Hereditary Leiomyomatosis and Renal Cell Cancer

引言 粘膜驻留共生菌在生物地球化学循环（biogeochemical cycles）和人类健康中起着至关重要的作用【1】。微生物群落的生物学特性是由它们的分类组成决定的。例如，肠道菌群的变化与多种慢性炎症性疾病 (包括癌症) 直接相关【2,3】。肿瘤发生可诱发应激性回肠病，促进肠道生态长期失调，且主要特征为比例显著上升的免疫抑制性肠闭菌属，这一菌属通常参与诱导PD-1阻断耐受【4】。然而，粪便微生物移植(fecal microbial transplantation，简称FMT) 可以通过诱导不同的肠道微生态变化，改善宿主肠道菌群和肿瘤微环境的炎性、免疫原性以及代谢水平，从而避免对黑色素瘤免疫治疗的原发性耐药性【5,6】。事实上，免疫检查点抑制剂或嵌合抗原受体- T细胞疗法的临床疗效与各种恶性肿瘤患者的肠道共生菌有关【7】。值得注意的是，抗生素 (万古霉素除外)、质子泵抑制剂和益生菌可能改变肠道菌群的分类组成，导致对免疫治疗产生耐药性。 健康的肠道生态系统，包括一些毛螺旋菌科和瘤胃球菌科的成员，以及来自粪杆菌属、阿克曼氏菌属和双歧杆菌属的物种，拥有模式识别受体配体，产生对应代谢产物 (如短链脂肪酸、l -精氨酸、肌苷或色氨酸)，并表达癌症抗原模拟物，可在免疫治疗期间引发1型干扰素 (IFN) 或白细胞介素-12 (IL-12) 介导的TH1或滤泡T辅助细胞免疫响应。尽管在至少18项辅助研究中有令人信服的证据表明有益和有害的宏基因组物种与临床结果相关，但关于微生物组特征通常与疗效的相关性却很少达成共识。此外，相关技术仍需迭代，以期对用户更为友好，来支持常规肿瘤学检查中合并微生物组分析。 导致上述情况的因素较为复杂，例如技术局限性 (粪便样本收集方法和DNA提取方案)、患者群体的地理差异 (不同国家的饮食和药物不同)、统计原因 (例如患者之间的差异、小样本量)、治疗结果的不同定义 (例如，将稳定的疾病分为无响应者或响应者，或使用无进展生存期 (PFS) 而不是最佳临床反应作为结果衡量标准)，以及由不同物种驱动的功能相关微生物信号。尽管共生肠道菌群越来越受到关注，但对微生物群落内相互作用的理解仍然有限。此外，很难预测哪些微生物群会形成一个稳定的群落，以及一个给定的群落如何对内在 (病理) 或外部 (治疗) 扰动作出反应。还有，尽管资源竞争、相互喂食（metabolic cross-feeding）和生态位可用性是微生物群落聚集的主要驱动因素，但宿主合并症和药物对肠道菌群的影响仍有待阐明。而通过丰度网络分析识别种类多样且相互合作的细菌功能群，有可能作为标准宿主代谢状态以及疾病进展情况的有效方法。 近日，来自法国ClinicObiome的Laurence Zitvogel研究组在Cell上发表题为Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome 的文章，通过肠道菌群的丰度网络分析，建立了肠道菌群与肿瘤免疫疗法疗效之间的相关性。 基于粪便宏基因组学测序，作者构建了一个共丰度网络，描述了245例晚期非小细胞肺癌患者的相对丰度相互关系。该网络确定了几个微生物亚群落，称为“物种相互作用群” (species-interacting groups，简称SIGs)，并鉴定出两个主要的SIGs，可以驱动晚期非小细胞肺癌对PD-1阻断的临床反应，即“SIG1”包括37个与不良反应相关的细菌，“SIG2”包括45个与良好反应相关的细菌。个体SIG1/SIG2比率可以反映个体的菌群平衡水平。而分数落在中间类别 (“灰色地带”，既不是SIG1也不是SIG2) 的个体可以根据Akkermansia spp（Akk）的相对丰度进一步分离。接下来，作者通过SIG1/SIG2比值和Akk丰度的结合产生了拓扑评分 (TOPOSCORE) ，预测了254名NSCLC患者 (一线或二线治疗)、216名肾细胞癌 (RCC) 和尿路上皮癌 (UC) 患者对PD1/PDL-1阻断疗法的可行性。通过拓扑评分，作者观察到分别为20%、53%、58%、35%和57%的健康志愿者、1期LNSCLC、2期NSCLC、2期LRCC和2期UC，表现出肠道生态失调。作者最终将拓扑评分的计算缩小到21个种属，并建立了一个基于qPCR的用户友好测试，能够准确识别所选的21种细菌的粪便存在。这21组基于宏基因组测序的拓扑评分与黑色素瘤和结直肠癌患者的免疫治疗疗效相关。通过将拓扑评分转换为基于qPCR的48小时测试，将有可能在常规临床实践中采用该评分来分流患者。 综上所述，作者的工作建立了基于粪便宏基因组测序的拓扑评分与黑色素瘤和结直肠癌患者的免疫治疗疗效的相关性。此外，本文报道的观察性队列共包括872例非小细胞肺癌、泌尿生殖系统癌和结直肠癌患者，也为免疫疗法响应与肠道菌群的相关性提供了资源。 模式图（Credit: Cell） 参考文献 1. Cho, I., and Blaser, M.J. (2012). The human microbiome: at the interface of health and disease. Nat. Rev. Genet. 13, 260–270. https://doi-org.libproxy1.nus.edu.sg/10. 1038/nrg3182. 2. Gilbert, J.A., Blaser, M.J., Caporaso, J.G., Jansson, J.K., Lynch, S.V., and Knight, R. (2018). Current understanding of the human microbiome. Nat. Med. 24, 392–400. https://doi-org.libproxy1.nus.edu.sg/10.1038/nm.4517. 