BTN3A1

ImCheck Receives FDA Fast Track Designation for ICT01in Combination with Azacitidine and Venetoclaxin First-Line Acute Myeloid Leukemiafor Patients Unfit for Induction Chemotherapy Treatment ICT01, a humanized anti-butyrophilin 3A monoclonal antibodydesigned to selectively activate Vγ9Vδ2 T cells, has shown encouraging clinical datain AML in its ongoing Phase 1/2a EVICTION study Marseille, France, September 18, 2024, 11 am CET – ImCheck Therapeutics announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to ICT01 in combination with azacitidine and venetoclax for the treatment of acute myeloid leukemia (AML) patients 75 years or older, or who have comorbidities that preclude use of standard intensive induction chemotherapy. Based on encouraging results from the Phase 1 dose-escalation portion of the EVICTION study evaluating ICT01 monotherapy in relapsed/refractory hematological malignancies (European Society for Medical Oncology Congress 2023), ImCheck initiated in October 2023 a randomized dose-optimization cohort (NCT04243499), evaluating two doses of ICT01 in combination with azacitidine and venetoclax, the current standard of care for newly diagnosed patients with AML who are deemed unfit for induction chemotherapy. “The growing body of data on ICT01 together with the FDA’s Fast Track designation further validates our development of ICT01 in first-line AML patients and highlights the critical need for therapies that generate higher response rates and improve overall survival for these patients,” said Stephan Braun, MD, PhD, Chief Medical Officer of ImCheck Therapeutics. “We are highly encouraged by ICT01’s potentially broad applicability in solid tumor and hematological cancer indications and look forward to sharing updates from the EVICTION study at upcoming scientific conferences.” The FDA designed Fast Track status to facilitate the development and expedite the review of therapeutic candidates that have the potential to treat serious conditions and address an unmet medical need. A therapeutic candidate that receives Fast Track designation may be eligible for more frequent interactions with the FDA to discuss the candidate’s development plan. Candidates with Fast Track designation may also be eligible for Priority Review and Accelerated Approval if supported by clinical data, with the goal of bringing approved therapies to patients earlier. EVICTION is an open-label multicohort Phase 1/2a trial studying ICT01, a humanized anti-butyrophilin 3A monoclonal antibody that selectively activates γ9δ2 T cells; the study comprises cohorts investigating ICT01 as a monotherapy and combination therapy in solid and hematological tumors. As reported at ESMO 2023, the Phase 1 dose-escalation cohort in relapsed/refractory hematological cancers included 26 patients who failed all available treatment options, 24 of which had AML, one with diffuse large B-cell lymphoma and one with follicular lymphoma. No dose-limiting toxicities were revealed for ICT01 administered at doses ranging from 200 μg to 75 mg every 21 days. Based on encouraging safety, pharmacokinetic and pharmacodynamic data, a dose-optimizing and efficacy-estimating part was initiated for patients with newly diagnosed AML who are older or deemed unfit for standard chemotherapy, which has enrolled 29 patients to date. Emerging pharmacodynamic and pharmacokinetic data for ICT01 in combination with azacitidine-venetoclax showed reproducible activation and migration of γ9δ2 T cells from the blood within hours of dosing, suggesting effective target engagement as the basis for the observed efficacy. *** About IMCHECK THERAPEUTICS ImCheck Therapeutics is designing and developing a new generation of immunotherapeutic antibodies