HS-20093

欢迎关注凯莱英药闻 今日，宜联生物宣布，公司与阿斯利康建立临床研究合作，共同探索YL201（靶向B7H3的抗体偶联药物）与度伐利尤单抗（抗PD-L1免疫检查点抑制剂）联用，治疗多种实体瘤的潜力。双方将共同启动一项多中心、开放性、I/Ib期研究，旨在评估YL201联合度伐利尤单抗在实体肿瘤患者中的安全性、有效性和药代动力学。 这是公司第二次就该药物与MNC达成临床合作。2024年10月，公司宣布与安进达成全球临床研究和药品供应合作协议；双方将合作开展YL201与靶向DLL3和CD3的双特异性T细胞衔接蛋白tarlatamab联用的临床试验，用于联合治疗广泛期小细胞肺癌（ES-SCLC）。根据协议条款，安进将主导该试验，宜联生物将为该联合研究提供YL201。 关于YL201 YL201是一款靶向B7H3的ADC，基于宜联生物TMALIN®平台所开发；该ADC由一种抗B7H3人单克隆抗体通过蛋白酶可切割连接物与一种新型拓扑异构酶1抑制剂结合。新颖的连接物有效载荷和YL201的位点特异性偶联导致该ADC更亲水，此外，偶联后抗体的结合特异性、亲和力和亲和度均不受影响。 临床前研究显示，在耐受良好的剂量下，YL201在细胞系和患者来源的异种移植(CDX和PDX)小鼠模型中都能有效地引起肿瘤消退。猴子体内药代动力学表明，YL201在循环中被认为是“高度稳定的”。安全性评估表明，猴子的安全性可接受，无脱靶毒性。 2023年11月，YL201获得美国食品和药物管理局（FDA）授予的孤儿药资格，用于治疗食管癌（EC）。 2024年9月，宜联生物在2024年欧洲肿瘤内科学会（ESMO）上，公布了YL201的积极临床数据，这是公司首次公布的该药物的临床数据，显示YL201在包括小细胞肺癌、鼻咽癌、野生型非小细胞肺癌在内的多种实体瘤展示出令人鼓舞的抗肿瘤效果。具体来看： 截至2024年8月9日，在276例存在至少一次基线后肿瘤评估的患者中，客观缓解率(ORR)为44.6%，疾病控制率(DCR)为83.7%。 在广泛期小细胞肺癌（ES-SCLC，n=79）队列中，ORR为68.1%（≥2.0 mg/kg ORR为70.0%），mPFS为6.2个月（≥2.0 mg/kg mPFS为6.2个月）。在脑转移患者中的疗效与整体人群可比，ORR为52.2%，mPFS为5.3个月。 在鼻咽癌（NPC，n=75）队列中，ORR为48.6%（≥2.0 mg/kg ORR为48.6%），mPFS为7.2个月（≥2.0 mg/kg mPFS为7.2个月）。在接受过2线及以上标准治疗的患者中，ORR为51.0%，mPFS为7.0个月，与NPC总体人群相当。 在驱动基因阴性的非小细胞肺癌（NSCLC，n=68）队列中，在腺癌和淋巴上皮瘤样癌（LELC）亚型中的ORR分别为29.2%和60.9%，mPFS分别为未成熟和8.1个月。 在安全性上，312例总体人群中≥G3 TRAE发生率为51%，SAE发生率为28%。最常见的TRAE为血液学毒性，包括白细胞减少症（≥G3 29%）、贫血（≥G3 22%）、中性粒细胞减少症（≥G3 30%）等；非血液学TRAE包括食欲减少（≥G3 1%）、恶心（≥G3 1%）等，间质性肺炎（ILD）仅有3例报道（1.0%）。 关于B7-H3 ADC B7-H3（又称CD276）是一种Ⅰ型跨膜糖蛋白，属于B7超家族中的一员，在单核细胞和粒细胞及人体正常组织中均无表达，而在一些树突状细胞、T 细胞、自然杀伤（NK） 细胞和B 细胞上有表达是近年来新发现的免疫检查点。该靶点不仅可通过抑制免疫系统促成肿瘤细胞的免疫逃逸，还可通过一些非免疫途径介导肿瘤的转移、耐药、血管生成从而促进癌症进展。 研究发现，B7-H3在非小细胞肺癌、胰腺癌、原发性肝癌、结直肠癌、乳腺癌、前列腺癌、咽喉癌、黑色素瘤等多种肿瘤组织中有异常大量表达，且在肿瘤微环境（TME）中的基质细胞、纤维原细胞、上皮细胞等表面也有表达，其在肿瘤组织中的过量表达往往伴随患者不良预后与较短的总生存期和无进展生存期。 据不完全统计，目前在研的B7H3 ADC药物约四十余种。 关于PD-(L)1与B7H3 ADC联用的探索 近日，中国国家药监局（NMPA）批准安斯泰来维恩妥尤单抗（enfortumab vedotin）和默沙东的帕博利珠单抗联合用药的上市申请；其中，维恩妥尤单抗是一款靶向Nectin-4的ADC，帕博利珠单抗是一款抗PD-1单抗。近年来，PD-1+ADC 联合疗法在多种肿瘤一线治疗中表现十分亮眼，催生了更多PD-(L)1与B7H3 ADC联用的探索。 2023年10月，第一三共和默沙东宣布将以首付45亿共计220亿美金，合作开发三款候选DXd ADC药物，其中包含靶向B7-H3 ADC药物ifinatamab deruxtecan (I-DXd)。2024年4月，根据clinical trails网站，I-DXd联合罗氏PD-L1抗体Atezolizumab，在小细胞肺癌患者中开展1/2期临床试验，计划入组总人数为149例。 除此以外，2024年3月，豪森药业登记了一项关于靶向B7H3的ADC药物HS-20093和PD-L1抗体Adebrelimab、EGFR抗体Cetuximab、前列腺去势药物恩杂鲁胺(Enzalutamide)以及在卡铂、依托泊苷多种药物，在多种实体瘤中开展药物联用的一期临床试验，计划入组610例患者。HS-20093的海外授权曾于2023年12月以1.85亿美元首付款，最多15.25亿美元里程碑付款授于GSK。 除此以外，映恩生物的靶向PD-L1/B7H3双抗ADC药物DB-1419的临床试验申请于2024年9月受理，临床前研究显示，DB-1419在各类肿瘤细胞中均表现了抑制作用，相比于靶向B7H3 ADC药物，体现出更强的抗肿瘤活性。 关于宜联生物 宜联生物成立于2020年7月8日，是一家专注于抗体药物结合物（ADC）和相关技术的创新药物开发公司。 公司已开发出最新一代具有自主知识产权的Tumor Microenvironment Activable LINker-payload（TMALIN®）新型抗体偶联药平台技术，可利用肿瘤微环境和传统溶酶体在胞外胞内实现双重裂解机制、兼具高水溶性、高均一性、高体内外稳定性以及肿瘤组织富集特性。