3. Gacesa, R., Kurilshikov, A., Vila, V.A., Sinha, T., Klaassen, M., Gacesa, R., Kurilshikov, A., Vich Vila, A., Sinha, T., Klaassen, M.A.Y., Bolte, L.A., An- dreu-Sa ́ nchez, S., Chen, L., Collij, V., Hu, S., et al. (2022). Environmental factors shaping the gut microbiome in a Dutch population. Nature 604, 732–739. https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-04567-7. 4. Yonekura, S., Terrisse, S., Alves Costa Silva, C.A.C., Lafarge, A., Iebba, V., Ferrere, G., Goubet, A.-G., Fahrner, J.-E., Lahmar, I., Ueda, K., et al. (2022). Cancer induces a stress ileopathy depending on B-adrenergic re- ceptors and promoting dysbiosis that contribute to carcinogenesis. Cancer Discov. 12, 1128–1151. https://doi-org.libproxy1.nus.edu.sg/10.1158/2159-8290.CD- 21-0999. 5. Davar, D., Dzutsev, A.K., McCulloch, J.A., Rodrigues, R.R., Chauvin, J.- M., Morrison, R.M., Deblasio, R.N., Menna, C., Ding, Q., Pagliano, O., et al. (2021). Fecal microbiota transplant overcomes resistance to anti– PD-1 therapy in melanoma patients. Science 371, 595–602. https://doi. org/10.1126/science.abf3363. 6. Baruch, E.N., Youngster, I., Ben-Betzalel, G., Ortenberg, R., Lahat, A., Katz, L., Adler, K., Dick-Necula, D., Raskin, S., Bloch, N., et al. (2021). Fecal microbiota transplant promotes response in immunotherapy-refrac- tory melanoma patients. Science 371, 602–609. https://doi-org.libproxy1.nus.edu.sg/10.1126/ science.abb5920. 7. Routy, B., Le Chatelier, E., Derosa, L., Duong, C.P.M., Alou, M.T., Daille` re, R., Fluckiger, A., Messaoudene, M., Rauber, C., Roberti, M.P., et al. (2018). Gut microbiome influences efficacy of PD-1-based immuno- therapy against epithelial tumors. Science 359, 91–97. https://doi-org.libproxy1.nus.edu.sg/ 10.1126/science.aan3706. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2024.05.029 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

-- Industry veteran brings more than 30 years of operational experience, in large pharma and emerging stage biotech, private and public companies, with extensive commercial experience and an established track record of financing in the capital markets -- Lerodalcibep, a novel, next generation PCSK9 inhibitor and the Company’s lead program, is expected to complete Phase 3 in 4Q’23; BLA and MAA filings planned in 1H’24 CINCINNATI--(BUSINESS WIRE)-- LIB Therapeutics Inc. (LIB), a late-stage biopharmaceutical company developing subcutaneous and oral PCSK9 inhibitor therapies for patients at very high and high-risk of cardiovascular