targeting butyrophilins, a novel super-family of immunomodulators. As demonstrated by its lead clinical-stage program ICT01, which has a mechanism of action to simultaneously modulate innate and adaptive immunity, ImCheck's “first-in-class” activating antibodies may be able to produce superior clinical results as compared to the first-generation of immune checkpoint inhibitors and, when used in combination, to overcome resistance to this group of agents. In addition, ImCheck’s antagonist antibodies are being evaluated as potential treatments for a range of autoimmune and infectious diseases. ImCheck benefits from support from Prof. Daniel Olive (INSERM, CNRS, Institut Paoli Calmettes, Aix-Marseille University), a worldwide leader in γ9δ2 T cells and butyrophilins research, as well as from the experience of an expert management team and from the commitment of leading US and European investors. For further information: https://www.imchecktherapeutics.com/ Press contacts: US and EU Trophic CommunicationsGretchen Schweitzer +49 (0) 172 861 8540imcheck@trophic.eu FranceATCG PARTNERSCéline Voisin+33 (0)9 81 87 46 72 / +33 (0)6 62 12 53 39imcheck@atcg-partners.com Attachment PR in English

The latest funding is the fifth consecutive time ImCheck has received financial support from the French government. Image Credit: Mer_Studio / Shutterstock. ImCheck Therapeutics has received €20.18m ($22.35m) in non-dilutive funding from the French government to advance its pipeline. The funds were disbursed as part of the “i-Démo” call for projects under the France 2030 Plan operated by Bpifrance on behalf of the French government. The public capital will be used to advance ImCheck’s clinical pipeline consisting of a T cell-activating monoclonal antibody and an infectious disease therapy. The French company’s lead candidate is ICT01, a pathogen-agnostic γ9δ2 T cell-activating monoclonal antibody targeting BTN2A, also known as CD277. It is being evaluated in multiple solid tumours and blood cancer indications in Phase I/IIa trials . The company is also investigating ICT01 in combination with Merck &Co (MSD)’s checkpoint inhibitor Keytruda (pembrolizumab) in patients with refractory solid tumours. The interim data from 21 patients with refractory melanoma enrolled in the Phase I/II EVICTION study (NCT04243499) showed three atrial responses at 16 weeks. A disease control rate of 21% was also observed with the combination therapy. The most common adverse events were grade 1-2 in intensity and included infusion-related reactions and cytokine release syndrome. Another open-label study, the Phase I/II EVICTION-2 trial (NCT05307874), is evaluating ICT01 and Clinigen ’s low-dose subcutaneous interleukin-2 therapy, Proleukin (aldesleukin), in patients with advanced solid tumours. In November 2023, ImCheck reported data showing that 19 patients have completed at least one cycle, with mild to moderate adverse events and no dose-limiting toxicities. See Also: Emergent gains FDA approval for ACAM2000 vaccine for Mpox EC approves GSK’s RSV vaccine for adults aged 50-59 years The latest funding influx is the fifth consecutive time ImCheck has received financial support from the French Government, whose plans have earmarked €54bn (59.8bn) for supporting strategic sectors. This includes healthcare as part of the France 2030 Investment Plan . ImCheck also plans to funnel resources to advance an anti-BTN2A agnostic γ9δ2 T cell-activating monoclonal antibody, ICT41, as a therapy for bacterial and viral infections. The recent mpox outbreak has seen a rise in investment in infectious diseases. Earlier this week, the US Food and Drug Administration expanded the label for Emergent BioSolutions ’ mpox vaccine, ACAM2000.

