Acino International AG

2023年11月20日，在经历了一系列临床试验失败后，活体生物药公司Evelo Biosciences（下称Evelo）董事会向美国证券交易委员会提交了其注销计划（Dissolution Plans），并表示此举乃是保存公司股东利益的最佳之选。 Evelo在创立初期专注微生物组，力图利用微生物来调节肠道和调节免疫反应，并一度被资本相中，市值超20亿美元（超百亿元）。但后续产品失利导致的连锁反应让这颗曾经的明星一夜之间跌入深渊。为求生存，Evelo一度使出浑身解数力挽狂澜：从削减管线、研发转向、大规模裁员、更换管理层到寻求出售或合并，然而还是难逃倒闭结局。首先因为产品不力，融资前景黯淡，最终在现金流耗竭后，更是无人愿意收购其资产。Evelo最终发现，解散成为唯一可行的选择。 从明日新星到清算解散的巨大反差，让Evelo的结局令人唏嘘。这家由顶级投资机构Flagship孵化，探索空白领域，并凭借全新技术概念在一级市场累计融资2.13亿美元的biotech不应有如此下场。 从微生物疗法到外泌体领域，从市值20亿美元到股价暴跌50% 2015年，著名风险投资公司Flagship Pioneering创立Evelo Biosciences。Evelo是一家通过识别针对小肠免疫细胞的特定单克隆菌株，引导全身免疫反应，从而治疗癌症、炎症性等疾病的公司。癌症免疫疗法和微生物组的结合让这家公司成立之初便备受关注。 由此，Evelo成为全球第一个通过研究微生物免疫疗法，治疗癌症、自身免疫和炎性疾病的公司。 Evelo的首席执行官Simba Gill博士兼任Flagship Pioneering高级合伙人，在抗体、干细胞、定向分子演化、基因治疗和免疫诊断等领域均有涉猎。他曾在INSEAD商学院获得工商管理硕士学位，在伦敦国王学院获得博士学位。在加入Evelo之前，Simba Gill博士曾在moksha8 Pharmaceuticals担任总裁兼首席执行官。在2016年至2019年间，他还担任Realm Therapeutics PLC的董事。除此之外，Gill还在Maxygen，Systemix，Verdia，Avidia以及Valentis等公司担任过重要职位。 成立一年以后，Evelo与一家致力于研究如何治疗过敏、炎症和自身免疫性疾病的公司Epiva Biosciences合并，合并后保留Evelo的名字，但个公司发展重点依然是微生物组与免疫疗法。 值得一提的是，自成立以来，Evelo共计完成四轮融资。紧接着，在2018年完成C轮融资后，Evelo于纳斯达克成功上市，并且完成首次公开募股共计8500万美元。从成立到上市，Evelo只用了短短4年的时间。 期间，Evelo和芝加哥大学达成合作，共同推进基于微生物群的癌症免疫治疗。不久之后，Evelo与Mayo Clinic达成了一项关于免疫微生物癌症疗法的合作，即利用细菌激活机体免疫系统以治疗肿瘤，Evelo借助Mayo Clinic的专利技术建立一个与肿瘤相关的细菌文库，并在该文库中找出能够帮助对抗肿瘤的细菌菌株。 Evelo旨在开发基于小肠轴SINTAX™的口服递送药物。小肠是人体食物消化吸收的重要场所，同时也是人体免疫系统的重要组成之一。小肠轴是小肠与所有器官和组织的连接，它的存在使得小肠能够对人体生物系统发挥重要的控制作用。SINTAX在调节免疫、新陈代谢和神经系统方面起着核心作用，但其在抗击疾病中的重要性长时间被学界忽视，直到最近几年才获得重视。 Evelo构想用单一菌株来填充胶囊，胶囊被患者吞下后，会进入小肠以及与内脏相关的淋巴组织。而树突细胞能够感应到肠道发生的这种变化，并会向淋巴系统发出警报，然后机体会根据感应到的微生物，产生特定的免疫反应。为了寻找到这些特殊的单菌株，Evelo开发了一个集成平台。 Evelo自研平台的工作流程则分为以下四步：通过微生物学、体外人体试验、动物模型鉴定等令人信服的药理学鉴定微生物菌株；基于筛选出来的菌株确定单一菌株及产品形式；确定药物靶向的位置、合适的剂型以及正确的剂量；通过公司内部流程以及合作伙伴来开发药物，保证产品的活性和质量。 基于该平台， Evelo部署了一些列单一微生物菌株的口服药物研发，例如治疗癌症疾病的主要候选产品EDP1503以及针对炎症性疾病的主要候选产品EDP1815。此外，由于公司上市后遇上了新冠流行，因此Evelo一度蹭热点，宣布推进EDP1815治疗Covid-19，同时也筛选出了用于治疗肿瘤的药物EDP1503。只是，多点开花并未换来多线突破，反倒消耗了不少资金。 截至2021年4月，Evelo在研管线 然而，虽然Evelo的管线数量众多，但是实际仅有用于治疗炎症性疾病的EDP1867、EDP1815、EDP2939进度领先，被寄予众望。另一方面，进入2022年后，Evelo筹集的资金还在继续消耗，但自身的好运却到头了。 2022年4月， EDP1867治疗特应性皮炎的一期数据发布，由于未能有明显疗效，公司宣布搁置EDP1867的研发，专注于EDP1815。 截至2023年3月，Evelo在研管线 2023年2月，Evelo更新了EDP1815治疗特应性皮炎的Ⅱ期研究结果，在治疗特应性皮炎未能达到临床II期的主要终点，甚至效果不如安慰剂。这一数据导致Evelo的股价当天暴跌50%，公司随即宣布裁员48%，以节约现金支撑公司运营到2023年三季度。2023年4月26日， EDP1815在治疗特应性皮炎中的第四组队列的数据，依然未达临床试验主要终点，宣告了临床二期试验的失败。 随后Evelo紧急停止进一步开发EDP1815治疗特应性皮炎，将把资源集中到新一代外泌体平台以及细胞外囊泡（EV）药EDP2939项目上来。同时，Evelo公司还将进行裁员以节省成本。 外泌体药失败，压死骆驼的最后一根稻草 2023年3月，Evelo宣布其首个EV候选产品EDP2939，在完成第一批人类志愿者的安全性和耐受性审查后，已在II期银屑病临床试验中进行给药。多个递增剂量队列的安全性和耐受性评估仍在继续。 Evelo首席医疗官Duncan McHale博士表示，这是EDP2939和Evelo更广泛的口服外泌体平台的里程碑，并声称此次II期临床这是第一次在人体上进行潜在的细菌EV药物口服给药试验。其中，安全性和耐受性是Evelo开发药物以治疗所有阶段和所有类型炎症性疾病的核心要素。 外泌体和EDP2939作为一种新型SINTAX药物在临床前研究中显示出前景，具有基于三个因素的生物样疗效潜力：EV在临床前模型中的高内在效力，单个胶囊中可递送的EV数量和浓度以及递送至近端小肠的靶位点。 临床前数据表明EV为有效疗法 EDP2939-101是一项多中心随机、安慰剂对照的I/II期试验，评估EDP2939的安全性、耐受性和临床疗效。该试验的第1阶段旨在确定人类志愿者在多次递增剂量下的安全性和耐受性。第2阶段旨在确定EDP2939在建议治疗剂量下对中度斑块状银屑病患者的疗效。主要终点是在每天口服EDP2939或安慰剂16周后，银屑病面积和严重程度指数（PASI）评分（PASI-50反应）比基线改善50%的患者比例，之所以选择PASI-50反应，是因为这对于中度银屑病患者具有临床意义。