Irinotecan-eluting beads

成立仅7个月，顺利IPO；资本寒冬，IPO超募3亿美元；上市仅9个月，股价涨幅311%，市值达到40亿美元。你很难想象，这些战绩，都是一家核心管线均处于临床前biotech，Apogee创造的。当然，一切并非毫无迹象可循。癌症之外，市场对于自免热度极高。近两年，大额并购案不断，度普利尤单抗的持续进击，更是刺激着市场的神经。而Apogee要做的，则是挑战甚至超越度普利尤单抗。作为一家开发炎症和免疫学（I&I）适应症差异化疗法的biotech，Apogee核心管线有二，APG777和APG808。前者是一款延长半衰期的长效IL-13抗体，用于治疗特应性皮炎（AD），后者则是一款延长半衰期的畅销IL-4Ra抗体，用于治疗慢性阻塞性肺病(COPD)。由于APG808尚未进入临床，因此，市场当前的热情核心是源于APG777的潜力。在临床前研究中，APG777表现出与另一种IL-13药物（礼来的Lebrikizumab）“相当或优于”IL-13抑制作用，且半衰期明显更长，预计给药间隔可能是每两个月或每三个月。而度普利尤单抗需要每两周给药一次。而最新的1期研究的结果，超过了APG777的预期，其将加速二期临床，并探索3个月到6个月注射一次的治疗方案。APG777展露出优于当前同靶点药物甚至是IL-4Rα单抗的潜力，Apogee甚至称其能够成为未来500亿美元AD市场的领导者。基于此，尽管仍处于临床早期，但市场已将预期打满。那么，Apogee能撑起市场的期待吗？012年40亿美元Apogee成立于2022年，是Paragon Therapeutics拆分出的第一家公司。2022年12月7日，Apogee宣布完成1.69亿美元B轮融资。根据Apogee官网公布的信息，目前公司拥有四条具有数十亿美元潜力的管线，适应症集中于AD、COPD、哮喘等相关I&I领域。其中，APG777和APG808为核心管线。半年后，Apogee成功在美国完成IPO上市。尽管市场寒冬依旧，但Apogee依旧完成了超募，募资3亿美元，仅次于去年5月上市的Acelyrin（IPO募资额达5.4亿美元）。上市首日，公司股价首日暴涨24.88%。无论是IPO发行规模，还是首日涨幅，均显示出市场对Apogee的超高热情，然而，Apogee仅仅成立7个月时间，核心管线尚未正式进入临床阶段。如果算上IPO募资，意味着Apogee在成立半年多的时间，便累计获得了3.69亿美元的融资。这还是在市场下行、资本寒冬之中完成的。这样的成绩，对于绝大多数苦于寒冬融资无门的biotech，绝对是不敢想象的事情。那么，为什么Apogee获得资本市场的追捧？这背后是市场对于自免潜在重磅药物的追捧。2022年12月，辉瑞与Roivant Sciences宣布成立Telavant，专注于TL1A单抗RVT-3101的开发和商业化；12月，武田以60亿美元的价格从Nimbus Therapeutics收购口服的选择性变构酪氨酸激酶2（TYK2）抑制剂NDI-034858；2023年4月，默沙东以118亿美元收购Prometheus Biosciences，获得了TL1A资产；6月，礼来以24亿美元收购DICE Therapeutics；10月，罗氏以71亿美元收购Telavant，获得后者重磅核心产品溃疡性结肠炎候选治疗药物RVT-3101……在海外，自身免疫疾病药物市场一直是药王储备池。尽管老药王修美乐在专利悬崖之下，销量一路下滑，但度普利尤单抗等后来者的快速崛起，依旧让市场对自免领域充满想象。2023年底，Nature杂志子刊发布《TOP product forecasts for 2024》预测了2024年销售额排名TOP10的产品，修美乐掉出前十，度普利尤单抗预计将进入前三甲。2023年，度普利尤单抗销售额达到115.7亿美元，支撑度普利尤单抗销售额的一个重要适应症，便是特应性皮炎。今年，度普利尤单抗还有不少新适应症里程碑事件，未来其销售额天花板值得遐想。而Apogee要做的便是挑战甚至超越度普利尤单抗。02瞄准自免痛点度普利尤单抗的吸金力度之大，让后来者们蠢蠢欲动，特应性皮炎也成为了药企的必争之地。一来，这一市场患者规模庞大；二来，由于特应性皮炎致病机制尚未完全清晰，因此无法治愈，患者需要长期用药。最重要的是，由于现有药物普遍都有较大的副作用，或是依从性不高，如度普利尤单抗需要每两周给药一次，这使得，对特应性皮炎的治疗存在着极大的临床未满足需求。Apogee则瞄准这一痛点，其核心管线主打长效半衰期。这对于需要长期用药的自免患者，无疑是一大吸引力。其当前进展最快的管线，即意在挑战礼来Lebrikizumab、赛诺菲度普利尤单抗的重磅竞争对手APG777。与Lebrikizumab一样，APG777靶向IL-13细胞因子。在免疫系统异常炎症假说中，异常炎症，是指由于各种因素导致的患者皮肤屏障受损，患者接触过敏原后，被激活的由2型辅助性T细胞驱动异常免疫应答。理论上，阻断IL-4和IL-13这两个给Ⅱ型免疫反应通风报信的调节因子，能阻断Th2炎症的中枢通路，抑制过强的免疫反应。IL-13和IL-4作为配体，要和相应受体结合才能发挥功能。度普利尤单抗的机制是用IL-4Rα抗体与IL-4Rα结合，IL-13和IL-4自然无从与受体结合。而APG777则被设计为结合IL-13，从而通过阻止IL-13Rα1/IL-4Rα异二聚体的形成来破坏Th2信号传导。其独特之处在于，通过YTE突变优化抗体结构，使药物半衰期和给药周期大幅度延长，提高患者的用药依从性。APG777在片段可结晶（Fc）区含有三重氨基酸修饰，通常为M252Y/S254T/T256E（即“YTE”突变），旨在通过在酸性pH条件下增加与新生儿Fc受体（FcRn）的结合来延长其在非人灵长类动物和人类中的半衰期。