Innovent Biologics, Inc.

RAS是一种重要的致癌基因，此前一直被认为是“不可成药”靶点，直到全球首款获批的KRAS抑制剂上市，打破这一僵局。然而，Sotorasib近期受到了FDA ODAC对其疗效的质疑：ODAC认为主要研究终点盲态独立中心评估的无进展生存期（PFS）无法被可靠地解释；此外，全球第二款上市的KRAS G12C抑制剂Adagrasib也在欧盟上市时遇到阻碍，上市申请被EMA建议拒绝。尽管FDA和EMA暂时没有作出下一步动作，但对于KRAS抑制剂来说，其面临的严峻“大考”，随着时间的推移变得日渐扑朔迷离。01KRAS抑制剂的「生死劫」RAS突变是许多癌症的遗传驱动因素，包括结直肠癌、胰腺导管腺癌、肺腺癌、黑色素瘤和某些血液系统癌症。虽然这些肿瘤类型是由RAS突变驱动的，但亚型，密码子和RAS突变的频率因组织类型而异。大约32%的LUAD，86%的PDAC和41%的CRC由KRAS突变驱动，KRAS突变主要发生在这些肿瘤类型的密码子12处。相比之下，29%的黑色素瘤是由NRAS突变驱动的，与KRAS不同，这些突变发生在密码子61处（图1）。图1 KRAS突变与疾病关系图片来源：参考文献1此前，由于KRAS蛋白的无特征、近乎球形的结构以及KRAS与GTP、或GDP的结合非常强等原因，导致KRAS一直被认为“不可成药”靶点。直到首款KRAS G12C抑制剂Sotorasib的上市打破了这个僵局。目前，全球仅有的两款靶向KRAS G12C抑制剂Sotorasib和Adagrasib获批上市，然而上市后的表现不尽人意。近日，FDA肿瘤药物咨询委员会（ODAC）针对Sotorasib的III期验证临床CodeBreak 200进行一场论证会议，最终以2票赞同，10票反对，认为主要研究终点盲态独立中心评估的无进展生存期（PFS）无法被可靠地解释。Adagrasib是全球第二款获批上市的KRASG12C药物，于2022年12月12日被FDA批准上市。今年7月，该款药物在进军欧盟时，其上市申请被EMA建议拒绝。随着Sotorasib受到了FDA ODAC对其疗效的质疑，及Adagrasib在欧盟上市受阻，给其余在研KRAS抑制剂的未来，增添一丝不确定性。02KRAS抑制剂在研分析虽然药物进展一波三折，但KRAS抑制剂赛道依旧热火朝天，且目前上市的两款药物仅靶向KRAS G12C失活状态，仍需要新的KRAS抑制剂来满足巨大的临床需求。国内外药企纷纷布局KRAS G12C抑制剂，如安进、诺华、罗氏、Mirati、信达生物、加科思、益方生物和贝达药业等（图2）。图2 部分进入临床的KRAS抑制剂数据来源：公开数据整理1.Divarasib（GDC-6036）Divarasib是由罗氏研发的一款新型KRAS G12C抑制剂，针对KRAS G12C突变NSCLC适应症已开发至2/3期临床阶段。同时也在探索其他瘤种，如结直肠癌等。经过体外实验证实，Divarasib的疗效和选择性均优于Sotorasib和Adagrasib。近期，Adrian等人在新英格兰医学杂志上报道了Divarasib在KRAS G12C突变肿瘤中的1期临床结果（NCT04449874)：在NSCLC患者中，ORR为53.4%，中位无进展生存期为13.1个月。在结直肠癌患者中，ORR为29.1%，中位无进展生存期为5.6个月。在其他实体瘤中，36%的最佳反应为部分缓解。2.IBI-351IBI-351是由劲方医药研发的一款高效口服共价、高选择性的KRAS G12C抑制剂，信达生物于2021年9月与劲方医药宣布就IBI-351达成全球独家授权协议。IBI-351于2023年5月15日被CDE纳入突破性治疗药物（BTD）品种名单，成为国内首个纳入突破性治疗药物、治疗晚期结直肠癌的KRAS G12C抑制剂。在今年的AACR会议上，公布了IBI-351的一项1期剂量递增结果：截至2022年12月15日，在所有剂量水平的67个可评估反应的NSCLC患者中，ORR为58.2%，确认的ORR为44.8%；疾病控制率为92.5%。在600mg BID剂量水平（RP2D）下，ORR为63.3%，确认ORR为50.0%，DCR为96.7%。今年的ASCO会议上，公布了IBI-351单药治疗携带KRASG12C突变的转移性结直肠癌的有效性和安全性的两项1期研究初步结果(NCT05005234,NCT05497336)。研究结果显示：截至2022年12月15日，所有剂量水平的疗效可评估患者的ORR为47.5%，DCR为85.0%。未达到中位缓解持续时间（DOR）。对于32例600mg BID的疗效评估患者，ORR和DCR分别为43.8%（14/32）和87.5%。3.MRTX-1133KRAS G12D也是一种非常常见的突变，胰腺癌90%是KRAS基因突变，大部分的KRAS基因突变是G12D位点（占比40%）。相较于KRAS G12C抑制剂的火热研发赛道，KRAS G12D抑制剂的研发较为冷清，其中Mirati的MRTX-1133是目前进展最快的KRAS G12D抑制剂，于今年1月份被FDA批准进入临床1/2期。KRAS G12C抑制剂大部分都是共价抑制剂，需要与12位半胱氨酸共价结合，G12D抑制剂不需要此共价作用，所以MRTX-1133是一款非共价KRAS G12D抑制剂。MRTX1133结合KRAS G12D的非活性和活性状态，并通过SPR证明KRAS G12D与WT KRAS的选择性是>500倍，临床前研究中，MRTX1133给药对于KRAS G12D突变的胰腺癌模型以及肺癌和结肠癌症模型，有显著的抗肿瘤作用。MRTX1133在两年前就已经报道，但由于口服生物利用度极低，一直未能申报IND，最后通过制剂手段实现了口服给药，但AUC也仅仅提高了10倍左右，生物利用度仍然很低，存在很大的优化空间。4.HRS-4642HRS-4642是由恒瑞自主研发的一款靶向KRAS G12D突变创新药物，于去年8月被NMPA批准临床，成为国内首个获批临床的KRAS G12D抑制剂。今年10月20-24日即将召开的欧洲肿瘤内科学会（ESMO）上同济大学附属上海市肺科医院周彩存教授团队将首次报道HRS-4642注射液在携带KRAS G12D突变的晚期实体瘤受试者中的安全性、耐受性、药代动力学的1期临床数据。5.RMC-6236RMC-6236是由Revolution Medicines研发的一种首创的、口服生物可利用的、针对多种RAS突变和野生型RAS的pan-RAS选择性三复合物抑制剂，它与细胞内伴侣蛋白亲环蛋白A（CypA）结合，产生抑制性二元复合物，该复合物结合活性GTP结合的RAS形成三复合物，并通过破坏与效应物（如RAF激酶）的相互作用来抑制RAS信号传导。RMC-6236是首个进入临床的pan-KRAS抑制剂，目前正在临床1/1b期评价。除此之外，Revolution Medicines还开展了一系列KRAS抑制剂研究，包括KRAS G12C抑制剂RMC-6291和KRAS G13C抑制剂RMC-8839等。6.YL-17231YL-17231是由璎黎药业研发的pan-KRAS抑制剂，于今年7月份先后在美国和中国获批临床，是首个国产进入临床的pan-KRAS抑制剂。除此之外，璎黎药业还有一款靶向KRAS G12C的抑制剂YL-15293处于临床2期。03小结随着全球医药研发的不断深入，KRAS已经从“不可成药”靶点变成可成药靶点，相信近期KRAS抑制剂遇到的困难只是暂时的，期待全球药企的突破性进展。