A Phase 3, Randomized, Placebo-controlled, Double-blind Study to Investigate the Long Term Safety of Fezolinetant in Japanese Women Suffering From Vasomotor Symptoms (Hot Flashes) Associated With Menopause

Hot flashes are the most common reason women going through menopause seek medical attention. Hormone replacement therapy, or HRT, is most often prescribed to treat hot flashes. However, HRT can't be used by all women or for as long as may be needed.
Researchers want to find other ways to treat hot flashes. Fezolinetant is a medicine to treat hot flashes in women going through menopause. Fezolinetant is an approved medicine in the US. Further studies are needed before it is available in other regions such as Asia.
In this study fezolinetant will be used to treat hot flashes in Japanese women going through menopause. This study will confirm the safety of fezolinetant and how well the women tolerate the treatment.
Women will either take fezolinetant or a placebo. This is decided by chance alone. The placebo looks like fezolinetant but will not have any medicine in it.
The women will take 1 tablet of the study medicine (fezolinetant or the placebo) once a day for up to 52 weeks.
During the study, the women will visit their study clinic for a check-up about every 4 weeks for up to 52 weeks (1 year). At each visit they will be asked if they had any medical problems. Other checks will include a medical examination and vital signs (temperature, blood pressure and pulse). At some visits, the women will have an ECG to check their heart rhythm and some blood and urine samples will be taken for laboratory tests. During a couple of visits, women who have a womb (uterus) will also have a test called a transvaginal ultrasound. A probe is gently placed inside the vagina. Sound waves will create a picture of the organs in the pelvis. This will allow the study doctor to look more closely at the uterus and surrounding organs.
The last clinic visit will be 3 weeks after the women take their final tablet of the study medicine (fezolinetant or the placebo).

开始日期2024-02-22

申办/合作机构

Astellas Pharma, Inc.

NCT06206408 / Recruiting临床3期

A Phase 3, Randomized, Placebo-controlled, Double-blind Study to Assess the Efficacy and Safety of Fezolinetant in Japanese Women Experiencing Vasomotor Symptoms (Hot Flashes) Associated With Menopause

Hot flashes are the most common reason women going through menopause seek medical attention. Hormone replacement therapy, or HRT, is most often prescribed to treat hot flashes. However, HRT can't be used by all women or for as long as may be needed.
Researchers want to find other ways to treat hot flashes. Fezolinetant is a medicine to treat hot flashes in women going through menopause. Fezolinetant is an approved medicine in the US. Further studies are needed before it is available in other regions such as Asia.
This study will confirm if fezolintant helps reduce the number of hot flashes in Japanese women going through menopause.
Women that want to take part in the study will be given an electronic handheld device with an app to track their hot flashes. Some women may be able to use the app on their own smartphone. Before the women are assigned a treatment, they will record information about their hot flashes.
Women will either take a lower or higher dose of fezolinetant, or a placebo. This is decided by chance alone. The placebo looks like fezolinetant but will not have any medicine in it.
The women will take 2 tablets of the study medicine (lower or higher dose of fezolinetant, or the placebo) once a day for up to 12 weeks. They will either take 1 tablet of fezolinetant (higher or lower dose) and 1 placebo tablet, or they will take 2 placebo tablets. The women will continue to record information about their hot flashes on the electronic device or their smartphone.
During the study, the women will visit the study clinic a few times. At each visit they will be asked if they had any medical problems and will use an electronic device at the clinic to answer questions about how the hot flashes affect their daily life. Other checks will include a medical examination, vital signs (temperature, blood pressure and pulse). Some blood and urine samples will be taken for laboratory tests. At some visits, the women will also have an ECG to check their heart rhythm. Women who have a womb (uterus) will also have a test called a transvaginal ultrasound. A probe is gently placed inside the vagina. Sound waves will create a picture of the organs in the pelvis. This will allow the study doctor to look more closely at the uterus and surrounding organs.
The last clinic visit will be 3 weeks after the women take their final tablets of the study medicine (1 tablet of lower or higher dose of fezolinetant and 1 placebo tablet, or 2 placebo tablets).

开始日期2024-02-16

申办/合作机构

Astellas Pharma, Inc.

NCT06049797 / RecruitingN/A

A Phase IV, Longitudinal, Observational Study Examining Real-World Outcomes of Non-Hormonal Pharmacotherapies Among Individuals Treated for Bothersome Vasomotor Symptoms

Hot flashes and night sweats (also known as vasomotor symptoms or VMS) are the most common symptoms which bother women in menopause. This study will follow women going through menopause who have hot flashes and night sweats that cause them bother. They will be starting a non-hormonal therapy prescribed by their healthcare provider (HCP) to treat these symptoms. The women will visit their HCP's office, research center, or both. They will receive prescriptions for the non-hormonal therapy from their HCP for up to 1 year. This real-world study will provide information on outcomes from various non-hormonal therapies. The study sponsor (Astellas) will not decide which therapy the women receive. However, the sponsor will provide instructions on when the women visit their clinic, and what is recorded during the study. Some of the visits will be in-person, but most will be virtual. The virtual visits can be carried out at home using a smartphone, tablet or computer. The main aim of the study is to check if the hot flashes and night sweats that bother women change after 12 weeks (3 months) of treatment. The study will also check the women's sleep patterns, their productivity at work, and their general well-being before and after starting treatment. The overall safety of the non-hormonal therapies will also be examined.

开始日期2023-11-15

申办/合作机构

Astellas Pharma Global Development, Inc.