具体表现为： 独特的酶消化特性，具有在肿瘤微环境中细胞外溶解的能力，无论抗体是否具有内吞能力，所形成的ADC仍具有较高的抗肿瘤活性，大大拓宽了抗体的选择范围； 这种特殊的结构使ADC能够丰富肿瘤微环境，增加肿瘤中有效载荷的比例和血液浓度，并具有较高的治疗指数； 酶消化特性和肿瘤富集特性使有效载荷在肿瘤组织中大大富集，产生较强的旁观者效应，在抗原表达低甚至无抗原表达的肿瘤中产生良好的抗肿瘤作用。 此外，TMALIN技术形成的ADC具有许多优点，已在多个体内药效模型与大动物毒理评价实验中，展现出相比于现有ADC技术更宽的药物治疗窗。具体优势包括： 它具有极高的全身循环稳定性，可减少有效载荷在非靶组织中的脱落以及有效载荷在无靶组织中脱落所引起的“偏离靶”毒性。 它具有优异的溶解性和优异的化学稳定性，不存在传统ADC中马来酰亚胺连接方式引起的可逆Michael加成反应，可以获得高均匀度的ADC（DAR=8.0），并实现定点定量耦合。 耦合效率高(≥90%）。 目前，公司已有多款基于该平台的ADC产品进入临床试验阶段。 参考资料 1、各公司官网 2、UmabsDB 感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618”。 “在看”点一下

PLYMOUTH, MA, USA I January 13, 2025 I GSK plc (LSE/NYSE: GSK) and IDRx, Inc. (IDRx) today announced that they have entered into an agreement under which GSK will acquire IDRx, a Boston-based, clinical-stage biopharmaceutical company dedicated to developing precision therapeutics for the treatment of GIST. Under the agreement, GSK will pay $1 billion upfront, with potential for an additional $150 million success-based regulatory approval milestone payment. The acquisition includes lead molecule, IDRX-42, a highly selective KIT TKI being developed as a first- and second-line therapy for the treatment of GIST. GIST typically presents in the GI tract with 80% of cases driven by mutations in the KIT gene that lead to the growth, proliferation, and survival of tumour cells (primary or activating mutations). 1 90% of patients treated in the first-line develop new KIT mutations (secondary or resistance mutations) that typically lead to relapse with limited therapeutic options. 2 Currently, there are no approved TKIs that inhibit the full spectrum of clinically relevant primary and secondary mutations in KIT. IDRX-42 has demonstrated activity against all key primary and secondary KIT mutations, designed to improve outcomes for patients with GIST. This breadth of mutational coverage, in addition to high selectivity which could improve tolerability, provides potential for a best-in-class profile. Luke Miels, Chief Commercial Officer, GSK, said: “IDRX-42 complements our growing portfolio in gastrointestinal cancers. This acquisition is consistent with our approach of acquiring assets that address validated targets and where there is clear unmet medical need, despite existing approved products.” Tony Wood, Chief Scientific Officer, GSK, said: “We are excited by the early data from IDRX-42 and its unique ability to target all clinically relevant KIT mutations present in GIST, a major gap in the current standard of care. We look forward to accelerating its development in 2025 to redefine treatment.” Updated clinical data from StrateGIST 1, an ongoing phase I/Ib trial of IDRX-42 in patients with advanced GIST, were presented in an oral presentation at the Connective Tissue Oncology Society (CTOS) 2024 Annual Meeting. These data show promising anti-tumour activity of IDRX-42 