KA-2237

▎药明康德内容团队报道近日，甫康（上海）健康科技有限责任公司（Convalife Pharmaceuticals，下简称“甫康药业”）宣布，其开发的1类新药、PI3K β/δ双重抑制剂CVL237的2期临床试验申请（IND）获得美国FDA批准，适应症为PTEN基因缺失的晚期实体瘤。此前，该候选药已获得FDA批准开展用于治疗复发/难治性淋巴瘤患者的1期临床试验。随着本次临床试验获批，甫康药业即将在中国和全球开展CVL237针对PTEN缺失的晚期实体瘤的全球多中心临床试验。现有数据表明，PTEN基因缺失存在于多种癌症中，包括胶质母细胞瘤、前列腺癌、结直肠癌、子宫内膜癌、黑色素瘤和乳腺癌等等。根据文献报道，在高级别浆液性卵巢癌肿瘤中，超过30%表现为PTEN缺失[1]。在转移性去势抵抗性前列腺癌（mCRPC）中，伴PTEN缺失肿瘤患者占比约为47%[2-3]。在原发性散发性结直肠癌种中，PTEN缺失患者约占17%[4]。今年4月，国际权威期刊Nature发表的一项研究表明，在PTEN缺失的情况下，通过抑制PI3Kβ可以直接杀伤肿瘤，同时还可导致STAT3信号的减少和免疫刺激分子的表达增加，从而促进抗肿瘤免疫反应[5]。目前还没有针对PTEN基因缺失的靶向药物获批上市。根据甫康药业新闻稿介绍，CVL237是一款口服、强效和高选择性的PI3K β/δ双重抑制剂，可以通过抑制PI3Kβ引起抗肿瘤免疫，并与PD-1抑制剂等免疫疗法协同抑制肿瘤的生长。临床前研究显示，CVL237对PTEN缺失实体瘤有显著抑制作用，联合第二代PARP抑制剂CVL218更能发挥协同作用。因此，CVL237在PTEN缺失的晚期实体瘤中具有巨大的开发潜力。目前，CVL237已在美国安德森癌症中心（MD Anderson Cancer Center）完成1期临床试验，全球即将进入2期临床试验。1期试验结果显示，CVL237在多线复发/难治的淋巴瘤患者中具有良好的安全性和有效性。对包括弥散性大B细胞淋巴瘤（DLBCL）、滤泡性淋巴瘤（FL）、慢性淋巴细胞白血病（CLL）和套细胞淋巴瘤（MCL）在内的不同亚型淋巴瘤都有效。现有临床前及临床数据显示，CVL237对BTK耐药和其它PI3Kδ抑制剂耐药的患者也有明显治疗作用。进一步临床前研究证明，CVL237对PTEN突变实体瘤也有显著抑制作用。与此同时，CVL237还在其它疾病中表现出治疗潜力。对于本次获批2期临床，甫康药业首席执行官沈孝坤博士表示，PTEN缺失的晚期实体瘤患者存在巨大的未满足需求，我们很高兴CVL237获得FDA的认可，一旦临床试验成功，将有望极大地促进这一领域的研究。这一里程碑证明了甫康药业坚定不移地致力于通过开创性的研究来改善患者的生活。甫康药业热切期待为医学科学的进步做出贡献，成为开发突破性疗法的国际知名生物医药公司。参考文献：[1] Nero C， Ciccarone F， Pietragalla A， Scambia G. （2019）PTEN and Gynecological Cancers. Cancers (Basel). doi: 10.3390/cancers11101458. [2] Ito T， Takahara T， Taniguchi N， et al.（2023） PTEN loss in intraductal carcinoma of the prostate has low incidence in Japanese patients [published online ahead of print， 2023 Aug 23]. Pathol Int. doi:10.1111/pin.13369.[3] Matsubara N， de Bono J， Sweeney C， et al. （2023）Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer. Clin Genitourin Cancer. doi:10.1016/j.clgc.2023.01.001.[4] Nassif， N.， Lobo， G.， Wu， X. et al. (2004) PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene. https://doi.org/10.1038/sj.onc.12070. [5] Johann S. Bergholz et al. （2023）PI3Kβ controls immune evasion in PTEN-deficient breast tumours. Nature. doi:10.1038s41586-023-05940-w.本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权请在「医药观澜」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。

OXFORD, England--(BUSINESS WIRE)--Karus Therapeutics (‘Karus’), a leader in the development of innovative, orally-active medicines with breakthrough potential in the treatment of cancer, today announced that the first patients have been dosed in a Phase I study for its lead candidate, KA2237. This is the Company’s first product to enter clinical trials. KA2237 is a dual-selective inhibitor of two PI3K isoforms, p110ß and p110d. Inhibiting these two isoforms combines an immunotherapeutic response and a direct effect on tumor growth, through selective, targeting of the PI3K pathway. Karus believes that KA2237 has broad therapeutic applicability in the treatment of hematological and solid tumors, as a single agent and in combination with other drugs. This study forms part of the pre-clinical and clinical collaboration between Karus and the University of Texas MD Anderson Cancer Center, the world’s leading cancer research and care center. The first part of the trial has been designed to assess the safety of KA2237 alone in relapsed, treatment-resistant B cell lymphoma patients. An expansion cohort study will follow and is scheduled to start in 2017. Karus anticipates that up to 40 patients will be treated over the entire study. Dr. Simon Kerry, CEO of Karus Therapeutics, commented: “Our first clinical trial is a major milestone for the company. Karus has made exceptional progress and our collaboration with MD Anderson will help us to accelerate this clinical program. We believe that as an orally-active dual p110ß/d inhibitor, KA2237 has significant potential in the treatment of hematological and solid tumors in areas of high, unmet medical need.” Professor Stephen Shuttleworth, CSO, added: “Our R&D programs are built on many years’ investment in research that have given us a deep understanding of PI3K medicinal chemistry and tumor biology. To take a scientific concept through rational de novo-design to create KA2237, a dual-selective, small molecule PI3K inhibitor that has been designed specifically to address areas of unmet medical need, is a very rewarding moment in our journey towards developing new cancer treatments for patients with few remaining therapeutic options.” The agreement with MD Anderson covers a number of preclinical studies of Karus’s two cancer programs, KA2237 and KA2507, with a focus on identifying optimal drug combinations and the appropriate patient populations for further clinical development. The second program, KA2507, a selective-HDAC6 inhibitor, also has both a targeted therapy and immunotherapeutic action and has potential in the treatment of multiple myeloma, B- and T-cell lymphomas and PD-L1 expressing hematological and solid tumors. -Ends- About Karus Therapeutics Karus Therapeutics is a leader in the development of innovative medicines that have breakthrough potential in the treatment of cancer. The Company’s scientific excellence is reflected in its proprietary PI3K and HDAC6 inhibitor programs, from which innovative small molecule drugs with significant clinical and commercial potential have been developed. The UK-based Company is privately-held with a strong financial track record and experienced investors, including SV Life Sciences, New Leaf Ventures, Novo A/S and IP Group. For further information please visit www.karustherapeutics.com About MD Anderson The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute (NCI). For the past 25 years, MD Anderson has ranked as one of the nation's top two cancer centers in U.S. News & World Report's annual "Best Hospitals" survey. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).