Arsanis, Inc.

2011年春天，数据监测委员会要求默克公司及其合作者停止他们正在开展的金葡菌疫苗III期临床试验——这项针对全球细菌感染主要死因而开发的候选疫苗，在26个国家的8000名患者中进行了试验，但试验效果不佳（抗体显著增高，但VE=13.8%；-52.5, 51.6%，无显著意义），无法继续进行。 接下来一年的深入研究发现，在接受心胸手术的患者中测试候选疫苗，接种了候选疫苗的试验者比注射安慰剂的患者更有可能死亡。 默克公司负责该疫苗研发的首席医学官福勒博士指出，许多死亡的疫苗接种者都是死于多器官系统衰竭，专家推测这种风险可能部分源于炎症反应的扩大，但仍不确定这种试验性疫苗是如何使受试者变得更加脆弱的。 反复失败的金葡菌候选疫苗： 10余款候选疫苗和3款单抗前赴后继的失败 当疫苗界还沉浸在默克试验带来的伤害中时，2012年辉瑞公司推出了自己的候选疫苗试验，其中包括4种不同的金葡菌抗原。基于在小鼠中获得的良好疗效数据，辉瑞首先在健康成年人中进行了试验，随后又在3000多名接受择期手术的患者中进行了2b试验。 但到2018年，这款投入5亿美金的重组工艺候选疫苗希望也已破灭。血清数据显示，虽然接种疫苗的患者产生了金葡菌抗体，但疫苗组的感染率与安慰剂组相同（针对12个主要疗效终点的VE均无显著意义）。与默克公司之前的研究一样，这项2b期试验也被终止了。 后来人们进行了“曲线救国”策略，输注单克隆抗体以期提供短期保护的被动免疫。但研究发现，两种正在开发中的单克隆抗体——Arsanis公司的ASN100和Aridis公司的suvratoxumab和tosatoxumab相继在中期试验中失败。 事实上在过去的25年时间里，大约有14种在研金葡菌疫苗在2期或3期临床试验中失败。一个又一个疫苗开发商投入了数百万美元，开发出了一个又一个拥有高超科学依据的候选疫苗。 但无论疫苗研发策略多么有前途，无论候选疫苗在临床前研究中效果多么好，最终都没有一种疫苗能成功保护人类免受金葡菌的感染。 金葡菌疫苗失败原因探索： 若人体预先暴露金葡菌，疫苗就会失去作用 加州大学圣迭戈分校儿科传染病科主任George Liu说：默克公司试验失败后，一连串无法解释的疫苗失败成了“房间里的大象”（意思是一些非常显而易见的，可是却一直被忽略的问题）。科学家和制造商们逐渐意识到，在投入研发金葡菌疫苗之前，需要先弄清楚什么原因导致了疫苗失效。 George Liu的实验室研究表明，金葡菌疫苗并不像其他有有效疫苗那样与免疫系统相互作用。金葡菌有办法操纵免疫系统来保护自己，使宿主防御系统和传统疫苗策略失去保护作用。这就是多年来试验失败的原因，这也为可能有效的疫苗带来了希望。 金葡菌是一种与人类共存的病原体，在大多数情况下不会对人类造成伤害。多达1/3的成人和50%的儿童在鼻腔中持续携带这种病菌，但都没有任何症状。然而一旦金葡菌进入血液、肺部或软组织，就会致命。 医疗器械、外科手术、未愈合的伤口和注射毒品都是人们感染金葡菌的常见途径，可导致败血症、肺炎、心内膜炎和骨感染。每年造成全球100多万人死亡，美国因此的住院费用高达数十亿美元。这种微生物对抗生素的耐药性不断增加，也限制了治疗方案的选择，增加了疫苗的紧迫性。 几乎所有失败的金葡菌疫苗人体试验背后都有一个成功的小鼠临床前研究，但小鼠模型与人类有本质区别——人生活在金葡菌的环境中，而实验小鼠则不是。 George Liu在小鼠接种的疫苗与默克公司试验中使用的疫苗类似，让它们预先感染金葡菌，以观察接触金葡菌是否会影响它们随后对疫苗的反应。在从未接触过金葡菌的对照组小鼠中，疫苗 “效果很好”。但在预先暴露于金葡菌的小鼠中，疫苗没有保护作用。 2022年，研究人员在Cell Host & Microbe杂志上报告了这一结果，它反映了研究人员在临床试验中看到的情况：当金葡菌预先启动了免疫系统时，疫苗就不起作用了。 金葡菌疫苗无效的机制： 预先暴露的金葡菌留下了错误的免疫记忆 免疫系统会产生针对抗原的特异性抗体，在第一次遇到抗原后，免疫系统会产生免疫记忆。如果再次遇到病原体/抗原，这些抗体就会被迅速召回，这种免疫记忆对长期保护至关重要。 对小鼠体内抗体的深入研究表明：金葡菌扰乱了它们的免疫记忆。 但金葡菌已经学会了破解它：当实验室小鼠暴露于金葡菌时，病原体会留下错误的免疫反应印记。免疫系统学会了制造抗金葡菌抗体，这些抗体会迅速赶到现场，但却无法产生保护作用。 通常情况下，抗体会与细菌细胞壁上的抗原结合，然后将细菌拖到巨噬细胞或中性粒细胞等免疫细胞中，在一个称为吞噬的过程中被消化和消灭。 但在George Liu的研究中，接触金葡菌的小鼠产生了带有额外糖基的抗体。这些抗体仍然附着在细菌表面，但当它们到达巨噬细胞时，免疫细胞并没有消灭病原体。当研究人员移除糖基后，吞噬作用就恢复了。 这种免疫操作使金葡菌得以与人类共生，也破坏了疫苗策略。当小鼠或已经接触过这种细菌的人接种疫苗后，他们的免疫系统会优先恢复原来的免疫反应，而不是根据疫苗建立新的保护性反应。 去年年底George Liu发表在Cell Reports Medicine上的一项后续研究中扩大了研究范围，研究了10种金葡菌抗原，其中许多抗原在临床试验中都失败了。这些抗原包括8种能促使机体产生自身抗体的活性疫苗抗原，以及2种候选单克隆抗体：suvratoxumab和tefibazumab。 与金葡菌细胞壁相关的活性疫苗抗原对之前接触过金葡菌的小鼠没有保护作用，这些疫苗抗原只是唤醒并强化了无保护性的免疫印记。 单克隆抗体对暴露于金葡菌的小鼠也无效，但原因不同——它们无法与金葡菌预编程的非保护性内源抗体竞争。这些内源抗体与细菌细胞结合在一起，所以当单克隆抗体到来时，它们无处可躲。正常情况下，内源性抗体会扑上去杀死病原体，但相反内源性葡萄球菌抗体会进入病原体，并保护细菌不被治疗药物杀死。 新的变通办法： 优势抗原/T细胞免疫/多价/调整人群策略 尽管Liu在2023年的研究中检测的大多数抗原都被金葡菌的免疫逃避技术所击败，但这项工作表明仍有乐观的余地，以排除法的形式留给了金葡菌疫苗新思路：优势抗原策略（针对α毒素、抗原表面决定簇B）、T细胞免疫策略、多价疫苗策略、调整接种人群策略（考虑暴露于金葡菌前的生命早期人群接种）。 优势抗原诱导策略：其中一种活性疫苗抗原能诱导出针对金葡菌关键毒力因子α毒素的中和抗体——即使是之前接触过这种毒素的小鼠也能产生中和抗体。这种细菌毒素使细菌在宿主免疫反应中占据优势，中和它们可以给免疫系统提供更多抗感染的机会。 其次，优势抗原铁调控表面决定簇B（或称IsdB）会诱发非保护性抗体，针对引起较小免疫反应但可能因免疫印记缺陷而得不到保护的亚优势抗原区的研究更为有效。 T细胞免疫策略：研究发现了T细胞对抑制金葡菌的重要性，2014年对默克公司临床试验的一部分患者进行的跟踪分析发现，死亡率与疫苗接种者血清中某些T细胞细胞因子水平低密切相关。 虽然这项研究规模较小，但死亡患者似乎对接种疫苗的T细胞反应不恰当或不存在，尽管他们体内有大量抗体，全国儿童医院重症监护医师Chris Montgomery在一封电子邮件中写道。