临床前数据显示，APG777在抑制IL-13信号传导方面与礼来的Lebrikizumab有相同或更好的效力，且半衰期更长。预计APG777的人类半衰期约为80至110天。这样的研究数据，支持APG777每两个月一次的维持给药计划。因为许多AD患者会经历“针头疲劳”，尤其是儿科患者经常害怕针头，每两三个月给药一次，将会增加患者的用药依从性。这可能会为中度至重度AD患者护理标准，带来潜在的变革性变化。也正是基于这一预期，Apogee倍受资本追捧。临床前的优秀表现延续至一期临床，甚至大超Apogee预期。数据显示，APG777能够抑制AD关键生物标志物pSTAT6和TARC持续3个月以上；与IL-13类药物拥有类似的安全性，相比IL-4Rα单抗结膜炎发生率低、止痒方面表现不错；超长的半衰期，二期临床将探索3个月到6个月注射一次的治疗方案。Lebrikizumab在特应性皮炎的临床效果已经堪称优秀，相比度普利尤单抗用药方式更长效（四周一次）且安全性也更具优势，而APG777则展现出更优的潜力。3到6个月意味着，APG777每年仅需2-4次注射，而当前治疗范式为每年12-26次注射。如果能够继续保持，无疑将极大提升患者依从性。这一结果发布后，Apogee股价暴涨42%，目前总市值已达40亿美元。03一套行之有效的打法不止APG777，Apogee其他管线也主打长效。比如APG808。这是一种靶向IL-4Ra的延长半衰期单抗，用于治疗COPD。在头对头临床前试验中，已经证明，APG808在抑制IL-4Rα信号传导方面，与度普利尤单抗相同或更好的效力。此外，根据临床前研究，APG808可以每六周或每两个月维持给药一次，而第一代IL-4Rα抗体每两周给药一次，APG808将带来显著的改进。Apogee的第三个项目APG990是一种针对OX40L的延长半衰期单抗，同样用于治疗AD。虽然该靶点在肿瘤适应症研发方面遭遇挫折，但OX40或其配体OX40L的抗体一直是全球自免领域的研发热门方向。随着安进、赛诺菲的OX-40抗体的突破，竞争更是白热化。Apogee第四个项目APG222，是针对IL-13和OX40L的潜在联合疗法用于特应性皮炎。可以看到，Apogee的核心管线主打的就是半衰期延长，且围绕自免领域的热门靶点做了多重布局。除此之外，Apogee也希望不断扩大药物的适应症。比如针对APG777，Apogee表示可能会在2025年启动一项针对哮喘的2期试验，以进一步评估开发APG777用于其他I&I适应症的机会，包括斑秃、鼻窦炎、慢性自发性荨麻疹、嗜酸性粒细胞性食管炎和结节性痒疹等。表面来看，Apogee获得市场追捧，是基于其核心管线的巨大潜力。但更进一步来看，这更像是由Paragon背后的投资机构发起的，一场有预谋的“生物科技实验”。Paragon是由Fairmount Funds创办，Apogee创始股东也包括了Fairmount和Venrock两家机构。正如前文所说，Apogee是从Paragon拆分出来的第一家公司，Spyre Therapeutics则是Paragon拆出来的第二家公司。从管线策略来看，Spyre与Apogee极其相似。Spyre核心管线为针对炎性肠炎（IBD）的长效抗体，SPY001和SPY002预计2024年进入临床研究阶段。其中，SYP001的靶点为α4β7，即武田的重磅IBD药物维得利珠单抗的靶点。Spyre表示，相比维得利珠单抗目前是每两周一次给药，SYP001的目标是达到每两个月或每季度给药。SPY002则靶向重磅交易不断的TL1A。去年，默沙东和罗氏先后斥巨资收购相关管线。Spyre对SYP002同样充满信心。从资本市场表现来看，Spyre先Apogee一步完成借壳上市。去年6月，Aeglea宣布以换股交易的方式收购Spyre。尽管均处于临床前，但Spyre的管线同样吸引了大量投资者。Aeglea与PIPE投资（私募基金）达成无投票权可转换优先股的最终协议，筹集到2.1亿美元。这些资金将用于推进Spyre潜在同类最佳的IBD产品组合并支持运营，直至2026年。而自2023年11月至今，Spyre股价涨幅超过270%，最新市值达16亿美元。换句话说，在资本市场表现层面，Spyre与Apogee同样优秀。在资本情绪高涨时期，大部分管线仅处于I期临床阶段，甚至更早期的biotech也能完成上市融资。但如今的环境，市场更追求确定性。Spyre、Apogee却靠着临床前管线，迅速完成融资、上市。Paragon似乎形成了一套行之有效的路径，旗下公司所选择的领域，存在着巨大的未被满足的临床需求，均主打长效针对市场痛点，完美契合了市场对于自免潜在重磅药物的追捧。当然，一切还要靠数据说话。在自免这一大风口上，Apogee并非被吹得最高的那一个。去年5年，自身免疫新药公司Acelyrin以5.4亿美元融资，高调完成IPO上市，成为2023年美股IPO规模最大的生物医药企业，上市首日同样大涨30%。但随着其核心管线在治疗中度至重度化脓性汗腺炎的IIb/III期试验中失败，Acelyrin又回到了现实。如今，Acelyrin市值仅8亿美元。去年一年其股价较IPO发行价跌去56%，成为年内表现最差的生物医药新股。相比之下，Apogee已经用一期数据证明了其临床前数据的可延续性，也获得了市场的大力追捧；Spyre则还处于自证阶段。尽管早期数据亮眼，后期翻车的故事屡见不鲜，但华尔街大佬们愿意加入这场豪赌。注：以上图片来源氨基观察来源 | 氨基观察（药智网获取授权转载）撰稿 | 武月责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信） 阅读原文，是受欢迎的文章哦