次要终点包括医生和患者报告的几项银屑病结果，以及进一步的安全性评估。据悉，该试验将包括大约110名患者，他们以1:1的比例随机分配接受EDP2939胶囊或匹配的安慰剂。 随后，在2023年10月，Evelo宣布了其EDP2939治疗中度银屑病的II期临床研究的顶线结果。该研究的主要终点是，经过16周的每日给药后，EDP2939与安慰剂组银屑病面积和严重程度指数（PASI）评分（PASI-50反应）比基线改善50%的患者比例未到达预期。而总体安全性数据与本研究第1阶段之前报告的数据一致：EDP2939耐受性良好，不良事件（AE）与安慰剂相当。 以上结果对于在2022-2023年管线临床接二连三爆出“炸裂”负面数据，业内与市场信任度一再下跌的Evelo而言，无疑是最后一根稻草。外泌体先驱Codiak耗费大量资源未能走通的疗效之路，在短时间内想要扳回一局的Evelo当然也无从破局。 曾经“无人占领”的创新领域，诞生15亿美元交易 除管理层频繁变动，因资金使用效率不足（例如前期资金分配过于分散等）导致的财务压力过大等原因，Evelo在转向中途选择外泌体作为切入方向也并不为业界所看好，而Evelo转向的时机也称不上吉利，因为恰逢外泌体先驱Codiak因临床数据未达预期而破产。 Codiak此前曾面临从0到1的探索难题，在其初次步入市场时，外泌体还是“无人占领”的创新领域。尽管行业会面临“一鲸落，万物如何生”的问题，但Codiak或Evelo的失败并不意味外泌体开发的技术路径不行。与Codiak齐名的EVOX Therapeutics（下称EVOX），就在2023年6月20日完成了对Codiak的engEx-AAV™技术平台的收购，巩固了公司在外泌体治疗领域已占据的主导地位。 上市公司Capricor Therapeutics（NASDAQ：CAPR，下称Capricor）被视为一众外泌体疗法企业中走得最快的。Capricor致力于推进转化细胞和外泌体疗法，以重新定义罕见疾病的治疗前景。其创新前沿为主要候选产品 deramiocel (CAP-1002)，一种同种异体心脏衍生细胞疗法。广泛的临床前和临床研究表明，deramiocel 具有专门针对肌营养不良症和心脏病的免疫调节、抗纤维化和再生作用。 就在2024年9月17日，Capricor宣布已与日本新药株式会社就签订了具有约束力的条款清单。条款表示，日本新药株式会社将在欧洲商业化和分销Capricor的主要资产deramiocel，用于治疗杜氏肌营养不良症（DMD）。Capricor将以20%的溢价获得1500万美元的股权投资，并在签署最终协议后获得2000万美元的预付款，其中潜在里程碑金额高达7.15亿美元，产品收入占比达到两位数，综合分销协议的潜在里程碑目前总额约为15亿美元，为外泌体领域最大金额交易。 此外，其他“装备”更为充分的玩家也在进入这个赛道。截至2024年上半年，全球范围内从事外泌体相关产品开发的企业已经有超过50家。国内方面，据维渡纵横数据，外泌体相关企业主要包括15家，其中3家（青莲百奥、恩赛尔生物、深圳汇芯）主要从事外泌体分离提纯及检测服务的企业，7家开发外泌体载药平台及药物，4家专注在外泌体诊断业务，1家兼开发外泌体药物和诊断业务（微纳核酸生物）。 如果您想对接文章中提到的项目，或您的项目想被动脉网报道，或者发布融资新闻，请与我们联系；也可加入动脉网行业社群，结交更多志同道合的好友。 近 期 推 荐 声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。 动脉网，未来医疗服务平台

C4X Discovery Holdings Limited C4XD announces progress on immuno-inflammation programmes and appointment of new Board members 22 July 2024 - C4X Discovery Limited (“C4XD”), a pioneering drug discovery company, today provides an update on the business following its delisting from AIM earlier in the year. Clive Dix, Executive Chairman of C4XD, said: “The great work at C4XD continues. We are utilising our strong capital position to drive forward our immuno-inflammatory portfolio, underpinned by our unique genetic insights platform. Our business development and scientific teams are hard at work presenting and networking at key scientific conferences and industry events, showcasing our expertise in immuno-inflammation, whilst ensuring that we have the right contacts in place for future collaborations. “With the shift in direction for the Company away from the public markets, we sadly say goodbye to Simon Harford, who has decided to step down after three years to focus on other commitments. Simon has provided invaluable support and guidance during his time with us, and we wish him the very best for his future projects. At the same time, we are delighted to welcome two new Non-Executive Board members: Harmesh Suniara, who joins us from Lombard Odier 1798 Volantis, a great supporter of our business; and Richard Jones, a respected finance operator within the industry. Each bring unique and important skills which will broaden and enhance