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项与非唑奈坦相关的文献（医药）

2024-01-01·Menopause

Systematic review and network meta-analysis comparing the efficacy of fezolinetant with hormone and nonhormone therapies for treatment of vasomotor symptoms due to menopause

Review

作者: Kagan, Risa ; Siddiqui, Emad ; Gao, Emily ; Ajmera, Mayank ; Zhao, Angela ; Morga, Antonia ; Patterson-Lomba, Oscar ; Mancuso, Shayna

Abstract:

Importance:

The neurokinin 3 receptor antagonist fezolinetant 45 mg/d significantly reduced frequency/severity of moderate to severe vasomotor symptoms (VMS) of menopause compared with placebo in two phase 3 randomized controlled trials. Its efficacy relative to available therapies is unknown.

Objective:

We conducted a systematic review and Bayesian network meta-analysis to compare efficacy with fezolinetant 45 mg and hormone therapy (HT) and non-HT for VMS in postmenopausal women.

Evidence Review:

Using OvidSP, we systematically searched multiple databases for phase 3 or 4 randomized controlled trials in postmenopausal women with ≥7 moderate to severe VMS per day or ≥50 VMS per week published/presented in English through June 25, 2021. Mean change in frequency and severity of moderate to severe VMS from baseline to week 12 and proportion of women with ≥75% reduction in VMS frequency at week 12 were assessed using fixed-effect models.

Findings:

The network meta-analysis included data from the pooled phase 3 fezolinetant trials plus 23 comparator publications across the outcomes analyzed (frequency, 19 [34 regimens]; severity, 6 [7 regimens]; ≥75% response, 9 [15 regimens]). Changes in VMS frequency did not differ significantly between fezolinetant 45 mg and any of the 27 HT regimens studied. Fezolinetant 45 mg reduced the frequency of moderate to severe VMS events per day significantly more than all non-HTs evaluated: paroxetine 7.5 mg (mean difference [95% credible interval {CrI}], 1.66 [0.63-2.71]), desvenlafaxine 50 to 200 mg (mean differences [95% CrI], 1.12 [0.10-2.13] to 2.16 [0.90-3.40]), and gabapentin ER 1800 mg (mean difference [95% CrI], 1.63 [0.48-2.81]), and significantly more than placebo (mean difference, 2.78 [95% CrI], 1.93-3.62]). Tibolone 2.5 mg (the only HT regimen evaluable for severity) significantly reduced VMS severity compared with fezolinetant 45 mg. Fezolinetant 45 mg significantly reduced VMS severity compared with desvenlafaxine 50 mg and placebo and did not differ significantly from higher desvenlafaxine doses or gabapentin ER 1800 mg. For ≥75% responder rates, fezolinetant 45 mg was less effective than tibolone 2.5 mg (not available in the United States) and conjugated estrogens 0.625 mg/bazedoxifene 20 mg (available only as 0.45 mg/20 mg in the United States), did not differ significantly from other non-HT regimens studied and was superior to desvenlafaxine 50 mg and placebo.

Conclusions:

The only HT regimens that showed significantly greater efficacy than fezolinetant 45 mg on any of the outcomes analyzed are not available in the United States. Fezolinetant 45 mg once daily was statistically significantly more effective than other non-HTs in reducing the frequency of moderate to severe VMS.

Relevance:

These findings may inform decision making with regard to the individualized management of bothersome VMS due to menopause.

2023-12-15·Medicine

Efficacy and safety of fezolinetant, a neurokinin-3 antagonist, in treating vasomotor symptoms in postmenopausal women: A systematic review and meta-analysis

Review

作者: Jaffar, Huda ; Bhattarai, Pratik ; Rahman, Ummi Aiman ; Hasanain, Muhammad ; Kashif, Talha Bin ; Rana, Maham ; Usman, Muhammad ; Cheema, Huzaifa Ahmad ; Anjum, Muhammad Umair

Background::

Menopause causes a variety of symptoms such as hot flashes and night sweats. While menopausal hormonal therapy has been used for managing postmenopausal vasomotor symptoms (VMS) for quite a while, it has a considerably poor safety profile.

Objective::

To review and analyze existing data to evaluate the efficacy of the neurokinin-3 antagonist, fezolinetant, in treating postmenopausal VMS and to assess its safety profile.

Methods::

A thorough literature search was performed on PubMed, Cochrane Library, and Google Scholar in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020, to find publications on the efficacy of fezolinetant for postmenopausal VMS. Changes in the frequency and severity scores of moderate/severe VMS and changes in the Hot Flash-Related Daily Interference Scale (HFRDIS), Greene Climacteric Scale (GCS), and Menopause-Specific Quality of Life (MENQoL) were the efficacy outcomes. Adverse events, drug-related treatment-emergent adverse effects (TEAEs), drug-related dropouts, hepatotoxicity, endometrial hyperplasia or tumor, and uterine bleeding were all safety outcomes. We used Review Manager 5.4 for pooling risk ratios (RRs) and mean differences (MDs) for dichotomous and continuous outcomes, respectively. A P value of < .05 was considered significant.

Results::

There was a significant reduction in mean daily VMS frequency at weeks 4 and 12 (MD, −2.36; 95% confidence interval [CI], −2.85 to −1.87; P < .00001, for week 12) and also a significant decrease in VMS severity scores in the treatment group. Furthermore, improvements in MENQoL, HFRDIS, and GCS scores were observed. There was no significant difference in adverse events while drug-related TEAEs (RR, 1.21; 95% CI, 0.90–1.63; P = .21) showed a slight increase with fezolinetant. Drug-related dropouts were again similar across the 2 groups. Uterine bleeding had a lower incidence while endometrial events and hepatotoxicity showed a statistically insignificant, increasing trend in the fezolinetant group.