参考文献：1.Amanda R.Moore,Scott C.Rosenberg,Frank McCormick2 and Shiva Malek,RAS-targeted therapies:is the undruggable drugged?Nat Rev Drug Discov.2020 Aug;19(8):533-552.2.https://www.fda.gov/media/172696/download3.Adrian Sacher,M.D.et.al,Single-Agent Divarasib(GDC-6036)in Solid Tumors with a KRAS G12C Mutation,N Engl J Med 2023;389:710-21.4.https://aacrjournals.org/cancerres/article/83/8_Supplement/CT030/725402/Abstract-CT030-Phase-I-study-of-IBI351-GFH9255.https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.3586声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 八角转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信） 阅读原文，是昨天最受欢迎的文章哦

Synaffix to provide access to proprietary Antibody-Drug Conjugate (ADC) technologies SOTIO to develop up to three next generation bioconjugates Total potential deal value of up to $740 million, plus royalties on commercial sales for three ADC programs AMSTERDAM, Oct. 16, 2023 /PRNewswire/ -- Synaffix B.V., a Lonza company (SIX:LONN) focused on commercializing its clinical-stage platform technology for the development of antibody-drug conjugates (ADCs) with best-in-class therapeutic index, enters licensing agreement with SOTIO Biotech (SOTIO), a clinical stage immuno-oncology company owned by PPF Group. SOTIO will gain access to Synaffix's ADC technologies, GlycoConnect™, HydraSpace™ and toxSYN™ linker-payloads, in an initial ADC program with the option to expand research and commercial licenses into two additional programs at a later date. Under the terms of the agreement, Synaffix will be eligible to receive up to $740 million in payments spanning signature, target nomination and milestone payments plus additional royalties on commercial sales. SOTIO will be responsible for the research, development, and commercialization of the ADCs. Synaffix will be responsible for the manufacturing of components that are specifically related to its proprietary technologies. Peter van de Sande, Head of Synaffix, said: "The selection of our ADC technologies by a seasoned ADC player like SOTIO is a strong recognition of the potential of these technologies to maximize the therapeutic index of ADCs. We look forward to partnering with SOTIO, and believe that with their singular focus on cancer immunotherapies and robust clinical pipeline, this partnership can deliver innovative medicines for patients in areas of high unmet medical need." Radek Spisek, Chief Executive Officer of SOTIO, said: "At SOTIO, we are building a broad pipeline of next-generation ADCs to address the challenges of solid tumors – and access to Synaffix's ADC platform technologies will ensure we remain at the leading edge of this space. This collaboration combining SOTIO's deep expertise in solid tumor drug development with Synaffix's clinical-stage platform technology will drive important new innovations for the benefit of patients." Synaffix was fully acquired by Lonza in June 2023 and represents a newly formed 'Center of Excellence' for bioconjugation. As a Lonza company, Synaffix will continue to operate under the Synaffix name and further expand its operations in Oss (NL) to cater for further innovation and growth. About Synaffix Synaffix B.V. is a biotechnology company that enables ADC product candidates using its clinical-stage, site-specific ADC technology platform based on GlycoConnect™, HydraSpace™ and toxSYN™, that together enable any company with an antibody to