the Board’s guidance and strategic direction to drive a successful future for the Company.” PipelineWe continue to advance our small molecule drug discovery portfolio against a range of targets in the immuno-inflammatory space where we have identified a combination of unmet medical need, significant commercial potential and practicable application of our core platforms, PatientSeek and Conformetrix. Our lead programme is an oral a4b7 integrin inhibitor for use in the treatment of inflammatory bowel disease (‘IBD’). This integrin is the target for the clinically successful biologic therapy Vedolizumab, (Entyvio), but a small-molecule alternative would broaden patient access. Our Discovery scientists are closing in on the shortlist of pre-clinical candidates with planning for IND-enabling studies well underway. In parallel, our Human Genetics team are applying our PatientSeek platform to analyse a number of databases in order to define a genetic fingerprint as a predictive genetic biomarker for a4b7 response that will allow us to specifically design our pivotal clinical trials for success. We have recently published our first disclosure on the PatientSeek platform as applied to Target Identification in rheumatoid arthritis (Scientific Reports, 14, 14153 (2024) doi.org/10.1038/s41598-024-64970-0). https://c4xdiscovery.com/unveiling-new-genetic-insights-in-rheumatoid-arthritis-for-drug-discovery-through-taxonomy3-analysis/ As part of C4XD’s journey from a Discovery to a Therapeutics company with a clinical pipeline, we are building our internal skillset appropriately whilst maintaining flexibility through a range of external consultants, CROs and CDMOs in our network. We are now disclosing two programmes in our pipeline behind our a4b7 programme in the Hit-To-Lead phase and progressing towards Lead Optimisation. The first is an oral PAD4 inhibitor for treatment of rheumatoid arthritis (RA). PAD4 is an enzyme involved in modifying a range of proteins through a process known as citrullination; citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Attenuating this process therefore should provide an opportunity in moderate to severe rheumatoid arthritis with First-In-Class potential. Our second programme is an oral TNFa inhibitor targeting a Best-In-Class profile with multiple possible therapeutic applications, including RA and IBD. Tumor necrosis factor (TNF) is a cytokine with a major role in immune system homeostasis and is involved in a number of autoimmune and inflammatory diseases. Biologics have been developed to block TNF-dependant signalling cascades, but they are not without side-effects and have an effectiveness that often decreases over time. A small molecule therapy should be able to avoid such issues and provide an attractive alternative therapeutic option across a range of indications. We also have a number of programmes in early evaluation with the goal to assess their suitability for progression. BoardWe note the resignation of Simon Harford after