欢迎关注凯莱英药闻 2024年8月28日，根据中国国家药监局药品审评中心（CDE）官网公示，赛诺菲公司的替利珠单抗注射液的上市申请获得受理。替利珠单抗是一款抗CD3单克隆抗体，2023年3月，赛诺菲曾以每股25.00美元现金，股权价值约为 29 亿美元收购Provention Bio，将包含替利珠单抗在内多款自免药物收入囊中。 关于替利珠单抗 替利珠单抗（teplizumab）是人源化IgG1抗体，通过靶向CD4+或CD8+T淋巴细胞上CD3分子，抑制T细胞活性，从而调节1型糖尿病（T1D）的病理性免疫反应。Teplizumab的Fc段经氨基酸修饰后，构成了Fc受体非结合区域，减少与补体和Fc受体的结合，并降低了相关毒性反应。 2022年11月，teplizumab（商品名：Tzield）获FDA批准延迟2 期T1D成人患者和8 岁及以上儿童患者的3 期T1D的发病。Tzield是第一种可预防/延缓特定人群发展为临床T1D（3 期T1D）的疗法，是继一个世纪前胰岛素问世以来，T1D治疗方面取得的第一个重大进展。 Tzield的获批是基于一项关键的随机、双盲、事件驱动、安慰剂对照试验，衡量疗效的主要标准，是从随机入组到诊断为3期1型糖尿病的时间。结果显示： 在51个月的中位随访中，接受Tzield的患者中有45%进展为3期1型糖尿病，而接受安慰剂有72%被诊断为3期糖尿病。 接受Tzield的患者诊断为3期1型糖尿病的中位时间是50个月，接受安慰剂的病人是25个月。 C-peptide 相比安慰剂有显著提升，说明治疗促进了患者自身胰岛素的生成。 患者每日胰岛素所需剂量相比安慰剂，有明显下降，第一年时teplizumab 组有5%的患者不再需要使用胰岛素（安慰剂组为0）。 关于1型糖尿病 糖尿病是危害人类健康最常见的慢性疾病之一，我国已经成为全球糖尿病患病人数增长最快的国家，18岁以上人群糖尿病患病率超过10%。近年来，糖尿病发病年轻化也是不容小窥的公共卫生问题。根据2019年世界卫生组织（WHO）最新的糖尿病分型标准，糖尿病分为1型糖尿病、2型糖尿病、妊娠糖尿病、混合型糖尿病、未分类型糖尿病、特殊类型糖尿病。 1型糖尿病的病人是由于免疫系统的破坏导致的，主要是免疫系统对胰岛β细胞的破坏，造成绝大部分的胰岛β细胞受到严重的损害，导致胰岛β细胞死亡。残留的胰岛β细胞比较少，产生的胰岛素，不能满足身体的需要，造成血糖的升高。据推测，全球可能有230万人患有1型糖尿病。根据翁建平教授等人在2010~2013年调查发现，中国所有年龄段的T1DM发病率估计为1.01/10万人年。 除了每天注射胰岛素外，T1D患者还需要采取严格的管理计划，包括定期监测血糖、健康饮食和体育锻炼。 近年来，我国针对1型糖尿病开展了相关的研究，以期对T1D药物的开发起到推动作用： 翁建平教授团队对55例T1DM患者进行外周血T细胞亚群分布分析，结果提示CD4+ T细胞、调节性CD4+ T细胞、CD8+ T细胞比例及其表面Notch受体表达与HLA分型、病程、起病年龄均无明显相关性，且Notch信号分子在T细胞表面表达量较低。回顾文献提示外周血中T1DM相关致病性T细胞比例较低，后续对共刺激分子功能学研究难度较大，因此需重新寻找被高度活化的T1DM相关自身免疫性CD4+ T细胞克隆或细胞系的分离培养方法，并重新考虑Notch信号分子等共刺激分子在T1DM发病机制中作用。 中南大学湘雅二院周智广教授团队在国内首次建立四次跨膜蛋白7（Tetraspanin 7）抗体的检测平台，并发现Tetraspanin 7抗体阳性是LADA患者C肽衰竭的独立预测因子。 南京医科大学、中山大学和中南大学团队通过对2596例抗体阳性汉族T1DM患者和5082例对照进行全基因组关联分析（GWAS），在中国人群中发现了3个此前未报道的T1DM易感位点：BTN3A1基因附近的rs4320356位点、GATA3基因的rs3802604位点和HLA-C 275，并利用鉴定出的8个易感位点构建了T1DM风险预测模型，曲线下面积达到0.86。进一步分析发现，预测模型的遗传风险评分（GRS）越高，T1DM发病年龄越早、初诊时空腹C肽水平越低。