VE-303

VE303 is an orally administered, potential first-in-class live biotherapeutic product candidate being developed to prevent recurrence of Clostridioides difficile infection (CDI) BOSTON--(BUSINESS WIRE)-- PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company, noted today that its Founded Entity, Vedanta Biosciences, a clinical-stage company that is developing a potential new category of oral therapies based on defined bacterial consortia, announced that the first patient has been dosed in the global Phase 3 RESTORATiVE303 clinical study of VE303, which is an orally administered defined bacterial consortium candidate that is being developed for the prevention of recurrent C. difficile infection (rCDI). The RESTORATiVE303 trial is evaluating the efficacy and safety of VE303 in patients with rCDI and is intended to form the basis for a Biologics License Application to be filed with the U.S. Food and Drug Administration. The full text of the announcement from Vedanta is as follows: Vedanta Biosciences Enrolls First Patient in Pivotal Phase 3 RESTORATiVE303 Study of VE303 for the Prevention of Recurrent C. difficile Infection VE303 is an orally administered, potential first-in-class live biotherapeutic product candidate being developed to prevent recurrence of Clostridioides difficile infection (CDI) CAMBRIDGE, MA, May 21, 2024 – Vedanta Biosciences, a clinical-stage company that is developing a potential new category of oral therapies based on defined bacterial consortia, today announced that the first patient has been dosed in the global Phase 3 RESTORATiVE303 clinical study. VE303 is an orally administered defined bacterial consortium candidate that is being developed for the prevention of recurrent C. difficile infection (rCDI). The RESTORATiVE303 trial is evaluating the efficacy and safety of VE303 in patients with rCDI and is intended to form the basis for a Biologics License Application (BLA) to be filed with the U.S. Food and Drug Administration. “Initiation of the RESTORATiVE303 study represents a key clinical milestone for the VE303 program. Building on the successes of earlier VE303 clinical studies, RESTORATiVE303 is the first pivotal Phase 3 study of a live biotherapeutic product for prevention of recurrent CDI, a potentially serious infection that affects up to 175,000 patients and results in approximately 20,000 deaths annually in the U.S.,” said Jeffrey Silber, M.D., Chief Medical Officer of Vedanta Biosciences. “Based on the efficacy and safety data we have generated to date for this program, we believe that an oral, rationally designed, defined consortium candidate has the potential to offer patients with rCDI an attractive alternative to