HTRA1

不到4个月前，市场被安斯泰来溢价收购专注眼科疗法的Iveric Bio所惊讶——跟收购前股价相比，安斯泰来给出的溢价超过60%，总金额约59亿美元。引用GlobalData医药分析师Prashant Khadayate的评论，这是作为亚洲头部药企的安斯泰来“历史上最大的一次收购”。并且，“如此规模的纯眼科并购也非常罕见”。而正当一些投资者替安斯泰来的投资回报不确定性担忧时，该笔交易已成功给它带来新的监管里程碑。8月，Iveric开发的Izervay，被FDA批准用于治疗年龄相关性黄斑变性（AMD）引起的地图样萎缩（GA），比原本PDUFA订下的目标日期提前了两周。Iveric声称，Izervay是第一个在两个III期试验中显示在12个月的主要终点上显著降低GA进展率的药物。这无疑增加了该药在市场开发上的底气。而另一方面，竞争产品Syfovre近期显露的安全性问题，客观上也有助于安斯泰来打造一款新的“重磅炸弹”，以此接续即将失去专利保护的创收主力Xtandi。但安斯泰来的“钞能力”不足以成为躺赢的所有倚仗。GA赛道上，一再跌倒的罗氏尚未放弃，奋起直追。另一家MNC阿斯利康，也储备了两款进入II期的候选产品。此外，当前语境下，生物技术行业的回调让巨头并购拥有更多议价空间，买下产品的后续开发、业务整合等事项却并未变得更加轻松。考虑到安斯泰来此前有过的收购“教训”，Izervay是否真如其所期待的那样完成接棒，撑起公司营收近半边天，还有待后续观察。尽管如此，从安斯泰来的策略中，我们仍可以看到MNC如何应对专利悬崖、以资金撬动高值产品的范本。1争夺潜在“重磅炸弹”要了解安斯泰来对Iveric的浓厚兴趣，得回到这家Biotech专攻的眼科领域，尤其是Izervay此次获批所指向的AMD引起的GA。近十年来，AMD影响了全球大约30%的老年人。流行病学调查显示，AMD致盲者约占全球盲人的8.7%，全球约有3000万AMD患者，每年约有50万人因为AMD而致盲。而GA是晚期AMD的一种非渗出性形式，也是AMD治疗市场增长的重要推动因素。补体系统和C5蛋白的过度活跃，被怀疑在与继发于AMD的GA相关瘢痕形成和视力丧失的发展和生长中起关键作用。Izervay作为一种新型补体C5蛋白抑制剂，可通过靶向C5来降低补体系统的活性。临床结果显示，与假性试验相比，接受Izervay治疗的患者GA增长率在统计学上有显著降低，最早在6个月时就观察到疾病进展的减慢，在治疗的第一年中GA增长率的下降高达35%。不过，最先打破这个空白市场的却并非Izervay。早在半年前，Izervay的上市申请还未被FDA受理，来自Apellis的Syfovre就顶着“首款减缓GA进展药物”的名头成功获批。跟Izervay类似，Syfovre同样针对补体系统，通过阻断免疫系统的一部分，减缓眼部病变发展。Syfovre的市场潜力可谓惊人。该药每瓶定价为2190美元，销售额从今年第一季度的1800万美元飙升至第二季度的6700万美元左右。有分析师预测，Syfovre最终将在年销售额峰值时获得超过30亿美元的收入。然而7月中下旬，美国视网膜专家协会（ASRS）安全委员会发现，接受Syfovre治疗的患者存在视网膜血管炎病症，并对此进行了通报。Apellis在随后确认了Syfovre出现7例罕见但严重的副作用事件。时间分布上，4月出现2例，5月出现2例，6月出现3例。这7名患者出现的副作用为“视网膜血管炎”，其中4例被诊断为“闭塞性”，即流向视网膜的血液被阻断，属于一种可能致盲的严重眼部炎症。对外发言里，Apellis联合创始人、CEO Cedric Francois表示，他们除了知晓“这是一个极为罕见的偶发性事件之外”，其余所获不多。