Clear Cell Adenocarcinoma

//   • FDA 2022年ODAC会议主张采用随机对照试验而非单臂试验作为血液瘤中PI3K抑制剂的申报依据； • PI3K抑制剂基于单臂试验获批仍有可能； • 安全问题在PI3K抑制剂中受到特别关注； • PI3K抑制剂与其他疗法联合应用值得进一步探索。 近来PI3K抑制剂再次引起热议。 今年6月，恒瑞医药林普利塞片的新适应症上市申请出现在药监局药品通知件中，意味着未获批准。该药成为继信达生物帕萨利司和正大天晴TQ-B3525片之后，第三款在中国上市受挫的PI3K抑制剂。 根据公开资料，这三项上市申请均基于单臂2期研究数据，其中林普利塞申报适应症为外周T细胞淋巴瘤（PTCL），后两者申报的则是滤泡性淋巴瘤（FL）。 “这可能是CDE参考了FDA的立场。”阿诺医药研发负责人谢毅钊博士在接受研发客采访时表示，“过去多款PI3Kδ抑制剂曾基于单臂试验中的ORR数据获批用于血液瘤，后又主动或被动撤回这些适应症。FDA已在2022年召开的肿瘤咨询委员会（ODAC）会议中指出，这些高水平的ORR并不一定最终能带来OS获益，并主张采用随机对照试验（RCT）而非单臂试验作为血液瘤中PI3K抑制剂的申报依据。” 海和药物副总裁张毅翔博士认为：“林普利塞、帕萨利司与TQ-B3525均靶向PI3Kδ，且申报适应症同为血液瘤。2022年ODAC会议中的共识可能会对此类产品有一定的影响”，“FL和PTCL适应症对应线数患者人群中，国内已获批药物的疗效和安全性也会对后续产品的审评带来一定影响。” 阿诺医药与海和药物均是PI3K抑制剂研发赛道的一员。前者正在全球开展泛PI3K抑制剂buparlisib治疗头颈部鳞状细胞癌（HNSCC）的多中心3期临床，目前已完成全部患者入组；后者的PI3Kα选择性抑制剂CYH33拟用于多种实体瘤等，针对复发/持续性卵巢、输卵管或原发性腹膜透明细胞癌的研究已进入2期临床阶段，在HR+/HER2-、PIK3CA突变的晚期乳腺癌患者中的研究即将进入3期关键临床阶段。 据研发客不完全统计，曾参与研发PI3K抑制剂的中国公司有近20家，但其中近一半产品被搁置，有些甚至已剔除出公司管线。仍在开发的产品则以实体瘤适应症为主。 左右滑动查看 还能考虑单臂试验吗？ 随着药监局审评要求收紧，未来单臂临床试验用于支持PI3K抑制剂上市还有希望吗？张毅翔给出的答案是肯定的。 “FDA并不是对所有PI3K抑制剂的单臂试验说不。2022年FDA召开的ODAC会议共识仅限于PI3K抑制剂在血液瘤中的应用，如果新一代PI3K抑制剂表现出强效低毒的特征，也并不一定会受限于上述共识。此外，ODAC会议中也进行了澄清，FDA批准的PI3Kα抑制剂alpelisib，并不在会议讨论范围。”她说。 早在2019年5月，alpelisib就获得FDA批准用于HR+/HER2-携带PIK3CA突变的晚期转移性乳腺癌，成为首个获批实体瘤的PI3K抑制剂。2022年4月，该药又基于真实世界研究数据获得FDA加速批准，用于PIK3CA相关过度生长综合症（PROS）成人和2岁及以上儿童患者。 那么，什么样的PI3K抑制剂能够凭借单臂临床试验数据获批上市？ “这需要满足监管机构关于单臂试验的相关指导原则，能解决未满足的临床需求且获益风险比高的药物仍会有机会。”张毅翔表示。根据指导原则，单臂试验支持药物上市适用于患者无有效治疗选择，试验药物机制明确、疗效突出、安全性风险可控，对照组疗效数据明确，罕见病的情况。 拓展阅读  CDE收紧单臂临床试验申请 回过头来看国内上市受挫的三款PI3K抑制剂，它们的遭遇或许早已有迹可循。尤其在已有3款PI3K抑制剂获批的FL领域，后来者想要基于单臂试验获批的可能性几乎为零。即便花大力气完成确证性3期研究并获批，未来产品的商业化价值也要重新考量。 数据显示，FL约占所有非霍奇金淋巴瘤（NHL）病例的10%～20%，中国每年新发病例不足2万。 “虽然FL是一个小众适应症，但如果产品可以做到全球前三，机会还是有的。如果不是，在竞争对手的先发优势下，后来者几乎没什么潜力，尤其在中国，新药的价格和利润都很低。”谢毅钊说。 信达生物也曾在2023年9月发布的公告中提到，其帕萨利司申报的r/r FL适应症患者群体较小、市场竞争较为激烈。基于产品价值等多方考虑后，该公司决定主动撤回该产品在中国的上市申请。 如何克服毒性问题 一直以来，安全问题在PI3K抑制剂开发中受到特别关注，一些产品上市便伴有多项黑框警告，严重且致命的不良反应还会令患者OS受损。 在谢毅钊看来，“PI3K抑制剂大部分的毒性都是On-target off-tumor（非肿瘤靶向毒性），这很难避免。” 因为PI3K信号通路在许多正常细胞中扮演着重要角色，参与调节细胞的增殖、凋亡与分化等生理过程。并且，不同PI3K家族成员有不同的生理作用，针对不同亚型的选择性抑制剂，在副作用方面也有很大不同。比如PI3Kδ的毒性偏向于肝毒性和胃肠道反应，PI3Kα偏向高血糖和皮肤反应等。 但这并不意味着PI3K抑制剂的终结。 以阿诺医药为例，虽然知晓buparlisib在乳腺癌试验中因高毒性被诺华放弃，但公司仍引进该产品，之后将研发方向聚焦于HNSCC。 “HNSCC是一个临床需求严重未满足的治疗领域，患者在接受PD-1/L1抑制剂治疗后几乎没有其它标准治疗方法，他们的需求更多是延长生命，因此对新药毒性的容忍度比较高。相比之下，乳腺癌患者对毒性的接受度低很多，很多人经过多种治疗后已经能够正常工作与生活。”谢毅钊说。 拓展阅读  阿诺医药：收购诺华PI3K抑制剂并非孤注一掷 谁能改变全球头颈鳞癌治疗格局 海和药物的策略则是聚焦药物有竞争力的适应症，并进行稳健的剂量探索，确定临床获益风险比最佳剂量。 “FDA ODAC会议中已指出，PI3Kδ抑制剂在血液肿瘤的开发中存在剂量探索不足的问题，这也可能是导致OS受损的原因。因此，需要通过稳健的剂量探索来确定在不同的适应症、不同的药物联用情况下获益风险平衡比最佳的剂量。”张毅翔说。 她同时还提到，突变型PI3K亚型选择性抑制剂的开发也可能解决靶点相关的毒性问题，但其疗效还需等待临床试验的验证。 未来的研发方向 事实上，不同亚型的PI3K抑制剂潜在获益人群也有所不同，比如PI3Kα抑制剂治疗该靶点相关突变的肿瘤、泛PI3K抑制剂治疗头颈癌、PI3Kδ/γ抑制剂治疗淋巴瘤、PI3Kβ抑制剂治疗前列腺癌等。其中，受访者最看好的当属PI3Kα。 研究表明，编码PI3Kα催化亚基的PIK3CA基因是癌症中最常见的突变基因之一，该突变在多种恶性肿瘤中均有发现且比例较高（约10%~40%）。因此PI3Kα抑制剂可用于治疗PIK3CA基因突变驱动的多种实体瘤，适应症更为广泛。 当下，首款PI3Kα抑制剂alpelisib不仅斩获乳腺癌和PROS适应症，而且取得商业化成功。