in patients with advanced GIST with a manageable safety profile. Across patients with second-line or greater GIST, and amongst all KIT mutation subsets, the objective response rate (ORR) by modified RECIST v1.1 in the total efficacy evaluable population was 29% (n=87), including one complete response (CR) and 24 partial responses (PRs). Amongst patients who have had one prior line of therapy, the ORR was 53% (n=15) including one CR and 7 PRs. 3 Across all patients, two of the PRs were awaiting confirmation at the time of the data cut, both of which were subsequently confirmed. The emerging durability data from StrateGIST 1 was also favourable. IDRX-42 was generally well-tolerated and treatment-related adverse events (TRAEs) were mainly low grade at the recommended phase Ib dose. 4 Tim Clackson, CEO, IDRx, said: “We are looking forward to working with GSK to advance IDRX-42 for patients with GIST given there have been no major advances to the standard of care for almost 20 years. Combining our experience to date with GSK’s expertise in GI cancers, global clinical development capability, and strong commercial presence in oncology will help to accelerate the development of this novel medicine for patients.” GSK has a growing portfolio in development targeting the significant medical need in GI cancers, including ongoing trials with dostarlimab and GSK5764227 (GSK’227), a B7-H3-targeted antibody-drug conjugate. This agreement reflects GSK’s portfolio approach of identifying potentially best-in-class molecules with targeted mechanisms of action. The transaction supports GSK’s ambitions for growth through 2031 and beyond. IDRx was founded in 2021 with a mission to address the limitations of today’s precision cancer medicines with highly potent and selective targeted therapies to stop key tumor escape mechanisms and prolong patients’ response to therapy. IDRx investors include Andreessen Horowitz (a16z), Casdin Capital, Nextech Invest, Forge Life Science Partners, RA Capital Management, Commodore Capital, Blackstone Multi-Asset Investing and Rock Springs Capital. IDRx co-founders include George Demetri, M.D., FACP, FASCO, FAACR, Nicholas Lydon, Ph.D., Alexis Borisy, Robert Forrester and Ben Auspitz. Financial considerations Under the terms of the agreement, GSK will acquire one hundred percent (100%) of the outstanding equity interests (including all options and other incentive equity) in IDRx for up to $1.15 billion of total cash consideration, comprising an upfront payment of $1 billion with potential for an additional $150 million success-based regulatory approval milestone payment. GSK will also be responsible for success-based milestone payments as well as tiered royalties for IDRX-42 owed to Merck