Discussion and implications::

Fezolinetant can be a treatment option for postmenopausal VMS but warns of a risk increase in endometrial hyperplasia or tumors. The heterogeneity in the data being analyzed, short follow-up period, and small sample size in most of the included randomized controlled trials were the greatest limitations, which must be considered in further research and safety profile exploration.

2023-12-01·Journal of Pharmacy Technology

Fezolinetant: A New Nonhormonal Treatment for Vasomotor Symptoms

Review

作者: Onge, Erin St. ; Phillips, Bradley ; Miller, Lisa

Objective: To review the safety, efficacy, and tolerability of fezolinetant for the treatment of vasomotor symptoms associated with menopause. Data Sources: A literature search was conducted through PubMed using the following search terms: fezolinetant, ES259564, SKYLIGHT, vasomotor symptoms, and menopause. Study Selection and Data Extraction: Selected articles included those which described clinical studies of the pharmacology, pharmacokinetics, efficacy, safety, or tolerability of fezolinetant. Data Synthesis: Fezolinetant works by inhibiting neurokinin B from binding to its receptor in the hypothalamus, thereby decreasing the occurrence of vasomotor symptoms. Clinical trials have demonstrated fezolinetant is superior to placebo in decreasing the frequency and severity of vasomotor symptoms. Common adverse effects associated with the use of fezolinetant include headache and gastrointestinal disturbances, as well as elevations in liver transaminase levels. Conclusions: Clinical practice guidelines for the treatment of vasomotor symptoms associated with menopause recommend hormone therapy as the most effective treatment option. Risks associated with hormone use may limit the use of this option in some patients. Neurokinin B inhibitors, like fezolinetant, target the physiologic cause of vasomotor symptoms. With the approval of fezolinetant, as well as elinzanetant which is currently in phase 3 clinical trials, providers and patients have additional nonhormonal treatment options for vasomotor symptoms associated with menopause.