undefined, donor-derived fecal approaches.” In April 2023, Vedanta published results from the Phase 2 CONSORTIUM trial, in which treatment with VE303 was associated with a 30.5% adjusted absolute risk reduction in the rate of recurrence when compared with placebo, representing a greater than 80% reduction in the odds of a CDI recurrence. “CDI may recur in 25% or more of those affected, sometimes repeatedly, despite initially successful antibiotic treatment. With each subsequent recurrence, CDI can have a severe and worsening effect on quality of life, leading to hospitalization and increased risk of death,” said Paul Feuerstadt, M.D., FACG, AGAF, of Yale University School of Medicine, and a RESTORATiVE303 study investigator. “Precision approaches based on defined bacterial consortia represent the next generation of microbiome therapeutics for patients with CDI, and we welcome the opportunity to join the pivotal study for the first candidate based on this important new modality.” About the RESTORATiVE303 Study RESTORATiVE303 is a randomized, double-blind, placebo-controlled Phase 3 clinical trial evaluating the safety and efficacy of VE303 in patients at high risk for recurrence of CDI after completing a course of antibiotics for a prior CDI episode. The trial is being conducted at approximately 200 sites in 22 countries, across four continents. The primary endpoint is the comparison of CDI recurrence rates at eight weeks in the VE303 and placebo groups. The Phase 3 study design and VE303 dosing regimen are based on the completed Phase 2 trial, in which VE303 met its primary endpoint for preventing CDI recurrence at eight weeks and was observed to be generally well-tolerated. For more information on RESTORATiVE303 (NCT06237452) please visit clinicaltrials.gov. About VE303 VE303 is a potential first-in-class live biotherapeutic product (LBP) candidate consisting of a defined bacterial consortium designed for the prevention of recurrent Clostridioides difficile infection (rCDI). It consists of eight strains that were rationally selected using Vedanta’s product engine. VE303 is produced from pure, clonal bacterial cell banks, which yield a standardized drug product in powdered form and bypass the need to rely on donor fecal material of inconsistent composition. Vedanta published study results in April 2023 from the Phase 2 CONSORTIUM trial, in which treatment with the VE303 high dose was associated with a 30.5% adjusted absolute risk reduction in the rate of recurrence when compared with placebo, representing a greater than 80% reduction in the odds of a CDI recurrence. VE303 was granted Orphan Drug Designation in 2017 and Fast Track Designation in 2023 by the U.S. Food and Drug Administration (FDA) for the prevention of recurrent CDI. This project has been funded in part with federal funds from the U.S. Department of Health and Human Services (HHS); Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under contract number 75A5012C00177 for a contract value up to $104.2 million. This project has also received a $5.4 million research grant from the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB‑X) in 2017. About Vedanta Biosciences Vedanta Biosciences is a clinical-stage biopharmaceutical company developing medicines for the treatment of gastrointestinal diseases. The company’s lead assets are potential first-in-class oral therapies – VE303, in a Phase 3 registrational trial for prevention of recurrent C. difficile infection, and VE202, in a Phase 2 trial for treatment of ulcerative colitis. Vedanta’s pipeline has been built using the company’s industry-leading product engine for the development of therapies based on defined consortia of bacteria grown from pure clonal cell banks. The product engine, supported by broad foundational intellectual property, includes one of the largest libraries of bacteria isolated from the human microbiome, vast clinical datasets, proprietary capabilities in consortium design, and end-to-end CGMP manufacturing capabilities at commercial launch scale. About PureTech Health PureTech is a clinical-stage biotherapeutics company dedicated to giving life to new classes of medicine to change the lives of patients with devastating diseases. The Company has created a broad and deep pipeline through its experienced research and development team and its extensive network of scientists, clinicians and industry leaders that is being advanced both internally and through its Founded Entities. PureTech's R&D engine has resulted in the development of 29 therapeutics and therapeutic candidates, including two that have received both U.S. FDA clearance and European marketing authorization and a third (KarXT) that has been filed for FDA approval. A number of these programs are being advanced by PureTech or its Founded Entities in various indications and stages of clinical development, including registration enabling studies. All of the underlying programs and platforms that resulted in this pipeline of therapeutic candidates were initially identified or discovered and then advanced by the PureTech team through key validation points. For more information, visit or connect with us on X (formerly Twitter) @puretechh. Cautionary Note Regarding Forward-Looking Statements This press release contains statements that are or may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation those related to the VE303 development program, development plans and