KGaA, Darmstadt, Germany. This transaction is subject to customary conditions, including applicable regulatory agency clearances under the Hart-Scott-Rodino Act in the US. For IDRx, Centerview Partners LLC is acting as exclusive financial advisor and Goodwin Procter LLP as legal counsel. For GSK, Leerink Partners LLC is acting as the exclusive financial advisor. About GIST Gastrointestinal stromal tumours (GIST) are the most common subtype of soft tissue sarcoma, with about 80,000 to 120,000 patients diagnosed with GIST per year worldwide. 5 GIST typically presents in the GI tract with 80% of cases driven by mutations in the KIT gene that lead to the growth, proliferation, and survival of tumour cells (primary or activating mutations in exons 9 and 11). 6 Additionally, about 90% of patients treated in the first-line develop new KIT mutations (secondary or resistance mutations in exons 13 and 17) that typically lead to relapse with limited therapeutic options. 7 There are no approved TKIs that inhibit the full spectrum of clinically relevant primary and secondary mutations in KIT. About IDRX-42 IDRX-42 is a highly selective, investigational small molecule tyrosine kinase inhibitor (TKI) designed to target all key KIT mutations in GIST. The U.S. Food and Drug Administration (FDA) has granted IDRX-42 Fast Track designation for the treatment of patients with GIST after disease progression on or intolerance to imatinib, and Orphan Drug designations for the treatment of GIST. About IDRx IDRx is a clinical-stage biopharmaceutical company dedicated to transforming cancer care with intelligently designed precision therapies. IDRx aims to address the limitations of today’s precision cancer medicines with highly potent and selective targeted therapies to stop key tumour escape mechanisms and prolong response to therapy. About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com. References 1 Bauer S, George S, von Mehren M, Heinrich MC. Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor. Front Oncol. 2021 Jul 12;11:672500. 2 Zhou S, Abdihamid O, Tan F, Zhou H, Liu H, Li Z, Xiao S, Li B. KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST. Cell Commun Signal. 2024 Feb 27;22(1):153. 3 George et al CTOS 2024 4 George et al CTOS 2024 5 Søreide K, Sandvik OM, Søreide JA, Giljaca V, Jureckova A, Bulusu VR. Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies. Cancer Epidemiol. 2016 Feb;40:39-46. 6 Bauer S, George S, von Mehren M, Heinrich MC. Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor. Front Oncol. 2021 Jul 12;11:672500. 7 Zhou S, Abdihamid O, Tan F, Zhou H, Liu H, Li Z, Xiao S, Li B. KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST. Cell Commun Signal. 2024 Feb 27;22(1):153. SOURCE: GlaxoSmithKline