诺华财报显示，该产品2023年全球销售额达到5亿美元，同比增长35%。 另一款来自罗氏的PI3Kα抑制剂inavolisib（伊那利塞）也已在3期临床中取得积极结果，其联合CDK4/6抑制剂哌柏西利和雌激素受体拮抗剂氟维司群，可将一线PIK3CA突变乳腺癌患者的PFS翻倍。 在张毅翔看来：“PI3Kα抑制剂与其它抗肿瘤药物的联合用药是未来开发的重要方向之一，尤其与免疫疗法的联用值得探索。” 采访中，谢毅钊同样提及联合用药的概念。 “一直以来，PI3K抑制剂单药治疗面临较大的挑战，这可能与系统的反馈机制有关。当PI3K的活性受到抑制时，系统其它信号通路会很快将其回调至原有水平，这也是过去很多PI3K抑制剂疗效不足的原因。”他进一步表示，“未来，PI3K抑制剂与其它针对不同信号通路的产品联用更有可能成功，比如与免疫检查点抑制剂的联合使用，或者开发双靶点抑制剂，不过前提是两个靶点之间不能存在毒性的重叠。” 编辑 | 姚嘉 yao.jia@PharmaDJ.com  总第2177期 访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com

Melbourne, Australia, 17 October 2023 – Cartherics Pty Ltd (“Cartherics” or “Company”), a biotechnology company developing immune cell therapies for the treatment of cancer, announced today that it has appointed Dr Walid Azar as Chief Scientific Officer (CSO), effective immediately. He holds extensive experience from a diverse scientific background encompassing both academic research and the biotechnology industry. Prior to joining Cartherics three years ago, Dr Azar worked as a molecular biologist at CSL Limited, where he was part of the international R&D team. He brings valuable expertise in cancer research to the CSO role, having completed a PhD in molecular biology and biochemistry at the Murdoch Children’s Research Institute and a postdoctoral research fellowship at the Peter MacCallum Cancer Centre, focusing on clear cell carcinoma, a rare subtype of ovarian cancer. As CSO, Dr Azar will be responsible for overseeing the Company’s scientific activities, building on current capabilities, product pipeline, and platforms. This includes ensuring that the Company remains at the forefront of the latest developments in the immune cell therapy space. He will also be focused on managing and leading the team of highly skilled and committed scientists working at Cartherics. “I am passionate about developing novel treatments for cancer and there is a strong alignment between Cartherics’ mission and my commitment to delivering new options for cancer patients. It is great to be working alongside very talented and committed scientists with the same goal,” said Dr Azar. “CAR-T and CAR-NK cell therapies are yet to reach their potential in solid tumours. With the rapid developments in gene editing technologies and our evolving knowledge of the tumour microenvironment and NK cell biology, there is an opportunity for us to significantly improve the efficacy of CAR-NK therapy in solid tumours,” Dr Azar added. Cartherics CEO, Prof Alan Trounson AO, commented: “We are pleased to promote Walid to this important position. He has a strong background in molecular genomics cancer research, and science management, and will be a valuable addition to the Company’s executive team. Prof Richard Boyd will remain with the Company as Chief Scientific Advisor, a part-time advisory role, and will act as a mentor for Walid. The combination will enable us to maintain excellence in immunology and genomics/gene editing.” About Cartherics Cartherics is a privately held biotechnology company based in Melbourne, Australia that is rearming the body’s immune system to fight cancer.  