目前，Apellis正与相关医疗机构合作，继续调查潜在的促成因素，包括产品质量或批次问题、药物是否被污染、运输环节以及手术环节。找到确切问题之前，第二季度的惊艳表现，或许就是Syfovre这款明星产品的巅峰时刻。根据Spherix Global Insights对51名眼科医生进行的调查，副作用削弱了该药的市场领先优势。调查报告写道：“几乎所有接受调查的医生都说，该事件对他们未来的Syfovre处方至少有中等程度的影响，三分之二的医生认为该事件将对未来的治疗处方产生重大影响。”Izervay的上市或许会进一步放大“先驱”的短板。Izervay的定价是2100美元，与Syfovre相当。在ASRS报道Syfovre的副作用之前，GlobalData曾预计，Izervay的销售额将在2028年达到10.9亿美元，鉴于该药目前尚未像Syfovre那样遇到安全性问题，达到“重磅炸弹”门槛的速度有望更快。然而Syfovre之外，Izervay还有其他潜在竞争者，例如罗氏、阿斯利康等跨国巨头。黄斑地图状萎缩GA在研管线（2023.2），图源：凯莱英药闻罗氏在GA方面的探索之路并不顺畅。2018年，罗氏补体因子D抑制剂Lampalizumab治疗AMD继发GA的III期试验失败；去年10月，由于风险-获益比不支持进一步研究，罗氏将2019年启动的Galegenimab治疗AMD继发GA的II期研究从管线中剔除，该药是一种HtrA1抗体片段。目前，罗氏的研发管线中，还有一款处于II期临床的GA新药RG6147。数据显示，其能有效抑制HtrA1的活性，而HtrA1被认为是与GA相关的遗传风险因子。阿斯利康也布局了两款进入II期临床的GA在研药物，按照乐观估计，它们有望在2028年上市。2专利悬崖边上的突围作为一家志在国际化的药企，安斯泰来的海外业务已经颇有起色。2022年业绩报告中，安斯泰来日本业务营收同比几乎持平，占总销售额比重为17.27%；而美国、成熟市场、大中华区等业务都实现两位数增长，美国市场所占营收比重达到42.96%。可是，不论本土抑或海外，营收的增长都离不开“产品为王”的逻辑。如果产品在海外受挫，业绩增长疲软也并非无法想象。某种程度上，这样的隐忧已通过2023年第一季度报告有所显露。根据7月发布的数据，安斯泰来在最新一个财年的开局表现不尽人意：前三个月，销售收入3750亿日元，同比下降1.8%。这被归咎为仿制产品对Lexiscan的冲击。Lexiscan是一种心血管造影剂，安斯泰来从吉利德获得授权，2022年在美国销售额为7.20亿美元。其他仿制竞品的出现，预示着Lexiscan正迎来产品周期的暮年。“摊上事”的不只有Lexiscan，很快，Xtandi这一重磅产品也会失去专利保护。Xtandi由安斯泰来与辉瑞合作开发，2012年首次获FDA批准，用于治疗晚期前列腺癌。该药于2021年4月在欧洲获批转移性去势敏感性前列腺癌新适应症，2020年底，Xtandi纳入中国医保，用于雄激素剥夺治疗失败后无症状或有轻微症状且未接受化疗的转移性去势抵抗性前列腺癌成年患者的治疗。在2022财年，Xtandi销售额激增23.7%至6611亿日元，占总销售额超四成，成为该安斯泰来营收的主要支柱。不过，纵向来看，Xtandi的放量渐缓，2022年第一季度实现18.7%的同比增长峰值后，到2023年第一季度已经回落到7.2%的增速。2027年前后，对于专利到期的Xtandi，前景可能更加暗淡。为了弥补Xtandi下滑的销售额，有分析认为，安斯泰来将以巨额资金收购即将投向市场的成熟管线。这次Izervay的尝试，或许正验证了该策略的可行性。安斯泰来对Izervay寄予厚望，期待它成为年销售额超过10亿美元的“重磅炸弹”。