disease (CVD), today announced that the Board of Directors has appointed David Cory as Chief Executive Officer and a member of the Board of Directors, effective immediately. Evan Stein, MD, PhD, who has served as the CEO since co-founding LIB in 2015, will continue in a full-time operational role as Chief Operating Officer and Chief Scientific Officer. Mr. Cory brings more than 30 years of leadership and operational experience in public and private, large pharma and emerging stage biotechnology companies, with an extensive commercial background spanning launches of global blockbuster products and targeted therapeutics for rare diseases, an established track record in the capital markets with over $1B+ raised and multiple companies which have successfully resulted in acquisition. “We are pleased to welcome David as our new CEO and Board member,” said August Troendle, MD, LIB co-founder and Chairman of the LIB Board. “David’s track record and credibility in transforming private late-stage biopharma into public commercial companies makes him the ideal candidate for LIB and our late-stage lerodalcibep program.” “With development of lerodalcibep close to completion and BLA submission planned for Q1 next year, David’s well-proven operating and commercial experience, combined with his drive and enthusiasm, is optimally suited to lead the company as it transitions to commercialization of lerodalcibep in the U.S, Europe, and rest of world,” said Evan Stein, MD, PhD, LIB co-founder and Board member. David Cory said, "Lerodalcibep has a compelling clinical pro differentiates itself in a growing PCSK9 inhibitor market which will approach $3 billion in 2023 and on target to reach or exceed $5 billion in 2025 when we anticipate approval and launch. I look forward to working with the LIB Board and the LIB operating team to make this exciting new therapy available for patients and healthcare providers in the future.” About David Cory Mr. Cory co-founded and most recently was President, CEO, and Director of Eiger BioPharmaceuticals, a commercial-stage company focused on the development of innovative therapies for serious, orphan diseases, and was responsible for negotiating multiple technology and product licenses, taking the company public, and obtaining the company’s first FDA and EMA product approvals. Previously, Mr. Cory was President and Chief Operating Officer of Prestwick Pharmaceuticals, an orphan CNS specialty pharmaceutical company, which was acquired by Biovail. Earlier, Mr. Cory