A2B-694

Presentations Detail Ongoing CEA and Mesothelin Phase 1/2 Clinical Trials In Progress Evaluating Investigational Tmod™ CAR T-Cell Therapies for Patients with Solid Tumors Additional Poster Demonstrates Impact of Expanded Biomarker Prescreening to Improve Diversity in Clinical Trials CHICAGO--(BUSINESS WIRE)-- A2 Biotherapeutics , Inc. (A2 Bio), a clinical-stage cell therapy company developing first-in-class logic-gated cell therapies for solid tumors, will present updates on three ongoing clinical trials in poster presentations during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. A2 Bio will present two Trials in Progress posters on its first-in-human (FIH) Phase 1/2 studies, EVEREST-1 and EVEREST-2, as well as a poster highlighting how a greater understanding of the structure of Tmod™ allowed the BASECAMP-1 master prescreening study to increase the ethnic and racial diversity of patients enrolled in its clinical trials. “Diversity in clinical studies is essential to address racial and ethnic groups who are often underrepresented in clinical trials, especially in precision medicine studies using genetic data. We are creating the future of precision medicine by applying advanced bioinformatics in our BASECAMP-1 prescreening protocol to efficiently screen patients for enrollment in these ongoing CAR T-cell clinical trials. Expanding the enrollment criteria to include all HLA-A*02 patients will further enhance the diversity in our trial,” said Julian R. Molina, M.D., Ph.D., Professor of Oncology, Mayo Clinic, Rochester, MN. Significant challenges remain in harnessing the potential of cell-based therapies due to a lack of tumor‑specific targets that discriminate cancer from normal cells, resulting in on‑target, off‑tumor toxicity. The investigational therapies being studied by A2 Bio in EVEREST-1 (A2B530 targeting carcinoembryonic antigen [CEA]) and EVEREST-2 (A2B694 targeting mesothelin [MSLN]) apply the company’s proprietary Tmod™ platform which utilizes a dual-receptor design consisting of an activator that targets tumor cells and a blocker that protects normal cells to provide selective tumor killing.1 “We are encouraged by the clinical trial progress presented during ASCO 2024. A2 Bio is advancing the clinical development of our innovative CAR T-cell therapies and pioneering a new model for enhancing safety, efficiency and diversity in our interventional trials, and therefore addressing important unmet medical needs,” said William Go, M.D., Ph.D., chief medical officer of A2 Bio. The poster presentations are scheduled on Saturday, June 1, 9:00 am – 12:00 pm CT. EVEREST-1 (NCT05736731) is a FIH study evaluating A2B530 in patients with solid tumors that express CEA and have human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH). The first patient in EVEREST-1 was dosed in May 2023 and dose escalation continues, with 10 patients treated to date. EVEREST-2 (NCT06051695) is also a FIH