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. 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 () and is completed. 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. 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. Astellas Pharma.

中文翻译：

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Fezolinetant 用于治疗与更年期相关的中度至重度血管舒缩症状 (SKYLIGHT 1)：一项 3 期随机对照研究

神经激肽 3 受体拮抗剂是治疗更年期女性血管舒缩症状的潜在非激素疗法，因为对于那些不能或不想接受激素治疗的患者来说，选择很少。Fezolinetant 是首批开发的非激素神经激肽 3 受体拮抗剂之一，用于治疗更年期引起的血管舒缩症状。本研究调查了非唑林坦治疗与更年期相关的中度至重度血管舒缩症状的安全性和有效性。SKYLIGHT 1 是一项随机、双盲、安慰剂对照、为期 12 周的 3 期试验，其中积极治疗延长 40 周。该试验在美国、加拿大、捷克共和国、匈牙利、波兰、西班牙和英国的 97 个设施中进行。平均每天出现 7 次或以上中度至重度潮热的 40-65 岁女性被随机分配 (1:1:1) 至每日一次的完全匹配安慰剂组：fezolinetant 30 mg 或 fezolinetant 45 mg。随机化是使用基于网络的交互式响应系统完成的，研究人员、项目团队成员、临床工作人员和参与者对治疗分配情况不知情。共同主要终点是血管舒缩症状的频率和严重程度从基线到第 4 周和第 12 周的平均变化。疗效和安全性分析包括所有接受至少一剂研究药物的随机分配的参与者。本次试验已注册（）并已完成。2019年7月11日至2021年8月11日期间，招募了2205名女性，其中175名被分配到安慰剂组，176名被分配到30 mg fezolinetant，176名被分配到fezolinetant 45 mg（安慰剂组有175名，30 mg fezolinetant组有174名） ，173 名服用 45 毫克非佐林坦的患者至少接受了一剂[安全分析集]）。随机分配到 45 mg 菲佐林坦的一名参与者错误地接受了 30 mg 菲佐林坦，因此功效分析集（完整分析集）由非佐林坦 30 mg 组的 173 名受试者和非佐林坦 45 mg 组的 174 名受试者组成。安慰剂组的 23 名参与者、fezolinetant 30 mg 组的 31 名参与者和 fezolinetant 45 mg 组的 13 名参与者在第 12 周之前停止治疗，主要是由于不良事件或参与者退出。与安慰剂相比，fezolinetant 30 mg 和 fezolinetant 45 mg 显着降低第 4 周血管舒缩症状的频率（最小二乘平均值变化差异 –1·87 [SE 0·42；p<0·001]，–2·07 [SE 0·42；p<0·001]）和第 12 周（–2·39 [SE 0·44；p<0·001]、–2·55 [SE 0·43；p<0·001] ）。与安慰剂相比，非唑林坦 30 mg 和 45 mg 在第 4 周显着降低血管舒缩症状的严重程度 (–0·15 [0·06; p=0·012], –0·19 [0·06; p=0· 002]）和第 12 周（–0·24 [0·08；p=0·002]、–0·20 [0·08；p=0·007]）。1 周后观察到血管舒缩症状的频率和严重程度有所改善，并持续超过 52 周。在前 12 周内，非索林坦 30 mg 组的 174 名女性中有 65 名 (37%) 发生了治疗引起的不良事件，fezolinetant 45 mg 组的 173 名受试者中有 75 名（43%），安慰剂组的 175 名受试者中有 78 名（45%）。肝酶升高的发生率较低（安慰剂 n=1；非佐林坦 30 mg n=2；非佐林坦 45 mg n=0），这些事件通常是无症状的、短暂的，并在治疗期间或治疗停止后得到缓解。数据支持临床使用非佐林坦作为非激素治疗与更年期相关的血管舒缩症状。该研究采用安慰剂对照 12 周，随后进行 40 周盲法扩展，以评估效果的维持情况。此外，研究的人群多种多样，代表了非佐林坦治疗的潜在目标人群。进一步表征非佐林坦对生活质量（包括情绪和性健康症状）的益处值得研究。安斯泰来制药。