132

项与非唑奈坦相关的新闻（医药）

2024-04-15

·医药观澜

《自然》子刊揭示2023年获批创新靶点药物，这类药物占比最多！

▎药明康德内容团队编辑在2023年，共有49种创新药物（不含疫苗和基因疗法）在美国、欧盟、日本等国家和地区获得批准上市。近期，《自然》子刊Nature Reviews Drug Discovery发表了一篇文章，详细介绍了其中12种创新靶点以及相应的9种药物，这些靶点之前未在批准药物中使用过。值得注意的是，在这9种药物中，小分子药物占据了5种，超过半数；抗体药物有2种；反义寡核苷酸和siRNA药物各占1种。这表明小分子药物的开发创新依然在持续进步。本文还将结合公开资料，探讨这些药物的特点及其采用的创新机制。▲2023年获批药物中，9款具有创新靶点的药物（图片来源：药明康德内容团队根据参考资料[1]制表）药物：fezolinetant（商品名：Veozah）研发机构：安斯泰来（Astellas Pharma）靶点：神经激肽3受体（NK3R）适应症：更年期引起的血管舒缩症状▲Fezolinetant的结构式（图片来源：PubChem）Fezolinetant是一种神经激肽3受体拮抗剂，神经激肽3受体参与大脑调节体温的机制。Fezolinetant不是一种激素，而是靶向引起更年期潮热的神经活动。FDA曾授予fezolinetant优先审评资格，2023年5月，美国FDA批准fezolinetant上市，用于治疗由更年期引起的中度至重度血管舒缩症状。根据新闻稿，fezolinetant是首款获得FDA批准用以治疗此类患者的非激素类NK3R拮抗剂。药物：iptacopan（商品名：Fabhalta）研发机构：诺华（Novartis）靶点：补体因子B（CFB）适应症：成人阵发性夜间血红蛋白尿症（PNH）▲Iptacopan的结构式（图片来源：PubChem）Iptacopan是一种针对补体因子B的抑制剂，补体因子B在免疫系统的替代补体途径中起作用，全面控制血管内外的红细胞（RBC）破坏。Iptacopan可能在治疗多种替代通路功能异常导致的疾病的同时，不影响其它补体通路介导的对微生物入侵的免疫反应，降低患者受到感染的风险。美国FDA在2023年12月批准Iptacopan上市，用于治疗成人阵发性夜间血红蛋白尿症。新闻稿指出，该疗法是治疗PNH的首个口服单药疗法。药物：nirogacestat（商品名：Ogsiveo）研发机构：SpringWorks Therapeutics靶点：γ-分泌酶（PSEN1与PSEN2)适应症：硬纤维瘤▲Nirogacestat的结构式（图片来源：PubChem）Nirogacestat是一款口服特异性γ-分泌酶小分子抑制剂，γ-分泌酶能够切割多种跨膜蛋白复合体（其中包括Notch蛋白），防止其通过蛋白酶解活化。而Notch蛋白被认为能够激活导致硬纤维瘤生长的信号通路。美国FDA在2023年11月批准nirogacestat片剂用于需要全身治疗的进展性硬纤维瘤成人患者。根据FDA新闻稿，nirogacestat是首个被批准用于治疗硬纤维瘤患者的药物，硬纤维瘤是一种罕见的软组织肉瘤亚型。药物：capivasertib（商品名：Truqap）研发机构：阿斯利康（AstraZeneca）靶点：RAC-丝氨酸/苏氨酸蛋白激酶1、2和3（AKT1、AKT2和AKT3）适应症：乳腺癌▲Capivasertib的结构式（图片来源：PubChem）Capivasertib是一款具选择性、靶向3种AKT激酶异形体（AKT1/2/3）的腺苷三磷酸（ATP）竞争性抑制剂，具有潜力治疗携带PI3K/AKT/PTEN信号通路变异的肿瘤。在临床试验中，在氟维司群的基础上联合capivasertib能显著改善内分泌疗法芳香化酶抑制剂（AI）治疗（联合或不联合CDK4/6抑制剂）后疾病进展的HR阳性/HER2阴性（HR+/HER2-）晚期乳腺癌患者的无进展生存期（PFS）。此药品在2023年1月获FDA授予快速通道资格，随后在2023年11月17日获得FDA批准上市，与氟维司群联合使用，治疗HR阳性、HER2阴性的晚期或转移性乳腺癌成年患者。这些患者通过FDA认可的检测显示携带一个或多个PIK3CA/AKT1/PTEN变异，并且在完成辅助治疗后12个月内疾病复发，或者转移性疾病经历过至少一种内分泌治疗方案后出现进展。药物：momelotinib（商品名：Ojjaara）研发机构：GSK靶点：激活素A受体I型（ACVR1），亦同时靶向JAK1/JAK2与突变体JAK2 V617F适应症：骨髓纤维化▲Momelotinib的结构式（图片来源：PubChem）Momelotinib是一种小分子抑制剂，具有独特的作用机制，可抑制三条关键信号通路：ACVR1、JAK1和JAK2。抑制JAK1和JAK2可改善体征和脾肿大，这是骨髓纤维化的临床特征之一。此外，抑制ACVR1会导致循环中的铁调素减少，从而改善贫血症状。2023年9月，momelotinib被批准用于治疗中度或高风险骨髓纤维化，包括原发性骨髓纤维化或继发性骨髓纤维化（真性红细胞增多症后和原发性血小板增多症后）成人贫血患者。它是第四种被批准用于治疗骨髓纤维化的JAK1/2抑制剂，也是第一种同时可抑制ACVR1的JAK1/2抑制剂，可促进红细胞生成以改善贫血。药物：talquetamab（商品名：Talvey）研发机构：强生（Johnson & Johnson）靶点：G蛋白偶联受体家族C组5成员D（GPRC5D）和CD3适应症：多发性骨髓瘤Talquetamab是一种“first-in-class”双特异性T细胞结合抗体，可结合T细胞表面表达的CD3受体和GPRC5D，促进T细胞介导的癌细胞杀伤。GPRC5D是一种新型多发性骨髓瘤靶标，在多发性骨髓瘤细胞和非恶性浆细胞以及一些健康组织如皮肤和舌上皮细胞表面高度表达。2021年5月和2021年8月，Talvey分别被美国FDA和欧盟委员会授予治疗多发性骨髓瘤的孤儿药资格。Talvey也于2022年6月获得美国FDA授予的突破性疗法认定，用于既往接受过至少4线治疗（包括蛋白酶体抑制剂、免疫调节剂和抗CD38抗体）的复发性或难治性多发性骨髓瘤成人患者的治疗，并于2023年8月获美国FDA加速批准用于治疗该适应症。药物：Concizumab（商品名：Alhemo）研发机构：诺和诺德（Novo Nordisk）靶点：组织因子途径抑制物（TFPI）适应症：血友病A和血友病BConcizumab是一款靶向TFPI的单克隆抗体，通过与TFPI的Kunitz-2结构域结合，阻止TFPI与活化的凝血因子X结合从而防止凝血因子X的活性被抑制。TFPI是体内一种阻止血液凝集的蛋白，借由靶向TFPI，concizumab协助抗凝血酶的生产，进而促进血液凝集并避免出血。之前所公布的explorer7临床3期试验数据显示，试验达成主要目标，即接受concizumab预防性疗法的血友病患者需治疗的自发与创伤型出血降低86%。2023年2月，日本监管机构批准了concizumab的上市申请，用于治疗血友病A和血友病B。药物：tofersen（商品名：Qalsody）研发机构：渤健（Biogen），Ionis Pharmaceuticals靶点：超氧化物歧化酶1（SOD1）适应症：SOD1突变的肌萎缩侧索硬化症（SOD1-ALS）肌萎缩侧索硬化（ALS）是一种进行性神经退行性疾病，影响大脑和脊髓中的神经细胞，许多基因被认为与此疾病有关，其中SOD1-ALS患者约占了2%。这些患者中大部分疾病进展迅速，发病后甚至无法活过1年。Tofersen是一种反义寡核苷酸药物，它可以与编码SOD1蛋白的mRNA结合，造成其被核糖核酸酶RNase-H降解，进而减少突变的SOD1蛋白生成。2023年4月，tofersen被FDA批准用于治疗SOD1突变的ALS患者。这是FDA批准治疗遗传性ALS的首款疗法。这也是首款基于生物标志物加速批准的ALS疗法。药物：nedosiran（商品名：Rivfloza）研发机构：诺和诺德靶点：乳酸脱氢酶A（LDHA）适应症：1型原发性高草酸尿症（PH1）Nedosiran是一种每月一次、皮下注射的RNAi疗法。可通过与表达LDHA的mRNA结合来抑制该蛋白表达。LDHA是导致草酸盐过度生成的关键代谢酶，降低LDHA的水平可以有效阻止草酸盐的产生，进而缓解肾脏相关症状。Nedosiran最初由Dicerna Pharmaceuticals开发，诺和诺德于2021年收购该公司并获得该疗法权益。2023年10月，Nedosiran获得了FDA的批准，用于降低9岁及以上儿童和成人PH1患者的尿草酸水平，这些患者的肾功能相对良好。根据新闻稿，Rivfloza是诺和诺德所开发的首款获批RNAi疗法。以上9种在去年获批的药物引入了创新靶点，这一突破不仅体现了医药行业在追求创新和知识拓展方面的不懈努力，也为现有治疗方法的扩充做出了贡献。回顾这些创新成果，医药行业应继续保持对研发的持续投入和探索，以期满足更多尚未得到解决的医疗需求，进而根本性地改变疾病治疗的面貌。本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转发授权请在「药明康德」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