three years on the Board and thank him for his support and counsel during this time. Separately, in line with the delisting Circular, we are delighted to welcome two new Non-Executive members to the C4XD Board appointed by Richard Griffiths and Lombard Odier Asset Management (Europe) Limited: Richard Jones is an experienced healthcare and life sciences Director. He was most recently CFO of Medica Group, a PE backed international tele-medicine business which was taken private in a £270m deal by IK partners from the UK main market; and is currently SID and Chair of the Audit Committee at Alliance Pharma PLC, an AIM listed consumer healthcare company. Richard previously gained extensive experience in the healthcare sector as CFO at UK AIM Listed companies Mereo BioPharma Group PLC and Shield Therapeutics PLC. At Mereo, he had a leading role in the merger with US listed OncoMed Pharmaceuticals, Inc and its subsequent dual listing on Nasdaq in 2019. At Shield, he established the finance operations and guided the company through several private financing rounds and its 2016 IPO. Prior to his CFO roles, Richard held senior investment banking positions at Investec and Brewin Dolphin Securities, where he advised healthcare clients on a wide range of transactions and fundraisings including IPOs, M&A and fundraisings. Richard qualified as a Chartered Accountant with PwC. Harmesh Suniara has over 15 years' experience of working in investment management, with a particular focus on UK small and mid-cap equities including the technology and life sciences sectors. He brings a wealth of expertise in active engagement with companies that Lombard Odier has invested in. He has worked as a Portfolio Manager at Lombard Odier 1798 Volantis since 2017, and prior to this he was an Investment Manager at Henderson Volantis Capital and Gartmore Investment Management. Harmesh graduated in Physics from the University of Cambridge. Lombard Odier 1798 Volantis is a major shareholder in C4X Discovery. Contacts C4X Discovery HoldingsMo Noonan, Communications+44 (0)787 6444977 C4X Discovery Media – ICR ConsiliumMary-Jane Elliott, Chris Gardner, Angela Gray+44 (0)203 709 5700 Notes to Editors: About C4X DiscoveryC4X Discovery (C4XD) is a pioneering Drug Discovery company, combining scientific expertise with cutting-edge technologies to efficiently deliver world-leading medicines. We have a highly valuable and differentiated approach to Drug Discovery through our enhanced molecular design and patient stratification capabilities, generating small molecule drug candidates across multiple disease indications focused on immuno-inflammation. We are advancing our internal portfolio which ranges from early-stage target opportunities to late-stage Drug Discovery programmes and we have two commercially partnered programmes with Sanofi and AstraZeneca, and one clinical stage candidate which has been acquired by Indivior. For more information visit us at www.c4xdiscovery.com or follow us on twitter @C4XDiscovery.