was a co-founder of CoTherix, an orphan pulmonary arterial hypertension company, which was acquired by Actelion. Mr. Cory began his biotech career with the founding team at InterMune where he was Senior Vice President of Sales and Marketing. InterMune was acquired by Roche for $8 billion. Mr. Cory spent over a decade in large pharma in positions of increasing responsibility at Glaxo Smith Kline and The Upjohn Company. Mr. Cory earned a BS in Pharmacy from the University of Cincinnati, College of Pharmacy, was board certified in Pharmacy in the state of Ohio and holds an MBA from the University of Maryland. About Lerodalcibep Lerodalcibep is a next-generation, PCSK9 inhibitor in development to potentially overcome the limitations of current low-density lipoprotein (LDL-C), or ‘bad’ cholesterol, lowering treatments and reach new national and international guidelines to treat and prevent cardiovascular disease (CVD). The convenient, small injection volume, monthly dosing and long ambient stability combined with excellent and sustained LDL-C efficacy, lerodalcibep, if approved, will increase the treatment options for patients, including the 30 million with more severe inherited high-cholesterol, called familial hypercholesterolemia (FH). LIB Therapeutics expects to submit a biologics license application (BLA) with FDA in Q1 2024 and marketing authorization application (MAA) with EMA in Q2 2024. About Phase 3 LIBerate Program LIBerate is a large, comprehensive global Phase 3 program composed of 5 key studies with lerodalcibep in over 2,500 patients in patients with cardiovascular (CVD), very high and high-risk for CVD, heterozygous familial hypercholesterolemia (He-FH) and homozygous FH (Ho-FH). The Phase 3 studies LIBerate-HoFH (LIB-003-003, n=65) and LIBerate-HeFH (LIB-003-004, n=479) have completed and met their primary endpoints. The final two Phase 3 pivotal trials, LIBerate-CVD (LIB-003-005, n=923) and LIBerate-HR (LIB-003-006, n=923), added to maximally tolerated oral lipid-lowering therapies to assess LDL-lowering in CVD, very high and high-risk for CVD patients are anticipated to complete in early November. About LIB Therapeutics Inc. LIB Therapeutics is a privately held, late-stage biopharmaceutical company dedicated to bringing novel, safe and convenient subcutaneous and oral PCSK9 inhibitors to the millions of patients with cardiovascular disease, and the 30 million with familial hypercholesterolemia (FH), who require additional large reductions in low density lipoprotein-cholesterol (LDL-C) despite maximally tolerated statins and other lipid lowering agents. For more information, please visit: .