None By Marcus Perez, President, Altera Digital Health The end of the year is always a time for reflection, and looking back on 2023, it’s clear that job satisfaction and burnout remain industry-wide issues. So, where do we go from here? And how do we make that happen? Altera Digital Health aims to bring next-level healthcare within reach through sustainable progress. The core values of our parent company, Harris Healthcare, provide a blueprint to achieve that. One of those values is “Solutions, Not Problems.” Here’s where Altera is putting its time, energy and attention to create much needed, lasting change. Enhancing usability When EHRs first hit the market, there was a lot of hype around how they would transform healthcare. Incentives were created to accelerate adoption (i.e., the HITECH Act), and we’ve been pretty successful in that regard. But going from paper charts to EHRs was only the first step. As usage grew, unintended consequences emerged. Research in the Journal of the American Medical Informatics Association (JAMIA) found high levels of burnout correlate to high levels of EHR stress. Equally troubling, a study in the Journal of the American Medical Association (JAMA) suggests poor EHR usability is associated with poor EHR safety performance. Confronted with this reality, Altera leaned into another one of our values: “Understanding and Learning.” In order to build positive experiences with our products, we knew we needed to better understand providers’ daily lives and learn what did and didn’t fit into their workflows. We achieved (and continue to do) this by ensuring that, at every step in the design process, clinicians and our design, development and engineering teams identify problems and work together to identify new possibilities. This enables us to build products that support, rather than disrupt, the way providers work. Advancing interoperability Additional byproducts of EHR adoption include the data-sharing challenges that emerged. It is not uncommon for patients to seek care at different healthcare organizations, and these organizations may use different vendor systems. Even within individual organizations, different departments using different versions of the same EHR are often unable to exchange complete medical records. No matter the circumstances, making care decisions without access to comprehensive patient histories is frustrating at best and harmful at worst. While much progress has been made, there is room for improvement. Approximately 62% of non-federal acute care hospitals in the U.S. are able to send, receive, find