develop proprietary best-in-class ADC products under a single license from Synaffix. The Synaffix platform enables a rapid timeline to clinic due to the established supply chain of technology components. Granted patents covering Synaffix' technology provide end-to-end protection of the manufacturing technology as well as the resulting products through at least 2039. The business model of Synaffix is target-specific technology out-licensing, as exemplified through its existing deals with ADC Therapeutics, Mersana Therapeutics, Shanghai Miracogen (acquired by Lepu Biopharma), Innovent Biologics, ProfoundBio, Kyowa Kirin, Genmab, Macrogenics, Emergence Therapeutics (acquired by Eli Lilly), Amgen, Hummingbird Biosciences, Chong Kun Dang Pharma and ABL Bio. Synaffix was fully acquired by Lonza in June 2023. About The Synaffix ADC Platform Technology Synaffix' proprietary ADC technology platform consists of GlycoConnect™, HydraSpace™ and toxSYN™ technologies. These technologies are aimed at enabling best-in-class ADCs from any antibody, with significantly enhanced efficacy and tolerability. GlycoConnect™ is a clinical-stage conjugation technology that exploits the native antibody glycan for site-specific and stable payload attachment and is tunable to DAR1, DAR2 or DAR4 formats. HydraSpace™ is a clinical-stage compact and highly polar spacer technology that is designed to further enhance therapeutic index, particularly with hydrophobic payloads. toxSYN™ is a linker-payload platform that spans key, validated MOAs for ADC product development. This includes potent topoisomerase 1 inhibitor (SYNtecan E™), DNA damaging agents (SYNeamicin D™ and SYNeamicin G™), ⍺-Microtubule (SYNtansine™) and β-Microtubule (SYNstatin E™ and SYNstatin F™) inhibitors as well as several unlaunched proprietary linker-payloads that were generated through the ongoing innovative efforts of the Synaffix R&D team. The combination of these three technologies provides developers with a "one stop" and easy-to-use ADC technology platform, allowing any antibody developer to develop its own proprietary ADC and any ADC developer to expand its pipeline further and increase its competitive position. About Lonza Lonza is a preferred global partner to the pharmaceutical, biotech and nutrition markets. We work to enable a healthier world by supporting our customers to deliver new and innovative medicines that help treat a wide range of diseases. We achieve this by combining technological insight with world-class manufacturing, scientific expertise and process excellence. Our business is structured to meet our customers' complex needs across four divisions: Biologics, Small Molecules, Cell & Gene and Capsules & Health Ingredients. Our unparalleled breadth of offerings across divisions enables our customers to commercialize their discoveries and innovations in the healthcare industry. Founded in 1897 in the Swiss Alps, today, Lonza operates across five continents. With approximately 17,500 full-time employees, we comprise high-performing teams and individual talent who make a meaningful difference to our own business, as well as to the communities in which we operate. The company generated sales of CHF 3.1 billion with a CORE EBITDA of CHF 922 million in Half-Year 2023. Find out more at Follow @Lonza on