实验室的数据表明，金葡菌α毒素会损害T细胞发育，阻碍疫苗应答。T细胞功能障碍患者也更容易反复感染金葡菌，这可能表明这些免疫细胞发挥着关键的防御作用。 杜克大学福勒教授说，最终未来疫苗的最佳方法可能是多价疫苗，这些疫苗将针对金葡菌生命周期不同阶段和感染阶段的毒素、T细胞和其他多种抗原的某种组合。 还有一个问题是谁应该接种疫苗。疫苗研发人员一直把重点放在已被金葡菌定植并有高感染风险的患者身上。但一些专家表示，为婴儿接种疫苗是更好的策略。 欧林生物的金葡菌疫苗仍在“不确定”中 2015年，欧林生物与陆军军医大学联合开发的重组金葡菌疫苗获批临床试验。2023年II期临床研究结果发表于Vaccine杂志，安全性和免疫原性良好，疫苗组抗体水平显著提高，重复了默克和辉瑞等公司的结果。 2023年末，其适用于骨科手术人群的多中心RCT 3期临床试验中期数据，向DSMB（数据监查委员会）提交审查前期临床试验结果和III期临床试验方案，以判断试验无效的可能性及是否需要终止试验，从而减少I类新药研发的风险。但DSMB给出的建议是：继续进行研究。 这款“诺奖级”的新疫苗，有希望“花落”我国进度最快的欧林吗？ JAMA. Published online August 2, 2024. doi:10.1001/jama.2024.1015 欧林生物：重组金葡菌疫苗Ⅲ期临床试验已入组3,600余例，临床入组医院增加至60家以上 (baidu.com) 欧林生物重组金葡菌疫苗Ⅱ期临床试验研究论文在《疫苗》杂志发表 (cls.cn) 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Mike Gray appointed as CFO and COO, Lisa Fiering joins as SVP, People & Culture WALTHAM, Mass.--(BUSINESS WIRE)-- Upstream Bio, a clinical-stage biotech company advancing verekitug (UPB-101) for respiratory disorders, today announced strategic leadership changes including the appointment of Rand Sutherland, MD, as Chief Executive Officer. Upstream has also appointed Mike Gray as Chief Financial Officer and Chief Operating Officer, and Lisa Fiering as Senior Vice President of People & Culture. These leadership changes will support the growth and evolution of Upstream as the company works to advance verekitug, a recombinant fully human immunoglobulin G1 monoclonal antibody which blocks the thymic stromal lymphopoietin receptor (TLSPR), in ongoing Phase 2 clinical trials for severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). “I am thrilled to join Upstream Bio as CEO. I am committed to the company’s work to conquer inflammation at its source and intend to bring our team into the next stage of business and clinical operations,” said Dr. Sutherland. “Having dedicated much of my career to improving care for people living with asthma, I understand the substantial impact of severe respiratory diseases and I believe that verekitug could further improve standard of care for these patients. I am honored to lead this company at such an exciting time.” “Upstream Bio is at a critical period as the company advances verekitug, a potentially best-in-class therapeutic in the field of TSLP biology,” said Ron Renaud, Chair of the Board of Directors for Upstream Bio. “I want to thank Samantha Truex for serving as Upstream Bio’s CEO from launch through the initiation of our Phase 2 studies and leading the company to this juncture. By evolving and building our leadership team with these additions, we are further positioning Upstream Bio to become a leader in the immunotherapy landscape. I am pleased to welcome Rand, Mike and Lisa to the Upstream Bio team.” Dr. Sutherland joins Upstream Bio with more than 25 years of business and clinical experience, having most recently served as CEO of Seeker Biologics, and before that as President of Translate Bio prior to its acquisition by Sanofi. Previously, Dr. Sutherland held a number of R&D and medical affairs