and integrate summary of care records into EHRs. Until that figure reaches 100%, patients and providers will deal with the consequences. This brings us to another core value: “Communicate and Share Knowledge.” Having the right information in the right place at the right time is table stakes in our industry, and it is not limited to patient care delivery itself. For example, as more healthcare organizations transition to value-based care models, interoperability will be crucial to care coordination among different providers and accurate reimbursement for services rendered. Altera has a history of supporting information-sharing, and we continue to embrace it, leveraging current interoperability standards like FHIR to enable easier extraction and consumption of data between solutions. Additionally, our award-winning interoperability platform, dbMotion™ Solution, takes things a step further, enabling a high level of information exchange among disparate EHR systems. Improving incrementally Bettering usability and interoperability across Altera’s portfolio converges into our larger aim to continually improve our core products, including Sunrise™, Paragon® and TouchWorks® EHR. Many health IT organizations get caught up in “shiny object syndrome,” always chasing the next innovation they claim will revolutionize healthcare, overlooking existing products in the process. Altera is taking an alternative approach. Make no mistake, we are always working to bring new digital enhancements to our clients. We want our solutions to serve as valuable assets and springboards for further innovation. Our ultimate priority, however, is to be a little better for our clients every day. This is best represented by the core value of, “Discipline. Unwavering and Relentless Focus.” Altera is constantly soliciting client feedback, making changes on a monthly basis to strengthen our products and align them even more closely to clinician workflows. That means making meaningful yet management advancements that benefit our clients and their patients today. Onward and upward Altera’s efforts to advance usability and interoperability through incremental improvements get at the heart of another core value: “Empowerment at the Point of Contact.” From the point of care to the billing office, we know healthcare can be so much better. It should be easier to access, understand and navigate for everyone involved. A new era of healthcare has begun, and we’re not looking back.