LY-2780301

失败的III期临床试验 2024年6月18日，阿斯利康公布了一项III期临床的失败。 阿斯利康公布CAPItello-290研究最新进展（图源：阿斯利康官网） 该试验名为CAPItello-290，是一项随机双盲III期试验，共纳入患者923人，旨在评估其AKT抑制剂Capivasertib（商品名：Truqap）联合化疗（紫杉醇）作为局部晚期（无法手术）或转移性三阴乳腺癌（TNBC）患者一线治疗的疗效与安全性。 试验主要终点包括：（1）总体试验人群的OS（2）携带特定生物标志物改变（PIK3CA、AKT1或PTEN）亚组的OS。 试验结果显示，Truqap联用组合并未达总生存期改善（OS）双重主要终点，即无论是试验总人群，还是生物标志物亚组人群均未发现OS显著改善。此外，安全性方面与既往研究一致，未发现新的安全性问题。 目前，阿斯利康尚未披露该试验详细临床数据，具体公布时间未定。 阿斯利康的多重保险 Truqap是一款“First-in-class”AKT抑制剂，可选择性靶向3种AKT激酶异形体AKT1/2/3的腺苷三磷酸（ATP）。 该药物首次获批于2023年11月，被FDA批准用于与氟维司群联用治疗HR+/HER2-的晚期或转移性乳腺癌成年患者。 虽然Truqap上市时间较短，但在2023年第一季度（即第一个完整收益期），该药物却实现了5000万美元的销售额。有海外分析师认为，Truqap的峰值销售额可达38亿美元。 因此阿斯利康对Truqap十分重视，除了TNBC的适应症拓展，公司还相继开展了一项用于三联疗法的III期研究（Truqap+CDK4/6+氟维司群一线治疗HR+/HER2-晚期乳腺癌）; 两项关于前列腺癌的III期研究（Truqap+多西他赛治疗mCRPC；Truqap+阿比特龙治疗PTEN缺失的mhspc）。其中，关于Truqap与阿比特龙的联用数据（CAPItello-281研究）将于今年下半年读出。 多歧路，今安在 迄今为止，在HR+/HER2-乳腺癌一线治疗药物中，CDK4/6抑制剂可谓占据“半壁江山”；在前列腺癌治疗药物中，AR拮抗剂、CYP17抑制剂也均牢牢把握一线治疗市场。 而AKT作为PI3K/AKT/m-TOR信号级联的中心节点，在调节细胞存活、增殖、迁移和分化等多种细胞功能中发挥着关键作用。且目前AKT已被证明可以作为多种疾病的治疗靶点，如乳腺癌、前列腺癌、卵巢癌等。 Truqap便是个极好的例子，有望横跨乳腺癌与前列腺癌两大适应症，潜力不可谓不大。 然而这样的“宝藏分子”，研发格局却并算不上拥挤，上市产品仅有Truqap一款。根据智慧芽数据统计，目前进入三期临床的AKT抑制剂也仅只有6款。 进入三期临床的AKT抑制剂（图片来源：智慧芽数据库） 为何？ 因为在此之前，最早介入探索的公司和产品，如礼来的LY2780301、拜耳的BAY1125976、默沙东的MK-2206等均以失败告终，使得AKT赛道遇冷。 2023年2月，罗氏的AKT抑制剂ipatasertib虽在3期IPATential150研究中观察到了中位PFS改善。但rPFS获益一般，且未证明OS改善。 加上此次Truqap又在TNBC适应症上失利，使得该赛道再次蒙上阴影。 AKT抑制剂的作用机制非常复杂，且具有多靶点抑制、缺乏精准选择、生物利用度低、严重的不良反应等多重挑战，等待研发人员攻克。 如何探索更合适的给药间隔和频次，如何进一步提升药物效能，便成为了后继者们实现弯道超车的关键所在。 回顾国内，来凯医药、海昶生物、正大天晴等药企有所布局，且来凯医药的afuresertib处在临床三期阶段。 参考资料： 阿斯利康官网 智慧芽数据库 NMPA全球首批AKT靶点药物上市！乳腺癌患者治疗迎来新曙光（）（梅斯肿瘤新前沿） 横跨两大难病的下一个国产重磅炸弹（瞪羚社） 全球首款！阿斯利康Capivasertib申报上市，浅谈AKT抑制剂研发进展（药渡） 其他公开资料 封面图来源：pixabay 版权声明/免责声明 本文为原创文章。 本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。 文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。 如有任何问题，请与我们联系。 衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 止步II期临床？命途多舛的 “Wee 1” 股价暴涨477%，CD20 CAR-T再突破 >50%破发！2024年纳斯达克IPO的biotech公司依然面临挑战 点击这里，发现价值信息！

Akt, also known as protein kinase B, is a crucial enzyme that plays a significant role in various cellular processes within the human body. It is a key mediator of cell survival, growth, and metabolism. Akt is involved in regulating multiple signaling pathways, including those related to cell proliferation, apoptosis, and glucose metabolism. It promotes cell survival by inhibiting apoptosis and stimulating cell growth and proliferation. Akt also regulates glucose metabolism by promoting glucose uptake and utilization. Dysregulation of Akt signaling has been implicated in various diseases, including cancer, diabetes, and neurodegenerative disorders. Understanding the role of Akt is essential for developing targeted therapies in the pharmaceutical industry. Basic research related to AKT has a relatively high academic starting point, with the earliest literature recorded in the top-tier journal "Proceedings of the National Academy of Sciences (PANS)". The prototype AKT gene was published in the journal Science in 1991. Due to the solid academic foundation established at the beginning, AKT has garnered attention in drug development from many pharmaceutical giants. Reviewing the development history of AKT drugs, the earliest companies involved in the exploration and clinical development of AKT inhibitors were pharmaceutical giants such as GlaxoSmithKline, Merck, Eli Lilly, Bayer, AstraZeneca, and Roche (Genentech). However, despite their well-known backgrounds, these companies have either sold off or terminated their AKT inhibitor developments, such as Eli Lilly's LY2780301 and Bayer's BAY1125976. This to