此外，在高加索人群中报道的易感位点中，近一半与中国人群T1DM无关联或者频率较低，这可能是中国T1DM发病率较低的原因。 关于自疫治疗1型糖尿病策略 近年关于T1DM免疫调节治疗的研究主要集中在T效应细胞和B细胞免疫调节等方面。 抗CD3单克隆抗体：通过与效应T细胞表面的CD3结合，激发或阻断细胞活化的信号，清除效应T细胞或诱导调节性T细胞（Treg）产生，诱导免疫耐受，抑制T细胞对胰岛β细胞的攻击，从而延缓β细胞被破坏的进程。目前，主要研究药物包括奥昔珠单抗和替利珠单抗；临床试验结果提示，奥昔珠单抗具有一定延缓T1DM患者β细胞功能减退的作用，然而低剂量对新确诊的T1DM患者C肽水平的下降速度又没有改善，因此该药物在T1DM的进展落后于替利珠单抗。 抗CD20单克隆抗体：CD20是位于B细胞表面的标志性分子，能够调节B细胞活化；将抗CD20单克隆抗体作用于B细胞上表达的CD20抗原，启动介导B细胞溶解的免疫反应，减少自身抗原向T细胞的递呈，从而延缓β细胞的损伤。代表药物利妥昔单抗在一项II期临床显示，新诊断的T1DM患者接受1个疗程的利妥昔单抗治疗，可以将C肽的下降延迟8.2个月，但随访至30个月时两组之间无明显差异；此外，将利妥昔单抗与Treg疗法联用，延缓T1DM进展方面始终优于单一治疗。目前，针对利妥昔单抗治疗T1DM患者的III期研究正在进行中。 嵌合抗原受体T细胞疗法：该疗法通过从患者血液中收集免疫细胞，对其进行基因改造使之识别特定的靶细胞，被改造后被重新输注到患者体内，从而发挥免疫调节作用。目前，美国Abata 公司开发的新型Treg细胞疗法的候选药物ABA-201正在进行IND审批，有望于2025年进入临床。 人热休克蛋白60（Diapep277）：是源自人热休克蛋白60序列上的一段肽段，能够调节免疫系统，使胰岛细胞免受破坏并保护胰岛的分泌功能。III期临床显示，DiaPep277治疗组在不增加胰岛素剂量的情况下达到目标糖化血红蛋白的患者比例明显增加，降低了低血糖事件风险；与对照组相比，治疗组胰高糖素刺激的C肽曲线下面积下降幅度显著降低，说明DiaPep277在一定程度上能够减缓胰岛功能的衰退。 抗胸腺细胞球蛋白（ATG）：是一种多克隆IgG，能够破坏T细胞的活化，诱导免疫耐受从而可能治疗新发T1DM。临床研究表明，在诊断T1DM的3个月内使用1个疗程的小剂量ATG（2.5 mg/kg），可减缓β细胞的减少。由于目前低剂量ATG所提供的保护时间并不确定，需要更长时间的临床观察。 参考资料 1、公司官网、CDE 2、Weng J, Zhou Z, Guo L, et al.; T1D China Study Group. Incidence of type 1 diabetes in China, 2010-13: population based study. BMJ 2018;360:j5295 3、Yingxin Xian, Haixia Xu, Yifang Gao, Jinhua Yan, Jing Lv, Wenqian Ren, Qianwen Huang, Ziyu Jiang, Fen Xu, Bin Yao, Jianping Weng. Diabetes Metab Res Rev. 2019;e3228. 4、Shi X, Huang G, Wang Y, Liu Z, Deng C, Li X, Zheng P, Zhou Z  Tetraspanin 7 autoantibodies predict progressive decline of beta cell function in individuals with LADA. Diabetologia. 2019 Mar;62(3):399-407. 5、Zhu, M., et al., Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study. Diabetes Care, 2019. 42(8): p. 1414-1421. 6、公众号：中华糖尿病杂志、1型糖尿病学组 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