公司新任CEO Naoki Okamura直接将Izervay定位为“弥补Xtandi专利期结束导致的销售额减少的盈利支柱”。实际上，安斯泰来早有另谋出路的打算。在聚焦的失明与再生疗法、线粒体生物学、遗传调控、免疫肿瘤学领域等几大领域，该公司不遗余力地挖掘新的明日之星。前几个月，第一个用于治疗潮热的口服非激素类NK3受体拮抗剂Veozah被安斯泰来摘得。据美国Female Founders Fund的研究数据显示，预计2025年全球将有11亿更年期女性，而更年期市场将达到6000亿美元的规模。拜耳开发的Elinzanetant也在该赛道狂奔，这款NK1/NK3双受体口服拮抗剂的临床III期试验预计2024年完成。但至少目前，Veozah快了所有竞争对手几步，安斯泰来有一定时间来进行布局，打开相应的市场。Izervay之后，安斯泰来资产中即将看到商业化曙光的还有Zolbetuximab。2016年，安斯泰来从收购Ganymed中获得这款Claudin18.2抗体。今年7月，FDA接受Zolbetuximab的BLA，并授予其优先审评资格，拟定适应症为阳性局部晚期不可切除或转移性HER2阴性胃或胃食管结合部腺癌患者的一线治疗。相应的PDUFA日期定在2024年1月12日。8月里，安斯泰来还将手伸到CGT领域。通过投资总计5000万美元收购Poseida Therapeutics约8.8%的股份，安斯泰来获得拟用于实体瘤的同种异体CAR-T疗法P-MUC1C-ALLO1合作的独家谈判权和优先购买权。P-MUC1C-ALLO1正处于I期临床开发，Poseida表示，该疗法有潜力治疗多种源自上皮细胞的实体瘤，如乳腺癌、卵巢癌、结直肠癌、肺癌、胰腺癌和肾癌。有证据表明，在P-MUC1C-ALLO1针对乳腺癌和卵巢癌的临床前研究中，肿瘤细胞被消除到不可检测的水平。3外部创新的AB面跟Poseida的合作，让安斯泰来加速进军一个蓬勃发展的新赛道——CGT疗法。这是一个全球已有超过2700个活跃的细胞治疗管线的领域，以攻克实体瘤和通用型降低成本作为前沿方向。现在，得到Poseida的加持后，安斯泰来更加有望从红海市场中分一杯羹。如果纵观安斯泰来的业务，外部创新是其避之不及的标签。在安斯泰来的营收产品矩阵里，除了领跑的Xtandi之外，叫得上名号的Xospata、Padcev等都来自与其他药企的合作。其中，第二代FLT3抑制剂Xospata由安斯泰来和日本寿制药株式会社开发，2023年第一季度，该药销售额同比增长24.2%，达到130亿日元。Padcev则是基于Seagen技术推出的全球唯一一款Nectin-4 ADC，2023年第一季度，Padcev为安斯泰来带来152亿日元营收，同比增长44.2%。3月，CDE还受理了Padcev的上市申请，拟用于治疗既往接受过PD-1/PD-L1抑制剂和含铂化疗治疗的局部晚期或转移性尿路上皮癌患者。如果其最终获批，无疑进一步拉高安斯泰来大中华区业务的表现。在漫长的新药开发周期上，买产品并不是什么可耻的事情。而跟安斯泰来类似，遭逢专利悬崖的MNC，也对这种策略驾轻就熟。即使是对MNC来说，“丛0到1”的内部研发投入也是巨大的，实际的效益却并不总是乐观。而从战略伙伴引进或完全买入新药，往往可以满足其填补产品管线的诉求，并最大限度地降低风险和成本。需要看到，市场上很多的新药都是通过这种伙伴关系来进行联合开发的。Nature一篇文章，统计了2015年至2021年期间FDA批准的前20家制药公司药物来源。其中，有65%来自外部资产，而仅有28%是内部创新，另有5%源于合作。体量视角下，Biotech贡献了47%的新药。