上市批准优先审批siRNA寡核苷酸核酸药物

2024-04-12

·药明康德

小分子疗法占过半！《自然》子刊揭2023年获批创新靶点药物

▎药明康德内容团队编辑在2023年，共有49种创新药物（不含疫苗和基因疗法）在美国、欧盟、日本等国家和地区获得批准上市。近期，《自然》子刊Nature Reviews Drug Discovery发表了一篇文章，详细介绍了其中12种创新靶点以及相应的9种药物，这些靶点之前未在批准药物中使用过。值得注意的是，在这9种药物中，小分子药物占据了5种，超过半数；抗体药物有2种；反义寡核苷酸和siRNA药物各占1种。这表明小分子药物的开发创新依然在持续进步。本文还将结合公开资料，探讨这些药物的特点及其采用的创新机制。▲2023年获批药物中，9款具有创新靶点的药物（图片来源：药明康德内容团队根据参考资料[1]制表）药物：fezolinetant（商品名：Veozah）研发机构：安斯泰来（Astellas Pharma）靶点：神经激肽3受体（NK3R）适应症：更年期引起的血管舒缩症状▲Fezolinetant的结构式（图片来源：PubChem）Fezolinetant是一种神经激肽3受体拮抗剂，神经激肽3受体参与大脑调节体温的机制。Fezolinetant不是一种激素，而是靶向引起更年期潮热的神经活动。FDA曾授予fezolinetant优先审评资格，2023年5月，美国FDA批准fezolinetant上市，用于治疗由更年期引起的中度至重度血管舒缩症状。根据新闻稿，fezolinetant是首款获得FDA批准用以治疗此类患者的非激素类NK3R拮抗剂。药物：iptacopan（商品名：Fabhalta）研发机构：诺华（Novartis）靶点：补体因子B（CFB）适应症：成人阵发性夜间血红蛋白尿症（PNH）▲Iptacopan的结构式（图片来源：PubChem）Iptacopan是一种针对补体因子B的抑制剂，补体因子B在免疫系统的替代补体途径中起作用，全面控制血管内外的红细胞（RBC）破坏。Iptacopan可能在治疗多种替代通路功能异常导致的疾病的同时，不影响其它补体通路介导的对微生物入侵的免疫反应，降低患者受到感染的风险。美国FDA在2023年12月批准Iptacopan上市，用于治疗成人阵发性夜间血红蛋白尿症。新闻稿指出，该疗法是治疗PNH的首个口服单药疗法。药物：nirogacestat（商品名：Ogsiveo）研发机构：SpringWorks Therapeutics靶点：γ-分泌酶（PSEN1与PSEN2)适应症：硬纤维瘤▲Nirogacestat的结构式（图片来源：PubChem）Nirogacestat是一款口服特异性γ-分泌酶小分子抑制剂，γ-分泌酶能够切割多种跨膜蛋白复合体（其中包括Notch蛋白），防止其通过蛋白酶解活化。而Notch蛋白被认为能够激活导致硬纤维瘤生长的信号通路。美国FDA在2023年11月批准nirogacestat片剂用于需要全身治疗的进展性硬纤维瘤成人患者。根据FDA新闻稿，nirogacestat是首个被批准用于治疗硬纤维瘤患者的药物，硬纤维瘤是一种罕见的软组织肉瘤亚型。药物：capivasertib（商品名：Truqap）研发机构：阿斯利康（AstraZeneca）靶点：RAC-丝氨酸/苏氨酸蛋白激酶1、2和3（AKT1、AKT2和AKT3）适应症：乳腺癌▲Capivasertib的结构式（图片来源：PubChem）Capivasertib是一款具选择性、靶向3种AKT激酶异形体（AKT1/2/3）的腺苷三磷酸（ATP）竞争性抑制剂，具有潜力治疗携带PI3K/AKT/PTEN信号通路变异的肿瘤。在临床试验中，在氟维司群的基础上联合capivasertib能显著改善内分泌疗法芳香化酶抑制剂（AI）治疗（联合或不联合CDK4/6抑制剂）后疾病进展的HR阳性/HER2阴性（HR+/HER2-）晚期乳腺癌患者的无进展生存期（PFS）。此药品在2023年1月获FDA授予快速通道资格，随后在2023年11月17日获得FDA批准上市，与氟维司群联合使用，治疗HR阳性、HER2阴性的晚期或转移性乳腺癌成年患者。这些患者通过FDA认可的检测显示携带一个或多个PIK3CA/AKT1/PTEN变异，并且在完成辅助治疗后12个月内疾病复发，或者转移性疾病经历过至少一种内分泌治疗方案后出现进展。药物：momelotinib（商品名：Ojjaara）研发机构：GSK靶点：激活素A受体I型（ACVR1），亦同时靶向JAK1/JAK2与突变体JAK2 V617F适应症：骨髓纤维化▲Momelotinib的结构式（图片来源：PubChem）Momelotinib是一种小分子抑制剂，具有独特的作用机制，可抑制三条关键信号通路：ACVR1、JAK1和JAK2。