roles at Sanofi, providing leadership for the development of novel medicines in Immunology and Rare Diseases, and leading medical affairs globally for the Specialty Care business unit. Dr. Sutherland also serves as an independent director of Allakos, Krystal Biotech and Vanqua Bio. Before joining the biopharma industry, Dr. Sutherland was Professor of Medicine at the University of Colorado and Chief of Pulmonary and Critical Care Medicine at National Jewish Health in Denver. He earned an MD from the University of Chicago, after which he trained in Internal Medicine at UCSF and in Pulmonary and Critical Care Medicine at the University of Colorado. Mr. Gray has more than 25 years of public-private leadership experience and was most recently the CFO and COO of Carmot Therapeutics, where he helped to secure the company’s acquisition by Roche in 2024. Before this, he was CFO and COO of Imara and Arsanis, working with the leadership teams of each company in completing initial public offerings and building leading organizations. Mr. Gray previously held a number of leadership positions at Curis. Mr. Gray served on the Board of Directors of Therapeutics Acquisition Corporation, a special purpose acquisition corporation, through its merger with POINT Biopharma, which was subsequently acquired by Eli Lilly and Company in March 2024. He received his BS in business administration (accounting) from Bryant College and an MBA in corporate finance and entrepreneurial management from the F.W. Olin Graduate School of Business at Babson College. Ms. Fiering brings to Upstream 30 years of experience, having spent the past 20 years in various people and culture roles at life sciences companies including Genzyme, Ironwood Pharmaceuticals, Keryx and Trillium, where she developed a pragmatic approach to drive team effectiveness through talent and organizational development. Since 2022, she has provided strategic consulting to early-stage biotech companies, developing strategy and building the foundation for the people and culture function for these growing companies. Ms. Fiering earned her BA in Sociology from Ithaca College. About Upstream Bio Upstream Bio strives to reach the source of inflammation and conquer it, leveraging its team’s diverse industry experience to develop verekitug (UPB-101) to ease the burden of respiratory diseases. Verekitug is a clinical-stage monoclonal antibody that inhibits the TSLP receptor. TSLP is a validated target positioned upstream of multiple signaling cascades that affect a variety of immune cells pivotal to common and rare diseases. Upstream has completed a clinical trial in asthma with 32 weeks of observation which demonstrated compelling and sustained reductions in disease-related biomarkers and enabled the investigation of UPB-101 in ongoing Phase 2 trials of asthma and of CRSwNP that include extended dosing regimens of up to every 24 weeks. View source version on businesswire.com: Contacts Source: Upstream Bio View this news release online at:

BERKELEY, Calif., June 06, 2023 (GLOBE NEWSWIRE) -- Carmot Therapeutics, Inc., a clinical-stage biotechnology company developing disease-modifying therapies for metabolic diseases, is pleased to announce the appointment of Michael Gray as both Chief Operating Officer (COO) and Chief Financial Officer (CFO). Mr. Gray brings a wealth of financial expertise and strategic leadership to Carmot, and his appointment is expected to support the Company's growth and overall strategic objectives as it pursues the development of therapies to treat people with diabetes and obesity. Gray will be responsible for overseeing financial operations including the development and implementation of corporate finance strategies and tactics, leadership of investor relations and corporate communications, and supporting strategic initiatives and business operations. In addition, Gray will lead cross-functional teams that include Business Development, Human Resources, IT and Facilities. Gray joins Carmot with nearly 20 years of public-private leadership experience including broad strategic, financial and operating experience in global companies. "On behalf of the entire leadership team, we welcome Mike to Carmot, and together we look forward to pursuing the development of therapies to treat people with diabetes and obesity," said Heather Turner, CEO of Carmot Therapeutics. "Mike's track record of leading high-performing teams and driving financial performance, and in particular his knowledge of capital and financial markets, will make him an invaluable addition to our leadership team. Mike's previous accomplishments, especially as a leader and team member in transforming and scaling organizations, will be relevant to Carmot as we advance a pipeline of product candidates into later stage clinical development." "Throughout my career, I've been motivated to build effective teams, sound financial and business operations and, importantly, to bring life-altering medicines to patients. I am honored to be joining Carmot, a company that is committed to transforming patients' lives through potentially differentiated therapies for metabolic diseases," stated Gray. "I look forward to working with Carmot's talented Board of Directors and team members." Gray comes to Carmot from Imara, Inc., a public biotech company where he was CFO and COO and was instrumental in transitioning the private company through its initial public offering (IPO) in 2020, and in building Imara from a virtual to operating company conducting Phase 2b global clinical trials in non-malignant hematology indications. Gray was also a leader on Imara’s strategic initiative which resulted in a successful asset sale and entry into a reverse merger transaction with Enliven Therapeutics. Prior to Imara, Gray held several C Suite posts at Arsanis, Inc., a global biotech company, working with the Board of Directors and leadership team to build its U.S. operations, complete a private financing and