LinkedIn Follow @LonzaGroup on Twitter About SOTIO SOTIO Biotech (SOTIO) is shaping the future of cancer immunotherapies by translating compelling science into patient benefit. The SOTIO pipeline includes SOT102, a next-generation Claudin-18.2-targeted antibody-drug conjugate which entered the clinic in 2022; BOXR1030, a metabolically-enhanced CAR-T cell therapy targeting GPC3-expressing tumors as well as other molecules approaching clinical stage such as SOT201, our next-generation PD-1-inhibiting cytokine. SOTIO is a member of the PPF Group. For more information, please visit the company's website at . SOTIO is a registered trademark of SOTIO Biotech a.s. in selected countries. SOURCE Synaffix

SOTIO will leverage Synaffix’s antibody-drug conjugate platform for the design of up to three novel ADCs to address indications with high unmet medical need Collaboration bolsters SOTIO’s wider portfolio of differentiated immuno-oncology therapies tailored to address the specific challenges of solid tumors Synaffix will receive an upfront payment and potential development milestone payments totaling $740 million PRAGUE--(BUSINESS WIRE)-- SOTIO, a clinical-stage immuno-oncology company owned by PPF Group, today announced a license and option agreement with Synaffix B.V., a Lonza company, to develop next-generation antibody-drug conjugates (ADCs) for the treatment of solid tumors. SOTIO will leverage Synaffix’s ADC technology platform to develop up to three novel ADCs targeting distinct tumor-associated antigens. “At SOTIO, we are building a broad pipeline of next-generation ADCs to address the challenges of solid tumors – and access to Synaffix’s ADC platform technologies will ensure we remain at the leading edge of this space,” said Radek Spisek, M.D., Ph.D., chief executive officer of SOTIO. “This collaboration combining SOTIO’s deep expertise in solid tumor drug development with Synaffix’s clinical-stage platform technology will drive important new innovations for the benefit of patients.” The deal enables SOTIO to combine its proprietary antibodies with Synaffix’s ADC technology platform in order to deliver innovative new ADCs that can overcome the challenges of treating solid tumors. In addition to GlycoConnect™ and HydraSpace™, the deal also includes Synaffix’s potent linker-payload platform including multiple different payloads. “Synaffix’s ADC technology perfectly complements the technologies already in SOTIO’s ADC platform, including the iADC technology licensed from NBE-Therapeutics and the ConjuALL technology licensed from LegoChem,” said Martin Steegmaier, chief scientific officer of SOTIO. “The addition of Synaffix’s capabilities will greatly expand our ability to select and tailor the most suitable ADC technology and payload for the needs of a particular target and particular solid tumor indication.” Under the terms of the agreement, Synaffix is eligible to receive upfront and potential milestone payments worth up to $740 million, plus single-digit royalties on net sales. SOTIO will be responsible for research, development, manufacturing and commercialization of the ADC products, while Synaffix will closely support SOTIO’s research activities and be responsible for the manufacturing of components that are specifically related to its proprietary