It is developing cell-based immunotherapies for the treatment of cancer, with a portfolio of CAR-T and CAR-NK cell products.  The Company’s allogeneic (“off-the-shelf”) cell platform is based upon induced pluripotent stem cells (iPSCs) generated from donated cord blood that can be differentiated into NK cells, T cells and other cells of the immune system.  The iPSCs are genetically engineered to provide enhanced function for the derived NK and other immune cells. The Company is also developing autologous CAR-T cell therapies. These use the patient’s own immune system T cells, which are modified to be effective against the patient’s cancer cells. CTH-004 is created by genetically modifying patient T cells to insert a chimeric antigen receptor (CAR) to target a marker (TAG-72) on ovarian cancer cells and delete genes that are involved in suppression of T cell function. Cartherics media contact Christine Filippis Teraze Communications Phone: +61 419 119 866 Email: christine@teraze.com.au

SEATTLE, April 05, 2021 (GLOBE NEWSWIRE) -- SEngine Precision Medicine , a precision oncology company revolutionizing cancer therapies by pre-testing drugs on patient-derived tumor organoids, announced today that the PARIS® Test was utilized in a study to identify novel drug targets and combinations to combat ovarian clear cell carcinoma (OCCC). The study, “Targeting BET proteins BRD2 and BRD3 in combination with PI3K-AKT inhibition as a therapeutic strategy for ovarian clear cell carcinoma,” was recently published in American Association for Cancer Research’s Molecular Cancer Therapeutics and was co-authored by researchers from the Fred Hutchinson Cancer Research Center, SEngine Precision Medicine, Weill Cornell Medicine, and the University of Washington. Ovarian clear cell carcinoma, a relatively uncommon subtype of ovarian cancer, has historically been treated with the same platinum-based chemotherapies as patients with high grade serous carcinoma. However, clear cell carcinoma patients typically display a poorer response to chemotherapies, which leads to lower overall survival for these patients. In this study, researchers identified BET proteins BRD2 and BRD3 as novel targets against ovarian clear cell carcinoma, which could lead to more effective targeted therapies for this subtype. Additional drug sensitivity screening identified the combination of BET protein and PI3K-AKT pathway inhibitors as a promising therapeutic path for further investigation. SEngine’s PARIS® Test, a high-throughput drug sensitivity assay using patient-derived tumor organoids, was utilized in this study to validate the drug-response findings on ovarian cancer cell