potential benefits to patients, and our future prospects, developments and strategies. The forward-looking statements are based on current expectations and are subject to known and unknown risks, uncertainties and other important factors that could cause actual results, performance and achievements to differ materially from current expectations, including, but not limited to, those risks, uncertainties and other important factors described under the caption "Risk Factors" in our Annual Report on Form 20-F for the year ended December 31, 2023 filed with the SEC and in our other regulatory filings. These forward-looking statements are based on assumptions regarding the present and future business strategies of the Company and the environment in which it will operate in the future. Each forward-looking statement speaks only as at the date of this press release. Except as required by law and regulatory requirements, we disclaim any obligation to update or revise these forward-looking statements, whether as a result of new information, future events or otherwise. View source version on businesswire.com: Contacts PureTech Public Relations publicrelations@puretechhealth.com Investor Relations IR@puretechhealth.com UK/EU Media Ben Atwell, Rob Winder +44 (0) 20 3727 1000 puretech@fticonsulting.com US Media Nichole Bobbyn +1 774 278 8273 nichole@tenbridgecommunications.com Source: PureTech Health plc View this news release online at:

12月27日的《热心肠日报》，我们解读了 10 篇文献，关注：炎性衰老，饮食-菌群互作，食品微生物组，活菌药，菌群干预，大肠癌，结肠炎，抗生素，天然产物。 Cell子刊：肠道的炎症性衰老内源因素是肠道干细胞的衰老 Developmental Cell——[11.8] ① 衰老发生后，包括肠道干细胞（ISC）在内的肠道上皮细胞均表现显著的炎症特征；② 沿隐窝-绒毛轴，不同细胞呈现不同的炎性衰老状态；③ 肠道干细胞 (ISC) 炎性衰老表现为MHC-II表达上调，进而增加了其与CD4+ T细胞的相互作用；④ 类器官研究显示衰老ISC是类器官炎性衰老的内因，最初表现为炎症相关基因位点染色质的开放，进而使得依赖于STAT1信号的炎性衰老标志基因的上调表达；⑤ 炎性衰老ISC染色质的变化会通过细胞记忆传递，导致炎性衰老； 【主编评语】 衰老的主要特征是低水平的慢性炎症，伴随有组织的功能损伤和疾病的发生发展。这种所谓的炎症性衰老的发生被认为是来自细胞的内应和外界环境因素叠加而共同导致的，但是其具体的机制并不清楚。近期一篇发表在Cell子刊，Developmental Cell的一篇文章，以肠道这一特殊器官为研究材料，通过单细胞分析结合类器官等方法证明肠道的炎症性衰老主要是由于衰老的肠道干细胞导致的，衰老的肠道干细胞表现为在炎症相关的基因位点的染色质的开放，MHC-II表达上调等特征，其表达炎症相关基因是依赖于STAT1通路的。这些结果为炎症性衰老的发生机制提供了新的线索。（@Zhonghua） 【原文信息】 Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice 2023-12-18, doi: 10.1016/j.devcel.2023.11.013 Nature子刊：多模式活性分选法，鉴定与菊粉互作的肠菌 Nature Communications——[16.6] ① 通过结合多模式细胞分选法、生理试验、稳定同位素探测和基因组分析等，使用荧光标记纳米颗粒追踪菊粉与肠菌间互作；② 识别到大量肠菌可与菊粉结合，其中布劳特氏菌属、柯林斯菌属等是最突出的菊粉响应分类群；③ 利用RACS从11名受试者粪便中分离获得18种菊粉响应物种，其中大多数能在纯培养中降解菊粉，其降解过程会刺激迟缓埃格特菌和产尿石素戈登氏杆菌增殖；④ 使用另一种益生元低聚木糖，发现双歧杆菌属和产气柯林斯菌是其降解物种。 【主编评语】 益生元被定义为促进有益肠道微生物生长的不易消化的膳食成分。然而，在许多情况下，这种能力没有得到系统的评估。近日，维也纳大学研究人员在Nature Communications发表最新研究，通过结合多模式细胞分选法、生理试验、稳定同位素探测和基因组分析等，使用荧光标记纳米颗粒追踪益生元与肠菌间互作，能够鉴定出广泛的菊粉和低聚木糖响应肠道微生物群落，包括新的菊粉响应物种，值得关注。