study evaluating A2B694 in patients with solid tumors that express MSLN and have HLA-A*02 LOH. The first patient was dosed in May 2024 in this study to evaluate the safety and efficacy of A2B694. BASECAMP-1 (NCT04981119) is a master prescreening, precision medicine study identifying patients with unresectable, advanced or metastatic solid tumors with HLA-A*02 LOH; patients undergo leukapheresis and Tmod™ CAR T cells are manufactured for patients who may enroll in the ongoing EVEREST-1 and EVEREST-2 clinical trials. BASECAMP-1 enrollment began with screening for patients with the HLA-A*02:01 allele only. Nonclinical testing determined that the Tmod™ blocker was effective against other HLA-A*02:XX alleles, and enrollment was expanded to patients with any HLA-A*02 allele subtype. Because HLA-A*02:XX subtypes are more prevalent in non-whites, this change improved the racial and ethnic diversity of the BASECAMP-1 study population. By expanding enrollment, 16% more Hispanic, 43% more African-American, and 112% more Asian or Pacific Islander patients were identified. For more information on A2 Bio clinical trials, please visit About the Tmod™ Platform A2 Bio has pioneered a precision-targeting cellular system – the Tmod™ mechanism – that incorporates two receptors, an activator and a blocker, to aim the powerful armaments of immune cells directly at tumors to unequivocally differentiate tumors from normal tissues. The activator recognizes antigens on tumor cells that trigger their destruction, while the blocker recognizes antigens on normal cells that protect them. This novel blocker technology enables precise, personalized and effective T cell targeting. The blocker component equips Tmod™ cells with the capacity to identify tumors as distinct from normal cells. About EVEREST-1 EVEREST-1 (NCT05736731) is a seamless Phase 1/2 study for A2B530, an autologous logic-gated investigational cell therapy developed from A2 Bio’s proprietary Tmod™ platform. The Tmod™ platform provides selective killing of tumor cells and protection of normal cells via a dual-receptor design consisting of an activator that targets tumor cells and a blocker that protects normal cells. A2B530 consists of an activator that targets carcinoembryonic antigen (CEA) and a blocker that targets HLA-A*02. HLA-A*02 is lost in tumor cells and present in normal cells in the eligible patient population. The study is recruiting patients with non-small cell lung, colorectal and pancreatic cancers. About EVEREST-2 EVEREST-2 (NCT06051695) is a seamless Phase 1/2 study for A2B694, an autologous logic-gated investigational cell therapy developed from A2 Bio’s proprietary Tmod™ platform. The Tmod™ platform provides selective killing of tumor cells and protection of normal cells via a dual-receptor design consisting of an activator that targets tumor cells and a blocker that protects normal cells. A2B694 consists of an activator that targets mesothelin (MSLN) and