models. In addition to the PARIS® Test already being utilized as a clinical tool guiding oncologists’ treatment decisions for patients with ovarian cancer, this study demonstrates the power of SEngine’s functional drug sensitivity assay to identify novel therapeutic targets and drug synergies to combat hard-to-treat ovarian cancers. "We are excited to share these new findings that identified two novel BET proteins as candidate therapeutic targets for OCCC and suggest a potential drug combination therapeutic strategy for OCCC,” said Shogo Shigeta, MD, PhD, current Research Associate in the department of gynecology at the Tohoku University Graduate School of Medicine and lead author of the study. “The validation of our study with organoids derived from patient samples will help enable rapid clinical translation." “In this study, SEngine’s PARIS® Test was applied to patient derived tumor cells to identify new therapeutic strategies for hard-to-treat cancers. This is yet another example of the benefit that functional testing brings to oncologists seeking novel treatment options,” commented Carla Grandori, MD, PhD, co-founder and Chief Executive Officer of SEngine Precision Medicine. About PARIS® Test The PARIS® Test is based on the capability to propagate patient-specific cancer cells as organoids outside the body and is applicable to all solid tumors including colon, breast, lung, ovarian and pancreatic cancer. Organoids are cancer-derived cells grown in 3D outside the body, which maintain the functionality of the original tumor as well as its genomic characteristics. For cancers where a treatment path is not clear, such as many metastatic and recurrent cancers, the PARIS® Test provides crucial information to treating physicians to match the right drug to the right patient. About SEngine Precision Medicine SEngine Precision Medicine Inc. is a precision oncology company revolutionizing cancer therapies by pre-testing drugs on patient-derived organoids grown ex-vivo utilizing patient specific tumor cells. As a spin-out from the world-renowned Fred Hutchinson Cancer Research Center, SEngine is leveraging over two decades of R&D in diagnostics and drug discovery. The Company is commercializing the PARIS® Test, a next generation diagnostic test that predicts drug responses integrating knowledge of cancer genomics with organoids, robotics, and AI-driven computational tools. SEngine’s CLIA certified PARIS® Test generates predictive drug sensitivity reports for patients with solid tumors. SEngine is also pursuing drug discovery via strategic collaborations with biopharmaceutical / pharma companies leveraging its precision oncology platform. Discover more at SengineMedicine.com and follow the latest news from SEngine on Twitter at @SEngineMedicine and on LinkedIn . Contact: Stephanie Carrington stephanie.carrington@westwicke.com 646-277-1282