some extent reflects the uncertainty of new drug development as well as the enormous complexity and challenges of the AKT signalling pathway. Merck's MK-2206 also ultimately failed after more than 40 early trials. Inherent or acquired drug resistance has always been the main reason why cancer drugs cannot maintain effectiveness, and eventually leads to treatment failure. Therefore, with the continuous exploration of potential mechanisms, discovering more promising drug targets has become the optimal treatment method for cancer treatment and prevention. The aberrant activation of the PI3K/AKT pathway and the transduction of its upstream or downstream targets play a crucial role as an important signalling pathway responsible for the resistance formation of various tumours. To enhance the sensitivity of tumour cells and combat tumour drug resistance, AKT inhibitors have also made some progress in clinical research. For example, in breast cancer, the PI3K/AKT pathway is considered a key player in the development of endocrine therapy resistance. The combined use of AKT inhibitors counteracts the activation of the PI3K/AKT pathway, thus exerting cytotoxic activity to prevent tumour cell resistance. Therefore, AstraZeneca and Roche are also evaluating the use of AKT inhibitors alone or in combination to develop new therapies for tumour treatment and to address treatment resistance.  How do they work?AKT inhibitors are a type of medication that target and inhibit the activity of the AKT The AKT , also known as protein kinase B, plays a crucial role in cell survival, growth, and proliferation. It is involved in various signaling pathways that regulate cell processes such as metabolism, apoptosis (cell death), and cell cycle progression. In the context of biomedicine, AKT inhibitors are of particular interest in cancer research and treatment. Dysregulation or overactivation of the AKT is commonly observed in many types of cancer, leading to uncontrolled cell growth and survival. By inhibiting the activity of the AKT , these inhibitors aim to disrupt the signaling pathways that promote cancer cell growth and induce cell death. AKT inhibitors can be developed as small molecules or targeted therapies, such as monoclonal antibodies or kinase inhibitors. They work by binding to specific regions of the AKT protein, preventing its activation or downstream signaling cascades. These inhibitors have shown promise in preclinical and clinical studies as potential anticancer agents, either as standalone treatments or in combination with other therapies. It is important to note that the use of AKT inhibitors may have potential side effects and limitations. Since AKT is involved in various cellular processes, inhibiting its activity can affect normal cell functions as well. Therefore, careful evaluation of the therapeutic benefits and risks is necessary when considering the use of AKT inhibitors in clinical settings. List of Akt InhibitorsThe currently marketed Akt inhibitors include: CapivasertibAfuresertibDordaviproneHonokiolIpatasertib DihydrochloridePerifosineSR-0379AntroquinonolCLR-131HC0201For more information, please click on the image below. What are Akt inhibitors used for?Akt inhibitors are being studied for the treatment of multiple diseases, including ovarian, prostate, breast, gastric, multiple myeloma, and melanoma. For more information, please click on the image below to log in and search. How to obtain the latest development progress of Akt inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of Akt inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!