（@九卿臣） 【原文信息】 Identification of inulin-responsive bacteria in the gut microbiota via multi-modal activity-based sorting 2023-12-14, doi: 10.1038/s41467-023-43448-z 新方法，助力探究细菌、真菌与饮食间的互作 Microbiome——[15.5] ① 通过比较两种研究真菌群落的方法（宏基因组和ITS测序），提出一种富集方案，使用综合内部真菌数据库进行可靠的真菌组分析，并将饮食数据与细菌和真菌群落相关联；② 在真菌基因组物种水平上，霰弹枪宏基因组测序比ITS扩增子测序具有更高的准确性；③ 真菌群落在组成和功能水平上的变化明显大于细菌群落；④ 微生物多样性、成分和功能与习惯性饮食成分有关，而不是由全球饮食变化驱动；⑤ 在觅食方面，细菌和真菌间可能存在竞争性相互作用。 【主编评语】 ITS测序和散弹枪宏基因组学的准确性尚未得到可靠的评估，饮食对细菌和真菌肠道微生物群组成和功能的影响在纵向环境下的研究也很少。近日，巴塞罗那自治大学研究人员在Microbiome发表最新研究，通过比较两种研究真菌群落的方法，提出一种富集方案，发现在食物觅食方面，细菌和真菌间可能存在竞争性相互作用，值得关注。（@九卿臣） 【原文信息】 Shotgun metagenomics reveals interkingdom association between intestinal bacteria and fungi involving competition for nutrients 2023-12-14, doi: 10.1186/s40168-023-01693-w Nature子刊：微生物相互作用塑造奶酪风味的形成 Nature Communications——[16.6] ① 切达干酪制作过程中，乳球菌株与嗜热链球菌株之间的竞争和合作显著影响风味化合物的形成；② 嗜热链球菌株的蛋白水解特性促进产生更多的肽和氨基酸，可缓解乳球菌的氮源缺乏，并促进核苷酸的从头生物合成；③ 克氏乳球菌株也可通过限制双乙酰和乙妥英的过量形成，减少奶酪异味；④ 乳球菌株间的竞争性代谢机制为克氏乳杆菌与乳酸乳杆菌竞争可用的柠檬酸盐，从而促进双乙酰和乙妥英向α酮戊二酸的转变。 【主编评语】 奶酪发酵和风味形成是由多种微生物活性驱动的复杂生物化学反应的结果。Nature Communications近期发表的文章，对奶酪形成过程中，菌株之间竞争和合作对风味化合物的形成进行探究。（@章台柳） 【原文信息】 Microbial interactions shape cheese flavour formation 2023-12-21, doi: 10.1038/s41467-023-41059-2 刘尽尧等：小分子和活菌药物联合递送可实现协同治疗 Journal of the American Chemical Society——[15] ① 采用活性氧响应的芳香族硫缩醛连接键制备阳离子壳聚糖-药物缀合物，通过静电互作在活菌表面形成纳米涂层；② 口服给药后，包裹的细菌通过涂层屏蔽作用增加对胃肠液抵抗性，以时空同步方式与缀合药物共同递送；③ 到达病变部位后，通过触发硫缩醛键的原位裂解，释放偶联药物和衍生物肉桂醛，发挥抗炎和杀灭致病菌作用，同时诱导纳米涂层解离，实现活菌释放激活；④ 构建结肠炎小鼠模型，联合疗法可实现药物同步靶向递送，发挥协同治疗效果。 【主编评语】 活体微生物药物和小分子化学药物因其各自独特的优势，广泛应用于不同疾病的治疗。然而，二者的联合疗法目前仍然面临生物利用度低、时空分布不均和药物释放不匹配等问题。近日，上海交通大学刘尽尧、吴冯、李茜及团队在Journal of the American Chemical Society发表最新研究，报道了一种可原位降解的前药纳米涂层，同步激活微生物和小分子药物以实现联合治疗，值得关注。（@九卿臣） 【原文信息】 Triggerable Prodrug Nanocoating Enables On-Demand Activation of Microbial and Small-Molecular Therapeutics for Combination Treatment 2023-11-21, doi: 10.1021/jacs.3c10015 用于预防复发性艰难梭菌感染的菌群药品：2023进展更新 Clinical Microbiology and Infection——[14.2] ① 目前FDA批准了2种商业化菌群衍生药品用于预防rCDI：Rebyota®（RBX2660，辉凌制药）和VOWST®（SER-109，Seres），二者均基于加工健康供体粪便，Vedanta的VE303（源自人粪便的组成明确的细菌群落）也将进行3期试验；② 这些产品都在高风险患者中降低rCDI风险，但幅度小于FMT（与安慰剂相比的风险降低：FMT 50.5%，RBX2660（3期）13.1%，SER-109（3期）28%，VE303（2期）31.7%），不同试验间难以直接比较；③ 所有治疗安全性良好。 【主编评语】 粪菌移植（FMT）是治疗多次复发艰难梭菌感染（rCDI）的标准疗法，一些人类菌群衍生药品也在临床研究方面取得进展。Clinical Microbiology and Infection发表的这篇文章，总结了关于菌群衍生药品用于预防rCDI的2期和3期临床试验，比较了这些药品与FMT在疗效等方面的差异，表明这些菌群衍生药品在预防rCDI上有效，但效果不如传统FMT，在实际应用中需要进一步研究以确定这些药品在治疗策略中的位置。（@mildbreeze） 【原文信息】 Update on Microbiota-derived therapies for recurrent Clostridioides difficile infections, 2023 2023-12-13, doi: 10.1016/j.cmi.2023.12.007 肠道菌群与免疫相关性结肠炎互相影响 Cancer Immunology Research——[10.1] ① 本研究包含18例免疫检查点抑制剂治疗引起的免疫相关性结肠炎（irColitis）；② 虽然在irColitis发病时收集的粪便样本与存在胃肠道症状的对照组具有相当的肠道菌群α-多样性，但irColitis存在粪便微生态失调；③ 5例对类固醇和生物抗炎药难治的irColitis患者接受了健康供体的粪菌移植（FMT），4名患者irColitis症状得到初步改善，两人随后在抗生素疗程后出现ircolitis症状复发，他们接受了第二次FMT，结肠炎临床症状得到改善。 