Elsevier

The Lancet

Volume 401, Issue 10382, 1–7 April 2023, Pages 1091-1102
The Lancet

Articles
Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study

https://doi.org/10.1016/S0140-6736(23)00085-5Get rights and content

Summary

Background

Neurokinin 3 receptor antagonists are potential non-hormonal therapies for the treatment of vasomotor symptoms in menopausal women as options are scarce for those who cannot or do not want to take hormone therapy. Fezolinetant is one of the first non-hormonal neurokinin 3 receptor antagonists in development for the treatment of vasomotor symptoms due to menopause. This study investigated the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause.

Methods

SKYLIGHT 1 is a randomised, double-blind, placebo-controlled, 12-week, phase 3 trial with a 40-week active treatment extension. This trial was done at 97 facilities across the USA, Canada, Czech Republic, Hungary, Poland, Spain, and the UK. Women aged 40–65 years with an average of seven or more moderate-to-severe hot flashes per day were randomly assigned (1:1:1) to once-daily exact-matched placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Randomisation was done using a web-based interactive response system and investigators, project team members, clinical staff, and participants were masked to treatment assignment. Coprimary endpoints were mean change in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12. The efficacy and safety analyses comprised all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04003155) and is completed.

Findings

Between July 11, 2019, and Aug 11, 2021, 2205 women were recruited of whom 175 were assigned to placebo, 176 to fezolinetant 30 mg, and 176 to fezolinetant 45 mg (175 in the placebo group, 174 in the fezolinetant 30 mg group, and 173 in the fezolinetant 45 mg received at least one dose [safety analysis set]). One participant randomly assigned to fezolinetant 45 mg received fezolinetant 30 mg in error, so the efficacy analysis set (full analysis set) consisted of 173 in the fezolinetant 30 mg group and 174 in the fezolinetant 45 mg group. 23 participants in the placebo group, 31 in the fezolinetant 30 mg group, and 13 in the fezolinetant 45 mg group discontinued treatment before week 12, mostly due to adverse events or participant withdrawal. Compared with placebo, fezolinetant 30 mg and fezolinetant 45 mg significantly reduced the frequency of vasomotor symptoms at week 4 (difference in change in least squares mean –1·87 [SE 0·42; p<0·001], –2·07 [SE 0·42; p<0·001]) and week 12 (–2·39 [SE 0·44; p<0·001], –2·55 [SE 0·43; p<0·001]). Compared with placebo, fezolinetant 30 mg and 45 mg significantly reduced the severity of vasomotor symptoms at week 4 (–0·15 [0·06; p=0·012], –0·19 [0·06; p=0·002]) and week 12 (–0·24 [0·08; p=0·002], –0·20 [0·08; p=0·007]). Improvements in frequency and severity of vasomotor symptoms were observed after 1 week and maintained over 52 weeks. During the first 12 weeks, treatment-emergent adverse events occurred in 65 (37%) of 174 women in the fezolinetant 30 mg group, 75 (43%) of 173 in the fezolinetant 45 mg group, and 78 (45%) of 175 in the placebo group. The incidence of liver enzyme elevations was low (placebo n=1; fezolinetant 30 mg n=2; fezolinetant 45 mg n=0) and these events were generally asymptomatic, transient, and resolved while on treatment or after treatment discontinuation.

Interpretation

Data support the clinical use of fezolinetant as a non-hormonal treatment for vasomotor symptoms associated with menopause. The study was placebo-controlled for 12 weeks followed by a 40-week blinded extension to assess the maintenance of effect. Furthermore, the population studied was diverse and representative of the potential target population for fezolinetant therapy. Further characterisation of the benefit of fezolinetant on quality of life, including on symptoms of mood and sexual wellbeing, merits investigation.

Funding

Astellas Pharma.

Introduction

The burden of vasomotor symptoms characterised by hot flashes (ie, hot flushes or night sweats) in women undergoing menopausal transition is substantial, with up to 80% having vasomotor symptoms.1 Most women rate vasomotor symptoms as moderate-to-severe,2 comprising heat sensation and sweating that can cause cessation of usual activities.3 Vasomotor symptoms can begin months to years before menopause (12 months after the last menstrual period), and persist for a median of 7·4 years.4 However, a third of women continue to have moderate-to-severe vasomotor symptoms for more than 10 years.2 Vasomotor symptoms can have a substantial negative impact on quality of life, contributing to physical and psychosocial impairment that can affect work performance, social activities, and personal and social relationships.5 The negative association between vasomotor symptoms and health-related quality of life is strongest in women with frequent vasomotor symptoms,6 and the discomfort associated with vasomotor symptoms can substantially affect sleep, leading to fatigue.7, 8 Vasomotor symptoms are also associated with anxiety and depressed mood,7, 8, 9 and are independently associated with indicators of physical health risk in women, including cardiovascular disease, bone loss, and bone turnover.10, 11, 12

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.