抑制JAK1和JAK2可改善体征和脾肿大，这是骨髓纤维化的临床特征之一。此外，抑制ACVR1会导致循环中的铁调素减少，从而改善贫血症状。2023年9月，momelotinib被批准用于治疗中度或高风险骨髓纤维化，包括原发性骨髓纤维化或继发性骨髓纤维化（真性红细胞增多症后和原发性血小板增多症后）成人贫血患者。它是第四种被批准用于治疗骨髓纤维化的JAK1/2抑制剂，也是第一种同时可抑制ACVR1的JAK1/2抑制剂，可促进红细胞生成以改善贫血。药物：talquetamab（商品名：Talvey）研发机构：强生（Johnson & Johnson）靶点：G蛋白偶联受体家族C组5成员D（GPRC5D）和CD3适应症：多发性骨髓瘤Talquetamab是一种“first-in-class”双特异性T细胞结合抗体，可结合T细胞表面表达的CD3受体和GPRC5D，促进T细胞介导的癌细胞杀伤。GPRC5D是一种新型多发性骨髓瘤靶标，在多发性骨髓瘤细胞和非恶性浆细胞以及一些健康组织如皮肤和舌上皮细胞表面高度表达。2021年5月和2021年8月，Talvey分别被美国FDA和欧盟委员会授予治疗多发性骨髓瘤的孤儿药资格。Talvey也于2022年6月获得美国FDA授予的突破性疗法认定，用于既往接受过至少4线治疗（包括蛋白酶体抑制剂、免疫调节剂和抗CD38抗体）的复发性或难治性多发性骨髓瘤成人患者的治疗，并于2023年8月获美国FDA加速批准用于治疗该适应症。药物：Concizumab（商品名：Alhemo）研发机构：诺和诺德（Novo Nordisk）靶点：组织因子途径抑制物（TFPI）适应症：血友病A和血友病BConcizumab是一款靶向TFPI的单克隆抗体，通过与TFPI的Kunitz-2结构域结合，阻止TFPI与活化的凝血因子X结合从而防止凝血因子X的活性被抑制。TFPI是体内一种阻止血液凝集的蛋白，借由靶向TFPI，concizumab协助抗凝血酶的生产，进而促进血液凝集并避免出血。之前所公布的explorer7临床3期试验数据显示，试验达成主要目标，即接受concizumab预防性疗法的血友病患者需治疗的自发与创伤型出血降低86%。2023年2月，日本监管机构批准了concizumab的上市申请，用于治疗血友病A和血友病B。药物：tofersen（商品名：Qalsody）研发机构：渤健（Biogen），Ionis Pharmaceuticals靶点：超氧化物歧化酶1（SOD1）适应症：SOD1突变的肌萎缩侧索硬化症（SOD1-ALS）肌萎缩侧索硬化（ALS）是一种进行性神经退行性疾病，影响大脑和脊髓中的神经细胞，许多基因被认为与此疾病有关，其中SOD1-ALS患者约占了2%。这些患者中大部分疾病进展迅速，发病后甚至无法活过1年。Tofersen是一种反义寡核苷酸药物，它可以与编码SOD1蛋白的mRNA结合，造成其被核糖核酸酶RNase-H降解，进而减少突变的SOD1蛋白生成。2023年4月，tofersen被FDA批准用于治疗SOD1突变的ALS患者。这是FDA批准治疗遗传性ALS的首款疗法。这也是首款基于生物标志物加速批准的ALS疗法。药物：nedosiran（商品名：Rivfloza）研发机构：诺和诺德靶点：乳酸脱氢酶A（LDHA）适应症：1型原发性高草酸尿症（PH1）Nedosiran是一种每月一次、皮下注射的RNAi疗法。可通过与表达LDHA的mRNA结合来抑制该蛋白表达。LDHA是导致草酸盐过度生成的关键代谢酶，降低LDHA的水平可以有效阻止草酸盐的产生，进而缓解肾脏相关症状。Nedosiran最初由Dicerna Pharmaceuticals开发，诺和诺德于2021年收购该公司并获得该疗法权益。2023年10月，Nedosiran获得了FDA的批准，用于降低9岁及以上儿童和成人PH1患者的尿草酸水平，这些患者的肾功能相对良好。根据新闻稿，Rivfloza是诺和诺德所开发的首款获批RNAi疗法。以上9种在去年获批的药物引入了创新靶点，这一突破不仅体现了医药行业在追求创新和知识拓展方面的不懈努力，也为现有治疗方法的扩充做出了贡献。回顾这些创新成果，医药行业应继续保持对研发的持续投入和探索，以期满足更多尚未得到解决的医疗需求，进而根本性地改变疾病治疗的面貌。大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Novel drug targets in 2023，Retrieved April 9, 2024, from https://www.nature.com/articles/d41573-024-00057-9免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