a blocker that targets HLA-A*02. HLA-A*02 is lost in tumor cells and present in normal cells in the eligible patient population. The study is recruiting patients with non-small cell lung, colorectal, pancreatic, ovarian and mesothelioma cancers. About BASECAMP-1 BASECAMP-1 (NCT04981119) is a prescreening study to identify patients for potential treatment in A2 Bio’s clinical trials. It is a novel approach to help optimize patient treatment outcomes by enabling patients' immune cells to be banked in their healthiest state earlier in their course of cancer treatment. Next-generation sequencing is used to identify patients who have lost HLA-A*02, the biomarker of interest for A2 Bio’s studies. Patients then undergo leukapheresis to collect, process, and store patient T cells for future Tmod™ CAR T cell therapy. BASECAMP-1 is currently enrolling patients with non-small cell lung, colorectal, pancreatic, ovarian and mesothelioma cancers. About A2 Biotherapeutics A2 Biotherapeutics, Inc. (A2 Bio) is a clinical-stage biotech company developing first-in-class logic-gated cell therapies to address the high unmet need in cancers. A2 Bio invented the proprietary Tmod™ cell therapy platform to tackle the fundamental challenge in cancer treatment—the ability of cancer medicines to distinguish between tumor and normal cells. For more information, please visit the company’s website at . References: 1 Breanna DiAndreth, Agnes E. Hamburger, Han Xu, Alexander Kamb: The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clinical Immunology, Volume 241, 2022, 109030.

▎药明康德内容团队编辑近期，全球细胞和基因疗法（CGT）领域迎来系列进展。百时美施贵宝嵌合抗原受体（CAR）T细胞疗法Breyanzi再获FDA加速批准，治疗复发/难治性滤泡性淋巴瘤（FL）。Rocket Pharmaceuticals公司公布了3项在研基因疗法的积极数据，其中两款疗法已分别在美国和欧洲递交上市许可申请。PTC Therapeutics的基因疗法Upstaza获得了FDA授予的优先审评资格。本文将节选其中部分重要进展做简单介绍，仅供读者参阅。图片来源：123RF———✦研发进展✦———◇ 美国FDA宣布，加速批准百时美施贵宝的CD19靶向自体CAR-T细胞疗法Breyanzi扩展适应症，用于治疗复发/难治性FL成人患者，这些患者已经接受过两种及以上前期系统治疗。这是Breyanzi在今年3月获得FDA加速批准治疗复发/难治性慢性淋巴细胞白血病（R/R CLL）或小淋巴细胞淋巴瘤（SLL）成人患者后，再度获批扩展适用范围。这一加速批准是基于2期临床试验TRANSCEND-FL的积极结果。在这项单臂，开放标签临床试验中，接受Breyanzi治疗的患者在中位随访时间为16.8个月时，总缓解率（ORR）达到95.7%，中位缓解持续时间尚未达到。◇ PTC Therapeutics宣布，美国FDA已接受该公司为Upstaza（eladocagene exuparvovec）递交的生物制品许可申请（BLA），并授予其优先审评资格，用于治疗芳香族L-氨基酸脱羧酶缺乏症（AADCD）患者。FDA预计在今年11月13日之前完成审评。Upstaza的疗效和安全性特征在多个临床试验和同情用药项目中得到验证，首例患者在2010年接受治疗。在临床研究中，无法达到预期运动发育里程碑的患者早在接受治疗3个月后就能观察到具有临床意义的运动功能改善，这一转变持续到接受治疗后5年以上。此外，所有接受治疗患者的认知能力得到改善。临床试验的结果已经在《细胞》旗下的Molecular Therapy上发表。2022年，它首次获得欧盟委员会批准上市，成为直接注入大脑的首款获批基因疗法，也是改变AADCD疾病进程的首款获批疗法。Upstaza是一款基于腺相关病毒2（AAV2）载体的基因疗法，携带正常的人类DDC基因。它旨在通过一次性治疗，将功能正常的DDC基因直接递送到大脑的壳核中，提高AADC酶的水平并恢复多巴胺的生产。◇ Rocket Pharmaceuticals公司在美国基因和细胞治疗学会（ASGCT）年会中，公布了数款慢病毒（LV）载体基因疗法的最新数据。分析显示，其用以治疗严重白细胞粘附缺陷-I（LAD-I）的基因疗法Kresladi（marnetegragene autotemcel），与用以治疗范可尼贫血（FA）的RP-L102皆在1/2期关键研究中展现良好的有效性与安全性。其另一款用以治疗丙酮酸激酶缺乏症（PKD）的在研基因疗法RP-L301也在1期试验中展现积极结果。目前，美国FDA正在对Kresladi用以治疗LAD-I的BLA申请进行审评，PDUFA目标日期为2024年6月30日。同时，欧洲药品管理局（EMA）也已接收RP-L102的上市许可申请（MAA），Rocket预计将在2024年上半年向美国FDA提交相关BLA。