GlycoConnect™, HydraSpace™, and linker-payload technologies. Peter van de Sande, head of Synaffix, added, “The selection of our ADC technologies by a seasoned ADC player like SOTIO is a strong recognition of the potential of these technologies to maximize the therapeutic index of ADCs. We look forward to partnering with SOTIO, and believe that with their singular focus on cancer immunotherapies and robust clinical pipeline, this partnership can deliver innovative medicines for patients in areas of high unmet medical need.” SOTIO is advancing a pipeline of novel ADCs tailored to address the treatment needs of specific solid tumor types. SOT102, the company’s most advanced ADC program, is a CLDN18.2-targeting ADC in Phase 1/2 development for the treatment of gastric, pancreatic and other cancers that have very few targeted treatment options available. The company is progressing dose-finding studies in the trial’s monotherapy arm, with SOT102 as a later-stage treatment, and recently announced the initiation of the trial’s combination therapy arm in first-line treatment of gastric and pancreatic cancer patients. SOTIO additionally has two other ADC programs in preclinical development. About Synaffix Synaffix B.V. is a biotechnology company that enables ADC product candidates using its clinical-stage, site-specific ADC technology platform based on GlycoConnect™, HydraSpace™ and toxSYN™, that together enable any company with an antibody to develop proprietary best-in-class ADC products under a single license from Synaffix. The Synaffix platform enables a rapid timeline to clinic due to the established supply chain of technology components. Granted patents covering Synaffix’ technology provide end-to-end protection of the manufacturing technology as well as the resulting products through at least 2039. The business model of Synaffix is target-specific technology out-licensing, as exemplified through its existing deals with ADC Therapeutics, Mersana Therapeutics, Shanghai Miracogen (acquired by Lepu Biopharma), Innovent Biologics, ProfoundBio, Kyowa Kirin, Genmab, Macrogenics, Emergence Therapeutics (acquired by Eli Lilly), Amgen, Hummingbird Biosciences, Chong Kun Dang Pharma and ABL Bio. Synaffix was fully acquired by Lonza in June 2023. For more information, please visit the website at . About SOTIO SOTIO Biotech (SOTIO) is shaping the future of cancer immunotherapies by translating compelling science into patient benefit. The SOTIO pipeline includes SOT102, a next-generation Claudin-18.2-targeted antibody-drug conjugate which entered the clinic in 2022; BOXR1030, a metabolically-enhanced CAR-T cell therapy targeting GPC3-expressing tumors as well as other molecules approaching clinical stage such as SOT201, our next-generation PD-1-inhibiting cytokine. SOTIO is a member of the PPF Group. For more information, please visit the company’s website at . SOTIO is a registered trademark of SOTIO Biotech a.s. in selected countries. View source version on businesswire.com: Contacts Company contact: Richard Kapsa Head of Communication T: (+420) 224 174 448 M: (+420) 603 280 971 kapsa@sotio.com Media contact: Lisa Raffensperger Ten Bridge Communications M: +1 (617) 903-8783 lisa@tenbridgecommunications.com Source: SOTIO Biotech View this news release online at: