GFH-018

2017年初创的劲方医药或许是下一个踏足独角兽俱乐部的Biotech，除了备受各大资本青睐之外，其布局管线的“硬实力”也不容小觑，多条管线处于临床前沿。而该公司不仅License-Out将CDK9抑制剂授权了SELLAS生命科学集团，还License-in了BioLineRx的CXCR4抑制剂motixafortide，此外在国内方面KRAS抑制的全球化权益也license-out给了信达生物，包括里程碑付款和首付款在内的交易总额可达3.2亿美元，是国内to国内中交易额中创纪录的。而本文将详细分析劲方医药的各条自研管线及其优劣。KRAS G12C抑制剂竞速GFH925（又名IBI351）是劲方医药研发的一款KRAS G12C抑制剂，GFH925也可以说是劲方医药的众多管线中较为受到瞩目的管线，首先在授权方面就备受国内外大药厂信赖，在国内合作授权给了信达生物，而信达又有和德国默克的合作临床。在临床进展方面，GFH925处于国产KRAS抑制剂的临床进展前沿，特别是，国内开发方面先后两种适应症（KRAS G12C适用的非小细胞肺癌和结直肠癌）获得突破性疗法认定。由于KRAS G12C抑制剂会遇到耐药性问题，因此寻找可靠的联用治疗方案是解决手段之一。而此前KRAS G12C抑制剂的一种可能联用手段SHP2抑制剂遭到了多家大药企如艾伯维，赛诺菲，诺华，安进的退货或暂停临床。因此另外一种与EGFR靶向药物联用的手段可能相对更适用于KRAS G12C抑制剂。目前，GFH925正在欧洲与德国默克的合作，将默克的西妥昔单抗（EGFR单抗）以及GFH925进行联用。从通路来看EGFR属于KRAS的上游通路，一些文献表明KRAS G12C的耐药性可能可以通过上游通路的抑制进行克服。同样位于临床开发前列的加科思，以及已经有KRAS G12C上市的安进也采用这一方案，这或许是开发KRAS G12C的可行方案之一。靶点开发困难靶点，安全性致胜GFH312是劲方医药开发的RIPK1抑制剂，也是国内首个获批临床的RIPK1抑制剂，适应症为炎症领域。无独有偶，此前百济神州创始人王晓东院士创立的维泰瑞隆也选择了RIPK1作为靶点，因此也是相当具有潜力的靶点。从机制上来看，受体相互作用蛋白激酶（receptor-interacting protein kinase, RIPK）属于丝氨酸/苏氨酸激酶家族成员。通过抑制RIPK1激酶活性，可以改善各种疾病的小鼠模型中的坏死性凋亡相关的病理，包括炎性疾病(例如结肠炎和皮炎)和神经退行性疾病(例如多发性硬化(MS)和肌萎缩性侧索硬化(ALS))。问题在于，这一靶点的开发并不简单，无数国际大药企都在此地折戟。例如，GSK曾经就RIPK1抑制剂开发过两款管线，GSK3145095和GSK2982772但都因为不明原因暂停，赛诺菲/Denali Therapeutics试图开发DNL104，DNL747，可仅仅只是安全性问题，就让人望而却步，出现的肝毒性和脱靶毒性事件不得不终止其开发。不过GFH312在I期临床展现出的安全性和耐受性数据较为良好，且实现了在中枢神经系统的充分暴露，为治疗神经系统疾病也提供了证据，期待后续能在多领域再接再厉。CDK9抑制剂中潜在的Best-in-classGFH009是一款CDK9抑制剂，劲方自主研发、首个独立递交FDA临床获批项目，而全球目前尚未有CDK9抑制剂上市，GFH009处于CDK9抑制剂临床进展的前列（其他前沿产品例如阿斯利康的AZD4573，礼来的LY-2857785等等）。在去年4月时，劲方医药将大中华区之外的商业化权利授予了SELLAS生命科学集团。这一肯定来源于对方确信GFH009具有Best-in-class的潜力：和其他同类型临床研究阶段产品相比，GFH009对CDK9蛋白的高选择性抑制有望大大降低毒性并提升疗效。从机制上来看，根据GFH009的专利描述研究发现CDK9的表达水平或/和激酶活性的异常会引起细胞内多种蛋白表达或/和其mRNA水平异常。已经证实与肿瘤密切相关的就有抗凋亡蛋白(如Bcl-2)、细胞周期相关调节蛋白(如cyclin D1)、p53途径相关蛋白、NF-κB途径的某些蛋白和以及与肿瘤微环境有关的蛋白(如VEGF)等。可见CDK9是肿瘤发生发展过程中关键分子之一。从目前双方合作已披露的信息来看，潜在的联用对象包括Bcl2抑制剂维奈托克（venetoclax）等药物，有趣的是SELLAS自己的肿瘤疫苗GPS的适应症也在慢性髓系白血病（AML）上与GFH009有所叠加。可以期待该药物的未来更多发展。TGF-β R1小分子抑制剂能否找到前路从专利来看，劲方医药的TGF-β R1小分子抑制剂GFH018是和药明康德旗下的明德新药共同研发的，是礼来开发的Galunisertib的fast-follower。图：GFH018的结构尽管礼来的Galunisertib是目前得到最广泛开发的TGF-β R1小分子抑制剂，但是迄今为止Galunisertib仍未上市，一些临床疗效并不理想，例如与O药的疗效不及预期因此被BMS束之高阁。尽管前行探索者前途未卜，但劲方医药此前与君实生物采用GFH018联合特瑞普利单抗（PD-1抑制剂）在转移性或复发性鼻咽癌进行临床的数据相对还不错（同比与一些同样线治疗的PD-1/L1抑制剂的数据），在40%患者经历三线或以上既往治疗患者中达到了31.3%的客观缓解率，降低了放化疗导致的、伴TGF-β致纤维化的重症肺炎发生率。可以等待中位PFS（无进展生存期）的读出。总结总体来看，目前劲方医药的自研临床管线大都处于临床I/II期阶段，KRAS G12C抑制剂GFH925进展较快。此外，还在CDK9抑制剂GFH009，RIPK1抑制剂GFH312展现出了一定较好的势头，期望后续临床数据能够提供更惊艳的数据。参考来源：Ryan MB, Coker O, Sorokin A, Fella K, Barnes H, Wong E, Kanikarla P, Gao F, Zhang Y, Zhou L, Kopetz S, Corcoran RB. KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy. Cell Rep. 2022 Jun 21;39(12):110993. doi: 10.1016/j.celrep.2022.110993. PMID: 35732135; PMCID: PMC9809542.Mandal R, Becker S, Strebhardt K. Targeting CDK9 for Anti-Cancer Therapeutics. Cancers (Basel). 2021 May 1;13(9):2181. doi: 10.3390/cancers13092181. PMID: 34062779; PMCID: PMC8124690.公司官网及专利近期热门视频更多精彩视频，尽在佰傲谷视频号，欢迎关注~本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀‍‍ 点亮在看，传递信息♥

SHANGHAI and CHICAGO, June 6, 2023 /PRNewswire/ -- GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, today published the latest results from the phase Ib/II study of GFH018 (TGF-β R1 inhibitor) with toripalimab（anti-PD-1 antibody）at the 2023 American Society of Clinical Oncology Meeting in Chicago. The data demonstrated promising anti-tumor activity and tolerability among patients with recurrent/metastatic nasopharyngeal carcinoma (R/M NPC). Over 40% patients enrolled have received ≥3 lines of prior therapies and This combination therapy demonstrated significant potential to enhance efficacy of immune checkpoint inhibitors (ICIs) among ICI-naïve patients and subjects in late-line setting. A phase Ib/II study of GFH018 in combination with toripalimab in recurrent/metastatic nasopharyngeal carcinoma（R/M NPC）. Abstract #: 6026 This trial (NCT04914286) is the first global multi-center study of a TGF-β R1 inhibitor combined with an anti-PD-1 antibody conducted by a Chinese biotech. As of 20 April 2023, 41 patients with R/M NPC were enrolled in China (including the Chinese mainland and Taiwan) and Australia. As of 20 April 2023, among the 32 patients with post-baseline tumor assessments, the overall response rate (ORR) was 31.3%, and disease control rate (DCR) was 50%; 10 pts achieved partial response (PR), and 6 pts with stable disease (SD). Among 17 ICI-naïve patients (without prior treatment of ICIs), the ORR was 47.1%, and DCR was 64.7%, 8 pts achieved PR, and 3 pts SD; a total of 4 pts that achieved PR have their target lesion decreased by over 50% from baseline. The majority of patients experienced treatment-related adverse events (TRAEs) of 1/2 grades, and 11 patients (26.8%) had ≥ Grade 3. The most common TRAEs were anaemia, hyponatraemia, rash, fatigue, etc. No adverse events were observed that affected subjects' vital health conditions, and there were no bleeding events that have been reported in clinical trials of large molecules targeting TGF-β pathway. The team of Professor Mai Haiqiang, Director of the Department of Nasopharyngeal Carcinoma，Sun Yat-sen University Cancer Center visited the ASCO site together with GenFleet's clinical executives. As the principal investigator of the study （NCT04914286）, Professor Mai stated, "we are pleased to collaborate with GenFleet and present our latest results to the global audience at ASCO. The study suggested a potential immunomodulation effect of GFH018 enhancing efficacy of anti-PD-1 antibodies among ICI-naïve patients. Currently no innovative therapies targeting TGF-β pathway has been approved for the market and we look forward to further advances in this therapy." Yu Wang, M.D./Ph.D., Chief Medical Officer of GenFleet expressed his expectations about the product's clinical potential in future, "GFH018 as GenFleet's first product entering clinical trial is expected to alleviate the suppressed tumor immune microenvironment and reduce the incidence of severe chemoradiation-induced pneumonitis accompanying TGF-β-induced fibrosis. Thus, GFH018 combined with anti-PD-1 inhibitor will provide novel options for virus-related cancer patients. Currently, GenFleet is at the forefront in the development of the small-molecule immunotherapies targeting TGF-β pathway. More positive results from this combination therapy of GFH018 applying to multiple solid tumors will be disclosed in future academic conferences." About GFH018 and TGF-β R1 Developed by GenFleet Therapeutics, GFH018 is an orally administered TGF-β R1 inhibitor pand entered into phase I clinical trial in 2019. The phase Ib/II trial of GFH018 with PD-1 inhibitor treating patients with advanced solid tumors is underway in China (including the Chinese mainland and Taiwan) and Australia; the other study is a phase II trial of GFH018, PD-1 inhibitor with concurrent chemoradiotherapy treating patients with locally advanced & unresectable NSCLC in China. In the microenvironment of advanced solid tumors, TGF-β signaling pathway can promote epithelial mesenchymal transition (EMT) & metastasis, induce the formation of cancer stem cells and their functional maintenance, inhibit anti-tumor immunity, enhance vasculature and fibrosis, and ultimately result in tumor progression. Among patients of hepatocellular carcinoma, glioma, colorectal cancer, lung cancer, pancreatic cancer, urothelial cancer and other solid tumors, high expression of genes related to TGF-β signaling pathway is frequently discovered in their blood and tumor tissues. The expression level is positively correlated to the malignancy & poor differentiation of tumor and unfavorable prognosis in patients. TGF-β pathway also plays a crucial role especially for non-oncology diseases such as fibroblast-associated fibrosis with inflammation and tissue injury. Therefore, diseases could be treated with GFH018 such as idiopathic pulmonary fibrosis, interstitial pneumonia, primary biliary cirrhosis and others. About GenFleet GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies, is dedicated to serving significant global unmet medical needs in oncology and immunology. Based on the deep understanding of disease biology and translational medicine, GenFleet's proprietary and fully integrated R&D platform highlights multiple cutting-edge products with novel mechanisms and global IP. Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates - both small molecules and biologics. Its pipeline includes over 10 programs, many of which have entered multi-regional clinical trials across China (including Taiwan), the United States, Europe and Australia. To date, GenFleet has over 5 clinical studies encompassing IND stage to phase II studies and completed co-development partnerships with a number of publicly listed companies worldwide. GenFleet is expected to progress additional programs into the clinic, as well as transition from a clinical stage biotech company into a commercial stage biopharmaceutical company in the next 3-5 years. CONTACT: Yun Zeng, Phone: +86-13482182145 SOURCE GenFleet Therapeutics