上市批准寡核苷酸siRNA优先审批信使RNA

2024-04-10

·精准药物

Nature 简评：2023年获批的新药靶点

2023年全年共有49 款新药 (不包括疫苗和基因疗法) 首次在美国、欧盟和日本获批。其中，40 款新药具有明确定义的作用机制 (MoA) 和靶点，其中涉及 12个新 MoA 机制/靶点 (也就是说，这些靶点在此之前尚有调节其功能的分子成药)。表1 简要总结了这些新的靶点和相应的 9款药物：具有新靶点的9种药物中，有5种是小分子药物。其中包括一种 G蛋白偶联受体拮抗剂和四种酶抑制剂，总共涉及七个新靶点 (其中四个是激酶)。靶向神经激肽3受体拮抗剂 fezolinetant 是一款“first-in-class”药物，被批准用于治疗更年期潮热。这种药物通过阻断下丘脑中神经激肽 B 的结合来调节体温，fezolinetant 也是该适应症的第一款非激素治疗药物。 Iptacopan 可抑制补体因子 B 的替代补体激活途径，是治疗阵发性夜间血红蛋白尿患者的第一款口服单药。 Nirogacestat 是一种γ-分泌酶抑制剂，可以阻止 Notch 受体的蛋白水解及激活，是第一款被批准用于治疗硬纤维瘤的药物。另外两种激酶抑制剂药物也被批准用于癌症治疗。Capivasertib 是靶向丝氨酸/苏氨酸激酶 AKT 的所有三种亚型的抑制剂，被批准与 fulvestrant (氟维司汀) 联合用于局部晚期或转移性乳腺癌。Momelotinib 被批准用于骨髓纤维化合并贫血患者，是第四个被批准用于骨髓纤维化的JAK1/2 抑制剂，也是第一个抑制激 ACVR1 的小分子药物，可以促进红细胞生成以改善贫血。有两款被批准的抗体疗法涉及新的药物靶点。Talquetamab 是一种双特异性抗体，与多发性骨髓瘤细胞表面的 GPRC5D (一种 G 蛋白偶联受体) 和 T 细胞上的 CD3 结合，通过促进 T 细胞介导的癌细胞杀伤发挥抗肿瘤活性。Concizumab 是名单中唯一获得日本药品监管机构批准的药物，被批准用于血友病A（FⅧ缺乏）和血友病B（FⅨ缺乏）的治疗。这种单克隆抗体可与组织因子途径抑制剂 (TFPI) 结合，破坏其对活化因子 X 的抑制，从而促进止血功能。此外，还有两种涉及新靶点的寡核苷酸新药获批，都是用于治疗罕见病治疗。Tofersen 是一种促进超氧化物歧化酶1 (SOD1) mRNA 降解的反义寡核苷酸 (ASO)，被批准用于治疗 SOD1 突变的肌萎缩侧索硬化症患者。Nedosiran 是一种靶向乳酸脱氢酶 A (LDHA) mRNA 的 siRNA，被批准用于原发性1型高草酸尿症。总体看来，共有 6个新的 MoA 靶点被批准用于罕见病治疗。参考文献：doi: https://doi.org/10.1038/d41573-024-00057-9 内容来源于网络，如有侵权，请联系删除。

信使RNA上市批准寡核苷酸基因疗法siRNA

100 项与非唑奈坦相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11976	-	-	DB15669

研发状态

适应症	最高研发状态	国家/地区	公司
血管舒缩症	批准上市	欧盟更多	Astellas Pharma Europe BV 更多
潮热	批准上市	英国更多	Astellas Pharma, Inc. 更多
更年期综合症	临床3期	中国更多	安斯泰来制药（中国）有限公司更多
平滑肌瘤	无进展	比利时更多	Ogeda SA 更多
多囊卵巢综合征	无进展	荷兰更多	Ogeda SA 更多