IPO, as well as its merger with X4 Pharmaceuticals. Gray previously held a variety of leadership positions at Curis, Inc., including CFO, CBO and COO, leading multiple equity and debt financings and business development transactions and overseeing various business and strategic initiatives. Gray served on the board of directors of Therapeutics Acquisition Corporation, a special purpose acquisition corporation, from May 2020 to July 2021, when it completed its merger with POINT Biopharma. Gray received his M.B.A. in corporate finance and entrepreneurial management from the F.W. Olin Graduate School of Business at Babson College and a B.S. in accounting from Bryant University. Carmot's pipeline includes: CT-388 (once-weekly, dual GLP-1/GIP receptor modulator) which is currently in a Phase 1/2a clinical trial in overweight and obese adults with and without type 2 diabetes (T2D). Results from the multiple ascending dose cohorts will be presented at the 83rd American Diabetes Association Scientific Sessions taking place June 23–26, 2023 in San Diego, CA. Additional Phase 2 trials in obese adults are planned to begin in 2023. CT-868 (once-daily, dual GLP-1/GIP receptor modulator) which has completed a Phase 1 clinical trial in overweight and obese otherwise healthy adult volunteers, a Phase 2 trial in obese patients with T2D, and a mechanism of action (MOA) study in obese adults with and without T2D to assess its impact on glucose homeostasis. Results from the latter study will be presented at the 83rd American Diabetes Association Scientific Sessions. Carmot has recently initiated another Phase 1 MOA study in overweight and obese patients with type 1 diabetes (T1D) and expects to initiate a Phase 2 proof-of-concept clinical trial in overweight and obese patients with T1D in the second half of this year. CT-996 (oral, small molecule GLP-1 receptor agonist), which has recently initiated a Phase 1 clinical trial in overweight and obese otherwise healthy adults. A long-acting peptide tyrosine-tyrosine (PYY) analogue, which is in late preclinical development. About Carmot Therapeutics Carmot Therapeutics is a clinical-stage biotechnology company that is focused on the discovery and development of disease-modifying therapies for people living with metabolic diseases including obesity and diabetes. We are utilizing Chemotype Evolution, a pioneering drug discovery platform, to identify novel incretin receptor signaling targets and develop a broad pipeline of therapeutics that have the potential to produce significant weight loss and improved glycemic control. We have three clinical candidates: CT-388 (once-weekly, dual GLP-1/GIP receptor modulator), CT-868 (once-daily, dual GLP-1/GIP receptor modulator) and CT-996 (oral, small molecule GLP-1 receptor agonist). For more information, visit the Carmot Therapeutics website and follow us on LinkedIn. Carmot Contact: info@carmot.us Carmot Media Contact: Kelli Perkins Red House Consulting kelli@redhousecomms.com