▲接受Kresladi治疗的LAD-I患者发生严重感染而需要住院的发生率大幅下降（图片来源：参考资料[14]）▲接受RP-L102治疗的FA患者的疾病表型获得校正（图片来源：参考资料[14]）▲接受RP-L301治疗的PKD患者的血红蛋白水平获得改善（图片来源：参考资料[14]）◇ Immix Biopharma公司公布了其子公司Nexcella公司开发的靶向BCMA的自体CAR-T细胞疗法NXC-201的1b/2a期临床试验的新数据。数据显示，复发/难治性轻链（AL）淀粉样变性患者的ORR为92%（12/13），12例既往未接受过BCMA靶向双特异性治疗的患者均对NXC-201有应答，69.2%（9/13）的患者获得了完全缓解（CR）。1例既往接受过BCMA靶向双特异性治疗的患者对NXC-201没有应答。截至2024年5月10日，最佳缓解者的缓解持续时间已达28.0个月，并且缓解仍在持续。安全性方面，未发生免疫效应细胞相关神经毒性综合征（ICANS）事件，细胞因子释放综合征（CRS）的中位持续时间为2天（范围：1-5）。此前，NXC-201已被FDA授予孤儿药资格，用于治疗AL淀粉样变性和多发性骨髓瘤。◇ Immatics公司在2024年第一季度的财务报告上公布了其在研T细胞受体T细胞（TCR-T）疗法IMA203用以治疗经治转移性黑色素瘤患者的最新数据。分析显示，87%的患者实现肿瘤缩小，患者的确认ORR达55%。Immatics计划在2024年下半年的医学会议上，提供IMA203的下一次临床数据更新。同时，该公司亦计划在与美国FDA进一步讨论后，于今年启动IMA203作为二线及以上疗法，治疗黑色素瘤患者的注册性2/3期临床试验。▲IMA203的疗效结果（图片来源：参考资料[5]）IMA203是由Immatics专有ACTengine平台所开发的TCR-T细胞，靶向由HLA-A*02呈递的黑素瘤抗原PRAME。PRAME是一种在各种实体瘤中经常表达的蛋白质，因此IMA203具潜力治疗广泛的癌症患者群体。◇ CellProthera日前宣布，其主打在研产品ProtheraCytes在一项针对严重心肌梗死（AMI）患者的1/2b期研究中获得积极结果。数据显示，接受治疗6个月后，包括梗死面积、左心室尺寸和NT-proBNP水平在内的预后生物标志物的积极变化支持ProtheraCytes在心肌梗死后有心力衰竭风险患者中的疗效。ProtheraCytes来源于从患者外周血中采集的CD34阳性干细胞，这些细胞能促进血管再生，调节炎症、细胞凋亡和心肌细胞再生，并有望诱导受损心肌组织的修复过程。◇ Genprex公司宣布，其候选基因疗法Reqorsa联用PD-L1抑制剂Tecentriq治疗广泛期小细胞肺癌（SCLC）的1期临床试验已完成首例患者给药。近100%的SCLC的TUSC2蛋白（一种抑癌蛋白）表达会降低或根本不表达，41%的SCLC完全缺乏TUSC2蛋白表达。Reqorsa由包裹在带有正电荷脂质分子纳米颗粒中的抑癌基因TUSC2组成，而肿瘤细胞一般带有负电荷。Reqorsa经静脉注射，能特异性靶向肿瘤细胞，并在癌细胞中重新表达抑癌基因。◇ Carisma Therapeutics公司宣布，其在研CAR单核细胞疗法CT-0525治疗过度表达人表皮生长因子受体2（HER2）实体瘤的1期临床试验已完成在首例患者中的输注。单核细胞是巨噬细胞的前体细胞，CAR-单核细胞疗法有望解决细胞疗法治疗实体瘤的难题，包括肿瘤浸润、肿瘤微环境中的免疫抑制和抗原异质性。◇ A2 Biotherapeutics公司宣布，其在研细胞疗法A2B694用于治疗表达间皮素的实体瘤的1期临床试验已完成首例患者的输注。A2B694是基于该公司专有的Tmod平台开发而成的逻辑门控细胞疗法。Tmod平台采用双受体设计，包括靶向肿瘤细胞的激活剂和保护正常细胞的阻断剂，可选择性杀死肿瘤细胞并保护正常细胞。A2B694由靶向间皮素（MSLN）的激活剂和靶向HLA-A*02的阻断剂组成。在符合条件的患者群体中，HLA-A*02在肿瘤细胞中丢失，而在正常细胞中存在。该研究正在招募肺癌、结直肠癌、胰腺癌、卵巢癌和间皮瘤患者。◇ Verismo Therapeutics公司宣布，美国FDA已批准其在研CAR-T细胞疗法SynKIR-310用于治疗非霍奇金淋巴瘤（NHL）患者的1期临床试验。SynKIR-310基于该公司独特的KIR-CAR平台和专有的CD19结合剂（binder），旨在增强T细胞的抗肿瘤活性并延长其效力，从而治疗B细胞相关疾病和恶性肿瘤。接受现有已获批的CAR-T细胞疗法的患者中有40-50%会复发，SynKIR-310有潜力解决此类患者的未竟医疗需求。◇ 天泽云泰公布了VGR-R01治疗结晶样视网膜变性（BCD）的临床1/2期临床试验的最新数据。该临床研究证明，视网膜下注射VGR-R01能够显著改善患者视力或增强昏暗环境下的功能性视力，达到矫正视力损害或保护残余视觉功能的积极效果。VGR-R01是一款视网膜下注射的基因治疗产品，拟用于治疗CYP4V2基因突变导致的BCD患者。它的作用原理为一种基因替代疗法，通过视网膜下腔注射给药，AAV衣壳蛋白介导视网膜色素上皮（RPE）细胞的转导，将基因表达盒递送至细胞核。VGR-R01表达盒以游离DNA的形式存在，在RPE细胞表达CYP4V2蛋白，从而重建细胞的脂肪酸羟化酶活性。图片来源：123RF———✦融资、合作、M&A✦———◇ 济因生物完成了数千万人民币天使+轮融资，由天创资本独家投资。济因生物聚焦通用型细胞与基因治疗产品的开发，拥有iPSC重编程及定向分化、体内靶向递送等技术平台。该公司以体内CAR-T、iPS来源CAR-iNK为特色管线，致力于提供患者可及的细胞与基因治疗产品。该公司计划将此轮融资主要用于核心技术平台的优化升级以及体内CAR-T管线的临床阶段工作推进。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Immix Biopharma Announces Positive NXC-201 Relapsed/Refractory AL Amyloidosis Clinical Data in ASGCT 2024 Late Breaking Oral Presentation. Retrieved May 17, 2024, from https://www.globenewswire.com/news-release/2024/05/10/2879674/0/en/Immix-Biopharma-Announces-Positive-NXC-201-Relapsed-Refractory-AL-Amyloidosis-Clinical-Data-in-ASGCT-2024-Late-Breaking-Oral-Presentation.html[2] FDA grants accelerated approval