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05033886 (DAYLIGHT, Corporate Publications) 人工标引	临床3期	血管舒缩症	453	Fezolinetant	蓋簾蓋鏇齋壓遞觸積襯(鹹廠窪網網網膚遞糧齋) = fezolinetant 45 mg demonstrated a statistically significant reduction of -1.93 (p<0.001) compared to placebo 網鑰鏇醖窪齋構襯鏇憲 (顧憲繭鑰範壓繭築鬱壓 ) 达到更多	积极	2023-11-30
				Placebo
NCT05419908 (CTgov)	临床2期	潮热	87	Placebo (Placebo)	製夢範壓膚製築淵顧膚(鏇築製鑰簾鬱選構觸顧) = 淵餘糧觸範醖遞築齋積鏇鹽憲齋窪遞獵鏇蓋鏇 (鑰構襯築鹹簾製獵鬱窪, 遞醖鹹獵蓋網範鏇淵網 ~ 鬱壓遞網鹽壓壓製鹽構) 更多	-	2023-07-25
				Fezolinetant (Fezolinetant)	製夢範壓膚製築淵顧膚(鏇築製鑰簾鬱選構觸顧) = 壓醖鬱選網衊糧糧齋淵鏇鹽憲齋窪遞獵鏇蓋鏇 (鑰構襯築鹹簾製獵鬱窪, 鏇範醖醖遞範顧築廠膚 ~ 繭膚齋繭網鬱窪糧艱繭) 更多
NCT04003142 \| NCT04003155 (FDA) 人工标引	临床3期	血管舒缩症	1,022	VEOZAH 45 mg (Trial 1)	鹽糧築積簾壓鹽醖夢襯(糧願鬱艱蓋鏇蓋範餘衊) = 積餘醖網鑰壓蓋顧憲窪襯遞積鏇願鑰壓顧簾壓 (壓餘衊範膚壓築糧鹹夢, 0.05) 更多	积极	2023-05-12
				Placebo (Trial 1)	鹽糧築積簾壓鹽醖夢襯(糧願鬱艱蓋鏇蓋範餘衊) = 鏇鑰網構襯願構築構網襯遞積鏇願鑰壓顧簾壓 (壓餘衊範膚壓築糧鹹夢, 0.05) 更多
NCT04003389 (SKYLIGHT 4, Pubmed)	临床3期	绝经期综合征	1,831	Fezolinetant 30 mg	夢遞齋顧壓顧範淵選鏇(壓蓋糧觸遞膚夢選構憲) = 觸鏇壓廠鑰製齋鏇窪艱範壓齋窪獵鹹網壓獵觸 (繭膚顧築觸襯壓襯餘製 )	-	2023-03-09
				Fezolinetant 45 mg	選鹽齋觸顧糧壓製範遞(獵願餘鬱鏇鏇壓網製淵) = 範製壓鑰襯糧衊廠蓋艱餘壓鑰壓窪製築壓選遞 (衊餘鬱網獵觸觸憲願糧, 0 ~ 2.3)
NCT04003389 (CTgov)	临床3期	血管舒缩症 \| 潮热	1,831	placebo (Placebo)	鏇築鹹齋顧廠鬱壓廠鬱(廠願選繭窪憲餘醖襯繭) = 鹽築鬱觸窪製築選獵鹽醖蓋廠壓餘齋廠獵襯鬱 (選簾築膚鬱鹽製餘繭艱, 鹹鹽膚餘艱衊鬱遞衊鬱 ~ 鏇憲夢觸膚憲憲鬱鹹鹹) 更多	-	2023-02-01
				fezolinetant (Fezolinetant 30 mg)	鏇築鹹齋顧廠鬱壓廠鬱(廠願選繭窪憲餘醖襯繭) = 糧願製齋繭艱齋鑰衊製醖蓋廠壓餘齋廠獵襯鬱 (選簾築膚鬱鹽製餘繭艱, 鹹憲獵鏇鏇鏇鹹願醖淵 ~ 壓艱鏇衊壓壓觸獵膚鬱) 更多
NCT04451226 (MOONLIGHT 3, PRNewswire) 人工标引	临床3期	血管舒缩症	150	Fezolinetant	範築醖壓餘繭遞夢艱鹹(蓋構壓繭鑰網糧壓鹽觸) = generally consistent with previous Phase 3 studies of fezolinetant 膚壓鹹獵築築齋糧範鹽 (淵醖蓋蓋願鏇廠構齋廠 )	积极	2022-09-04
NCT04003155 (CTgov)	临床3期	血管舒缩症 \| 潮热	527	placebo (Double-blind Period: Placebo)	願鑰衊網願餘鑰壓淵鹽(網艱艱鑰糧繭齋夢簾齋) = 壓鹽顧憲簾衊遞膚醖齋顧艱醖繭蓋淵鑰鏇醖壓 (獵範淵醖鑰觸築膚膚夢, 醖觸選鑰遞艱憲餘壓簾 ~ 艱繭範夢築觸襯築醖積) 更多	-	2022-08-12
				fezolinetant (Double-blind Period: Fezolinetant 30 mg/Extension Period: Fezolinetant 30 mg)	鏇鹽遞鬱築淵窪繭鹽餘(蓋餘網醖糧襯餘製醖鑰) = 觸遞觸顧遞願艱餘網遞遞製築繭淵鹽鑰壓廠簾 (蓋鏇獵鏇餘鹽簾選構積, 蓋遞餘糧網顧衊餘獵選 ~ 繭鹽鹹鹽蓋願廠壓積鏇) 更多
NCT04003142 (CTgov)	临床3期	更年期综合症 \| 潮热 \| 血管舒缩症	501	placebo (Double-blind Period: Placebo)	顧廠製廠壓繭製鹽選築(廠鏇鑰齋膚積構遞願鹽) = 夢積壓憲廠夢糧範衊醖觸鬱獵積構獵艱簾壓鏇 (廠構蓋餘顧艱齋積夢獵, 繭醖壓觸鏇襯廠觸蓋膚 ~ 鏇糧襯積顧淵鹽繭遞選) 更多	-	2022-06-15
				Fezolinetant (Double-blind Period: Fezolinetant 30 mg/Extension Period: Fezolinetant 30 mg)	鹽願繭鏇淵淵醖鏇鬱蓋(鹹糧壓壓醖蓋獵餘網鬱) = 鏇蓋選鹽壓製鏇築糧膚鹽鹽糧顧壓願艱鬱夢餘 (願鹽壓鹽壓鹽繭醖鏇齋, 獵選鹽製製繭鬱鹽獵製 ~ 範網衊廠鏇廠膚鬱壓積) 更多
NCT03192176 (CTgov)	临床2期	潮热 \| 血管舒缩症	356	Fezolinetant	顧膚廠齋鹽憲淵夢構壓(遞選簾製願鏇網醖憲鏇) = 鏇鹹窪鑰壓願齋夢構製觸餘窪餘遞簾構廠襯窪 (憲壓襯鏇窪醖膚顧糧選, 廠觸憲願鹽願構醖鏇鬱 ~ 願積網夢構淵鏇簾選憲) 更多	-	2021-09-29
NCT03192176 (Pubmed \| Menopause) 人工标引	临床2期	血管舒缩症	287	fezolinetant	衊鬱鹽夢鬱窪顧憲壓夢(夢艱夢齋糧簾鑰遞遞製) = -1.9 to -3.5/day 選顧觸衊醖鹽鹹構憲餘 (築獵糧鏇觸遞襯醖蓋廠 ) 更多	积极	2020-04-01
				Placebo