Menopausal hormone therapy with combined oestrogen and progestogen, or oestrogen alone, is effective for symptom management. However, many women cannot or choose not to take hormone therapy.4, 13 In a 2021 global cross-sectional survey of 3460 postmenopausal women with vasomotor symptoms associated with menopause, hormone therapy was contraindicated for about one in ten women (9% from USA, 12% from Europe, and 8% from Japan; absolute numbers of women are not available). Additionally, a high proportion of women indicated they were eligible for but did not want to use hormone therapy (54% from USA, 56% from Europe, and 79% from Japan; absolute numbers are not available).13 Therefore, there is a need for safe, effective, targeted non-hormonal therapy for the relief of vasomotor symptoms associated with menopause, particularly for women who are unable or unwilling to take hormone therapy.

The thermoregulatory centre in the hypothalamus of the brain is innervated by kisspeptin–neurokinin B–dynorphin (KNDy) neurons. These neurons are stimulated by the neuropeptide neurokinin B, acting at the neurokinin 3 receptors, and inhibited by oestrogen. Declining and highly variable oestrogen concentrations during the menopausal transition alter neurokinin 3 receptor-mediated activation, resulting in hypertrophy of the KNDy neurons and dysregulation of the thermoregulatory centre. The thermoregulatory centre triggers heat dissipation effectors. Vasodilation in the skin causes heat loss, eliciting hot flashes, sweating, and chills.14, 15

Fezolinetant is a selective neurokinin 3 receptor (NK3R) antagonist that blocks binding of neurokinin B to the KNDy neurons to restore normal sensitivity of the thermoregulatory centre in the hypothalamus. Results from phase 2 fezolinetant clinical studies showed a rapid and substantial reduction in frequency and severity of vasomotor symptoms, with improvements in health-related quality of life in women undergoing menopausal transition.16, 17, 18 SKYLIGHT 1 (NCT04003155) and SKYLIGHT 2 (NCT04003142)19 are 12-week randomised, placebo-controlled trials of fezolinetant 30 mg/day and 45 mg/day followed by a 40-week active treatment extension period and safety and efficacy analysis. In this study, we focus on the safety and efficacy outcomes from SKYLIGHT 1.

Section snippets

Study design and participants

SKYLIGHT 1 was a randomised, double-blind, placebo-controlled, phase 3 study in women aged 40–65 years having an average of seven or more moderate-to-severe hot flashes per day before randomisation and seeking treatment or relief for vasomotor symptoms. All women had spontaneous amenorrhoea for at least 12 consecutive months, spontaneous amenorrhoea for at least 6 months with biochemical criteria of menopause (follicle-stimulating hormone >40 IU/L), or bilateral oophorectomy for at least 6

Results

Between July 11, 2019, and Aug 11, 2021, 2205 women were recruited and 527 were randomly assigned to treatment groups. 522 women had at least one dose of study drug and were included in the safety analysis set (175 in the placebo group, 174 in the fezolinetant 30 mg group, 173 in the fezolinetant 45 mg group; figure 1). One participant was randomly assigned to fezolinetant 45 mg but in error received fezolinetant 30 mg, meaning that the full analysis set consisted of 175 participants in the

Discussion

In this phase 3, randomised controlled trial, four coprimary efficacy endpoints were met. Fezolinetant 30 mg and 45 mg once daily significantly improved the frequency and severity of vasomotor symptoms at week 4. Fezolinetant efficacy was observed as early as week 1, with continued improvement to week 4 and a sustained benefit throughout the 12-week double-blind period. At week 12, least squares mean reduction in the frequency of vasomotor symptoms was greater than 50% in both fezolinetant

Data sharing

On request, and subject to specific criteria, conditions, and exceptions, Astellas will provide access to anonymised patient-level data from completed, Astellas-sponsored, phase 1 to 4 interventional clinical studies conducted for products and indications that have been approved in any country, and for terminated compounds. Approval must have been granted by the agencies of the main regions USA, EU, and Japan. If approval is sought in one or two regions, approval must have been granted by those

Declaration of interests

SL has received honoraria from AbbVie and research funding from AbbVie, Amgen, Aspira, Estetra, and Janssen. NS is a study investigator, member of the Scientific Advisory Board, and consultant for Astellas, a member of the Scientific Advisory Board for Amazon (Project Ember), Menogenix, and Que Oncology, a consultant for Ansh Labs, on the Program Committee for the North American Menopause Society (NAMS), past President of the Society for Reproductive Investigation, and is on the Nominating

References (30)

  • WH Utian

    Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review

    Health Qual Life Outcomes

    (2005)
  • NE Avis et al.

    Change in health-related quality of life over the menopausal transition in a multiethnic cohort of middle-aged women: Study of Women's Health Across the Nation

    Menopause

    (2009)
  • R Worsley et al.

    Moderate–severe vasomotor symptoms are associated with moderate-severe depressive symptoms

    J Womens Health (Larchmt)

    (2017)
  • CJ Crandall et al.

    Association of menopausal vasomotor symptoms with increased bone turnover during the menopausal transition

    J Bone Miner Res

    (2011)
  • RC Thurston et al.

    Menopausal vasomotor symptoms and risk of incident cardiovascular disease events in SWAN

    J Am Heart Assoc

    (2021)
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