormone therapy and selective serotonin receptor antagonists, are not appropriate for all women. Therefore, an unmet need exists for effective treatment alternatives for vasomotor symptoms in menopausal women. The thermoregulatory centre in the hypothalamus is innervated by kisspeptin–neurokinin B–dynorphin (KNDy) neurons. These neurons are stimulated by the neuropeptide neurokinin B, acting at neurokinin 3 receptors, and inhibited by oestrogen. Declining oestrogen concentrations during menopausal transition alters neurokinin 3 receptor-mediated activation leading to hypertrophy of KNDy neurons and dysregulation of the thermoregulatory centre. The thermoregulatory centre triggers heat dissipation effectors. Vasodilation in the skin causes heat loss, which can trigger hot flashes, sweating, and chills. Neurokinin 3 receptor antagonists, such as fezolinetant, are therefore of interest as potential non-hormonal therapies for treatment of moderate-to-severe vasomotor symptoms associated with menopause. We searched PubMed on March 16, 2022 using the terms “neurokinin 3 receptor” and “vasomotor symptoms or hot flash or hot flush” with an English language modifier only and identified 35 studies. Of these studies, five were animal studies, 16 were review or overview articles, three were comments or editorials, two discussed genetic variation associated with menopause symptoms, and nine were phase 2 or earlier clinical studies that addressed vasomotor symptoms in menopausal women using fezolinetant, MLE4901, SJX-653, or neurokinin B infusion. Fezolinetant phase 2 data supported continued exploration of the safety and efficacy of this non-hormonal selective neurokinin 3 receptor antagonist as a potentially novel therapy for vasomotor symptoms associated with menopause.
Added value of this study
This is a phase 3 randomised study assessing the use of a non-hormonal agent that targets the neurokinin 3 receptor to manage vasomotor symptoms associated with menopause. Women receiving fezolinetant 30 mg and 45 mg once daily had a reduced frequency and severity of vasomotor symptoms over a prolonged period that translated into a clinically meaningful improvement in quality of life, as measured by a menopause-specific patient-reported outcome tool. Although hormone therapy is the standard treatment for vasomotor symptoms, many women cannot take hormone therapy due to underlying medical conditions or medical history, or make a conscious choice not to take hormone therapy. This study highlights the efficacy and safety of fezolinetant in a diverse population that is representative of those women who might require non-hormonal therapy for vasomotor symptoms associated with menopause and who have limited treatment options.
Implications of all the available evidence
Results from this study add to the available data supporting the role of neurokinin 3 receptor antagonists in the treatment of vasomotor symptoms associated with menopause. The data indicate that fezolinetant 30 mg and 45 mg once daily were efficacious and well tolerated, supporting the potential use of fezolinetant as a first-in-class non-hormonal treatment option for women having vasomotor symptoms. Additional clinical studies to further define the safety and efficacy of fezolinetant are ongoing.