8月16日，NMPA批准信达生物制药（苏州）有限公司申报的托莱西单抗注射液（商品名：信必乐）上市，批准适应症为在控制饮食的基础上，与他汀类药物、或者与他汀类药物及其他降脂疗法联合用药，用于在接受中等剂量或中等剂量以上他汀类药物治疗，仍无法达到低密度脂蛋白胆固醇（LDL-C）目标的原发性高胆固醇血症和混合型血脂异常的成人患者。这是国内首款上市的国产PCSK9抑制剂。PCSK9是丝氨酸蛋白酶家族的第九个也是最后一个成员，该家族包括原蛋白转化酶1（PC1），PC2、PC4、PC5、PC7、Furin、配对碱性氨基酸裂解酶4（PACE4）、枯草杆菌蛋白酶Kexin同工酶1和PCSK9。这个丝氨酸蛋白酶家族更类似于细菌枯草杆菌蛋白酶。前八个转化酶裂解分泌性蛋白前体以产生调节发育和代谢的生物活性肽、多肽和激素。前蛋白转换酶枯草杆菌蛋白酶/kexin 9型（PCSK9）被发现为高胆固醇血症的遗传决定因素，近年来成为降低高胆固醇血症患者LDL-C水平的潜在靶点。PCSK9通过降解低密度脂蛋白受体（LDLR）来调节血清中LDL-C水平。因此，PCSK9抑制剂已成为一种血脂控制新疗法，可减轻动脉粥样硬化的发病机制，降低心血管事件和死亡率。目前，已有许多降脂疗法显示出治疗高脂血症的积极结果。其中以羟甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）、胆固醇酯转移蛋白抑制剂、胆固醇吸收抑制剂、和PCSK9抑制剂等为代表。PCSK9抑制剂比他汀类药物的优势是，他汀类药物不会显著降低脂蛋白水平，而PCSK9抑制剂则会降低。这是因为PCSK9参与LDL相关蛋白-1的降解，该蛋白分解LP(a)，因此，抑制PCSK9会提高LDL相关蛋白-1的水平，从而增加LP(a)的分解。国产首款的上市之路托莱西单抗的上市是基于多项关键注册临床研究CREDIT-2、CREDIT-1和 CREDIT-4。CREDIT-1研究是一项评估中国非家族性高胆固醇血症患者应用IBI306 疗效和安全性的随机、双盲、安慰剂对照的III期临床研究。主要临床终点为治疗48周 LDL-C较基线下降百分率。结果显示，在中国非家族性高胆固醇血症(non-FH) 合并高危/极高危心血管风险患者中，IBI306各剂量组连续治疗48周后，LDL-C相对基线下降水平，较安慰剂组均有显著改善。CREDIT-4研究是一项评估中国高胆固醇血症患者应用IBI306疗效和安全性的随机、双盲、安慰剂对照的III期临床研究。主要临床终点为治疗12周LDL-C较基线下降百分率。结果显示，在中国non-FH和HeFH患者中，IBI306治疗 12周后 LDL-C相对基线下降水平较安慰剂组也有明显改善。CREDIT-2研究是一项评估中国杂合子型家族性高胆固醇血症受试者应用IBI306疗效和安全性的随机、双盲、安慰剂对照III期临床研究。主要疗效终点为治疗12周LDL-C较基线下降百分率。结果显示，在接受他汀和/或依折麦布治疗的中国杂合子型家族性高胆固醇血症患者中使用IBI306 连续治疗12 周后，与安慰剂相比，LDL-C水平获得显著改善。有力的竞争者数据来自CPM新药研发监测数据库和PharmaONE智能药物大数据分析平台。目前全球已经上市的PCSK9抑制剂是赛诺菲的阿利西尤单抗、安进的依洛尤单抗和诺华的小干扰核酸疗法。托莱西单抗是继这三款药物之后上市的PCSK9创新药，将与他们争夺这一市场。表1: 全球PCSK9抑制剂获批情况数据来源：CPM新药研发监测数据库和PharmaONE智能药物大数据分析平台中国医药工业信息中心Pharma ONE智能药物大数据分析平台显示，除托莱西单抗，目前在国内共有两款靶向PCSK9的药物上市，分别为赛诺菲的阿利西尤单抗和安进的依洛尤单抗，此外，还有五款药物正处于上市申请阶段，分别是诺华的inclisiran、康荣东方的伊努西单抗、恒瑞医药的瑞卡西单抗和君实生物的昂戈瑞西单抗。图1: PCSK9药物国内研发获批情况数据来源：Pharma ONE药物大数据分析平台中国医药工业信息中心从市场角度看，新版PDB药物综合数据库，国内全渠道放大板块数据显示，PCSK9抑制剂整体市场在不断增长，2022年销售额达到了8.3亿元，安进的依洛尤单抗和赛诺菲的阿利西尤单抗的销售额分别为5.3亿元和3亿元。图2: 国内PCSK9药物销售格局数据来源：Pharma ONE药物大数据分析平台中国医药工业信息中心总结我国血脂异常患者数量庞大，临床需求迫切。根据国家心血管中心的统计数据显示，我国已有超过四亿人患有血脂异常。目前国内在血脂异常治疗领域的PCSK9抑制剂类药物仍相对匮乏，仅有进口的依洛尤单抗和阿利西尤单抗能为患者提供良好的临床治疗效果。随着托莱西单抗的获批，国产PCSK9降脂治疗药物领域的空白将被填补，为广大血脂异常患者提供了更多治疗选择。年度发布2023年《全球药研新动态》《中国医院市场用药格局》（2023版）2023年《数图药讯》权威发布2021年度中国医药工业百强榜单解读中国仿制药发展报告（2022版）《2023年专利到期药品概述》医药行业专项报告中国医药中间体和原料药行业调研报告中国非甾体抗炎类原料药市场调研报告中国祛痰类原料药市场调研报告中国钙拮抗剂类原料药市场调研报告中国血管紧张素Ⅱ受体拮抗剂类原料药市场调研报告中国口服血糖调节类原料药市场调研报告中国中枢兴奋类原料药市场调研报告中国抗痛风类原料药市场调研报告中国脑血管病类原料药市场调研报告END如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001