【主编评语】 由免疫检查点抑制剂（ICI）治疗引起的结肠炎（irColitis）是癌症治疗并发症的一个重要原因。近期Cancer Immunology Research发表了一项研究，研究者假设在irColitis发病时就存在异常的粪便微生物群特征，并且通过健康供体的粪便移植（FMT）恢复微生物群可以减轻疾病的严重程度。结果显示，irColitis发病时存在显著的微生物群落改变，在一些类固醇和生物制剂难治性结肠炎病例中，通过FMT治疗患者临床症状得到了改善。（@注册营养师陈彬林） 【原文信息】 Immune-related colitis is associated with fecal microbial dysbiosis and can be mitigated by fecal microbiota transplantation 2023-12-18, doi: 10.1158/2326-6066.CIR-23-0498 于君团队：用益生菌干预大肠癌（综述） Chinese Medical Journal——[6.1] ① 目前对结直肠癌益生菌的研究主要集中在降低结直肠癌发病率、减轻治疗相关副作用、增强抗癌治疗效果等方面；② 本综述介绍了传统益生菌和新干预措施（如下一代益生菌和后生元），在结直肠癌的防治作用；③ 本文还讨论了益生菌抗癌作用的潜在机制，包括恢复微生物组成、增强肠道屏障完整性、诱导癌细胞凋亡、致癌物失活和调节宿主免疫反应；④ 本文进一步评价了益生菌作为辅助治疗在提高化疗和免疫治疗疗效方面的新策略。 【主编评语】 肠道内有大量微生物与上皮细胞相互作用，维持宿主健康的生理状态。这些肠道微生物群参与营养底物的发酵，并产生有益的代谢物来调节宿主的体内平衡、代谢和免疫反应。近期香港中文大学于君作为通讯作者在Chinese Medical Journal发表了一篇综述，表明益生菌作为结直肠癌的预防和辅助治疗选择是不可替代的。由于宏基因组测序和细菌基因组编辑技术的进步，与益生菌相关的抗癌作用的证据正在迅速积累，对下一代益生菌（NGPs）和后生元的研究具有巨大的治疗潜力。（@注册营养师陈彬林） 【原文信息】 Probiotics intervention in colorectal cancer: From traditional approaches to novel strategies 2023-11-30, doi: 10.1097/CM9.0000000000002955 Nature：用可解释的深度学习模型，研发对抗超级耐药菌的全新抗生素 Nature——[64.8] ① 基于39312种化合物抗生素活性和人体细胞毒性特征，采用蒙特卡罗搜索树算法结合深度学习模型，筛选大约1200万种化合物，被预测对耐甲氧西林金黄色葡萄球菌（MRSA）具有活性；② 对模型识别的283种候选化合物进行验证，通过在培养皿测试MRSA，进而识别出两个来自同一类别化合物；③ 构建两种小鼠感染模型（皮肤和系统感染），发现这些化合物可将小鼠体内MRSA数量减少10倍；④ 这些化合物可通过破坏细菌维持细胞膜电化学梯度的能力来杀死细菌。 【主编评语】 据世界卫生组织数据显示，2019年全球约有120万人死于由抗生素耐药性加剧的细菌感染，这已超过艾滋病导致的死亡人数。近日，麻省理工学院研究人员在Nature发表最新研究，利用人工智能和可解释的深度学习模型，从超过1200万种化合物中识别出一种全新的新型抗生素类型，可以杀死临床上常见的超级细菌耐甲氧西林金黄色葡萄球菌。这些化合物对人类细胞的毒性很低，因此成为特别有希望的抗生素候选者，值得关注。（@九卿臣） 【原文信息】 Discovery of a structural class of antibiotics with explainable deep learning 2023-12-20, doi: 10.1038/s41586-023-06887-8 Cell子刊：海绵共生的酸杆菌是天然活性产物来源 Chem——[23.5] ① 通过建立的Trans-PACT法对细菌反式乙酰转移酶聚酮合酶（Trans-AT PKSs）和其聚酮类代谢产物进行了预测分析；② 发现石鳖杆菌中的两个杂合trans-AT PKS-NRPS，其中之一预测其代谢物为伏波唑及类似物；③ 通过靶向代谢分析分离并证实了相关代谢物的存在，并构建了其合成的模型；④ 另一个Trans AT PKS可以合成海绵诱癌素类似物，此外还鉴定了酸杆菌脂和多肽聚酮杂化物等活性物质；⑤ 富含生物合成基因簇的石鳖杆菌是海绵相关天然产物的重要来源。 【主编评语】 无脊椎动物海绵是丰富天然活性产物的来源之一。有研究显示其天然活性产物主要由与其共生生物合成。近期一篇发表在Cell子刊Chem上的研究论文报道了他们从海绵上分离得到一个共生的海洋酸杆菌属的石鳖杆菌，并发现其是生物活性物质的主要来源。（@Zhonghua） 【原文信息】 Animal-associated marine Acidobacteria with a rich natural-product repertoire 2023-12-14, doi: 10.1016/j.chempr.2023.11.003 感谢本期日报的创作者：湖人总冠军，orchid，Leo，九卿臣，mildbreeze，注册营养师陈彬林 点击阅读过去10天的日报： 12-26 | 《自然·综述》年度回顾：炎症性肠病疗法的新进展 12-25 | 口腔健康莫忽视！12页综述解析牙周炎与癌症的复杂关系 12-24 | 发酵食品如何促进胃肠健康？65分综述一文读懂 12-23 | 肠脑轴前沿：10文一览肠道与脑健康的紧密关系 12-22 | 《自然·综述》领衔，10文聚焦微生态干预 12-21 | 今日Nature：线粒体如何影响肠道脂代谢？ 12-20 | Nature重磅：从微生物暗物质中挖掘40万个新基因家族 12-19 | 周文/贺艳娟/贾伟/陈翔Cell子刊：从肠菌入手，改善多发性骨髓瘤治疗 12-18 | 《自然·综述》年度回顾：晚期大肠癌治疗的新选择 12-17 | Lancet子刊双文齐发：维生素D对心血管病和骨折的预防效果存疑