HYOGO, Japan--(BUSINESS WIRE)-- MEDIPAL HOLDINGS CORPORATION (TSE 7459 “MEDIPAL”) and JCR Pharmaceuticals Co., Ltd. (TSE 4552 “JCR”) today announced the completion of the regulatory review by the Pharmaceuticals and Medical Devices Agency (PMDA) for the clinical trial notification for the phase I/II study of JR-446, a blood-brain barrier-penetrating α-N-acetylglucosaminidase, for the treatment of mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome type B), a devastating and ultra-rare lysosomal storage disorder. MPS IIIB affects an estimated 500 to 1,000 individuals worldwide1, causing severe central nervous system symptoms. Despite the dire need, there are currently no approved treatments available for this condition. JR-446, developed using JCR’s proprietary J-Brain Cargo® technology, has shown promising preclinical results in addressing the symptoms of this challenging disorder. In September 2023, MEDIPAL and JCR secured a license to commercialize JR-446 overseas and partnered to develop and commercialize it in Japan, targeting MPS IIIB2. With the regulatory review now complete, we plan to start the clinical trial in Japan in the first half of FY2024 (April to September). This collaboration highlights the commitment of MEDIPAL and JCR to pioneer treatments for ultra- rare diseases. By advancing therapies like JR-446, we aim to bring hope to patients and their families, while enhancing corporate value and contributing to a society where everyone can live with physical and mental well-being. About Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome Type B) Mucopolysaccharidosis type IIIB, or Sanfilippo syndrome type B, is an autosomal recessive disease caused by pathogenic mutations in the NAGLU gene, encoding a lysosomal enzyme involved in the degradation of heparan sulfate. With the accumulation of heparan sulfate in the central nervous system in the brain, individuals with this condition present rapid neurological decline, including sleep disorders, loss of speech, and behavioral changes, which may significantly affect the quality of life of patients and their families. About MEDIPAL HOLDINGS CORPORATION MEDIPAL is a holding company which controls, administers and supports the operating activities of companies in which it holds shares in the Prescription Pharmaceutical Wholesale Business; the Cosmetics, Daily Necessities and OTC Pharmaceutical Wholesale Business; and the Animal Health Products and Food Processing Raw Materials Wholesale and Related Business, and conducts business development for the MEDIPAL Group. For more information, visit About JCR Pharmaceuticals Co., Ltd. JCR is a global specialty pharmaceuticals company dedicated to advancing treatments for rare and genetic diseases. With nearly 50 years of expertise in Japan, we are expanding to the US, Europe, and Latin America. Our innovative therapies address conditions like growth disorder, MPS II, Fabry disease, acute graft-versus-host disease, and renal anemia. We are also developing treatments for rare diseases like MPS I, MPS II, MPS IIIA and B, and more. Our core values of reliability, confidence, and persistence drive our mission to enhance global medical progress. For more information, visit . References 1 Based on data from the Ministry of Health, Labour and Welfare’s public research and JCR’s own investigations. 2 Reference: Press release on the licensing agreement for JR-446 between MEDIPAL and JCR (September 28, 2023). This news release is intended to provide the latest information on two companies businesses to shareholders and other investors, and members of the press. The information on pharmaceutical products (including those under development) in this document is not intended for advertising, providing medical advice or other such purposes. The English version of this document is a translation of the Japanese original and is provided for information purposes only. While reasonable efforts have been made to provide an accurate translation, no liability is assumed by MEDIPAL and JCR for any errors, omissions, or ambiguities in the translation. In the event of any inconsistency or conflict between the English version and the Japanese original, the Japanese original shall prevail.