to lisocabtagene maraleucel for follicular lymphoma. Retrieved May 15, 2024, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-follicular-lymphoma[3] Verismo Therapeutics Receives IND Clearance from the FDA for SynKIR™-310 in Relapsed/Refractory B-cell NHL. Retrieved May 17, 2024, from https://www.prnewswire.com/news-releases/verismo-therapeutics-receives-ind-clearance-from-the-fda-for-synkir-310-in-relapsedrefractory-b-cell-nhl-302144410.html[4] Immatics Announces First Quarter 2024 Financial Results and Business Update. Retrieved May 14, 2024 from https://investors.immatics.com/news-releases/news-release-details/immatics-announces-first-quarter-2024-financial-results-and-0[5] Immatics Corporate Presentation. Retrieved May 14, 2024 from https://investors.immatics.com/static-files/4eb058de-2c8c-4384-8b6e-2569e1379dab[6] PTC Therapeutics Announces FDA Acceptance and Priority Review of the BLA for Upstaza™. Retrieved May 14, 2024, from https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-acceptance-and-priority-review[7] A2 Bio Announces First Patient Dosed in EVEREST-2 Phase 1 Clinical Trial of Novel Mesothelin Logic-Gated CAR T. Retrieved May 17, 2024 from https://www.businesswire.com/news/home/20240516145046/en/[8] Carisma Therapeutics Announces First Patient Dosed in Phase 1 Clinical Trial of CT-0525, a Novel HER2-Targeting CAR-Monocyte. Retrieved May 17, 2024 from https://www.prnewswire.com/news-releases/carisma-therapeutics-announces-first-patient-dosed-in-phase-1-clinical-trial-of-ct-0525-a-novel-her2-targeting-car-monocyte-302146805.html[9] 天泽云泰ASGCT公布VGR-R01治疗BCD的临床I/II期最新数据. Retrieved May 10, 2024, from https://mp.weixin.qq.com/s/jYPp7iQulZlT3bHmNz-72w[10] Rocket Pharmaceuticals Presents Positive Data from LV Hematology Portfolio at the 27th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT). Retrieved May 10, 2024 from https://www.businesswire.com/news/home/20240510805823/en[11] CellProthera announces positive Phase I/IIb data for ProtheraCytes® cell therapy in acute myocardial infarction. Retrieved May 15, 2024, from https://www.cellprothera.com/en/cellprothera-announces-positive-phase-i-iib-data-for-protheracytes-cell-therapy-in-acute-myocardial-infarction/[12] Genprex Doses First Patient in Acclaim-3 Clinical Study of Reqorsa® Immunogene Therapy in Combination with Tecentriq® to Treat Small Cell Lung Cancer. Retrieved May 15, 2024, from https://www.prnewswire.com/news-releases/genprex-doses-first-patient-in-acclaim-3-clinical-study-of-reqorsa-immunogene-therapy-in-combination-with-tecentriq-to-treat-small-cell-lung-cancer-302144415.html[13] 济因生物完成数千万元天使+轮融资，加速推动体内CAR-T治疗技术开发. Retrieved May 17, 2024 from https://www.vbdata.cn/1518965589[14] Rocket Corporate Presentation. Retrieved May 10, 2024 from https://ir.rocketpharma.com/static-files/cd0d9ae3-5f6d-44ac-8874-27c46d0ed05c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。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新