国际知名咨询机构Informa/Citeline发布的《2023年医药研发年度回顾》也指出，全球大药企主要管线资产越来越依赖外部引进。面对生物技术行业周期性调整的当下，类似的并购和BD交易逐渐走高，买方们也愿意给出更多筹码。数据显示，2023上半年生物制药的并购交易额已接近2022年全年水平，达到658亿美元。2023年上半年，行业并购平均交易溢价为120%，通常每笔交易的溢价约为60%-100%。但回过头来说，做药总归是一门科学。“买进来”只是一小步，如何“走下去”才是更大的缺乏捷径的考验。当并购成为MNC的关键转型支点，资料却显示，药企并购整合失败率高达70%，部分药企或因资金链断裂而沦为被重组对象，或因业务整合不利而致使利润连续大幅下跌。2017年，强生以300亿美元巨资收购Actelion，希望将其肺动脉高压药物和自家旗下杨森制药的业务产品形成强势互补，填补原有业务面对专利悬崖的营收下滑。然而在一些分析师看来，这笔收购并不成功，反而会给强生带来约150亿美元的损失。另一家巨头艾伯维，2016年以58亿美元预付款收购Stemcentrx，获得靶向DLL3的ADC产品Rova-T。但是，Rova-T先后在二线治疗、维持治疗、联合化疗或免疫治疗等一系列探索中受挫，最终让艾伯维终止了相关研究和开发。安斯泰来也经历过类似的至暗时刻。2019年12月，安斯泰来以溢价110%、总计30亿美元，收购基因治疗领域的初创公司Audentes Therapeutics，获得包括AT132在内的多款潜力产品。可从2020年5月到2021年9月，AT132在II/III期试验中累计报告了4例患者因肝脏副作用而死亡的事件，期间遭到FDA两度叫停。其他资产，诸如AT702、AT751和AT753，也都因为安全性或疗效问题，不得不按下终止键。2022年4月安斯泰来披露的财报中，以上4项基因疗法的失利，加上另2项研发项目的终止（DNA疫苗ASP2390、GITR激动性抗体ASP1951），造成5.6亿美元的减值损失。如果Syfovre的安全性疑云“盲盒”揭开，补体抑制剂机制可行性存疑，难以想象，安斯泰来的Izervay可以完全置身事外。一如此前的PI3K、JAK、BTK等靶点被“黑框警告”波及一样，届时，安斯泰来也需要花费更多力气证明，自己的Izervay为什么是更优的选择。近期，AT132重新走上临床研究，安斯泰来借助与Kate Therapeutics的合作，找到了新的策略来应对基因疗法的毒性。而在接下来的并购大年，这种“自救”或许是深陷专利悬崖的药企更应把握的他山之石。参考文献：1、眼科 | 地图样萎缩（GA）新药研发：坎坷中前进，两款新药已报产；CPHI制药在线2、拓创生物 Mann Fung 博士：路漫漫其修远兮，新药跨境合作的“长安三万里”；医药魔方3、Astellas wins FDA approval of eye disease drug Izervay and may have edge in market battle with Apellis；fiercepharma4、当罗氏沉寂、AZ迸发，礼来超越强生，TOP20药企交出Big Pharma成长选规模or选创新的答案！；E药经理人5、燃！并购超2022全年，平均溢价120%，辉瑞、默沙东、AZ疯狂，发生了什么？有哪些新趋势？；E药经理人

鉴于转移复发是癌症患者的主要死亡原因，期待张翔团队在这个研究的基础上，取得更大的突破。 美国贝勒医学院张翔团队近日在《细胞·干细胞》上发表的一项研究成果，让我吃惊不小。 他们发现乳腺癌或肺癌细胞分泌的外囊泡，会远程奔赴骨髓，重塑骨髓微环境，导致造血干细胞往髓源免疫抑制性细胞的方向分化，造成全身性的免疫抑制[1]。 他们不仅揭示了详细的分子机制，还基于人体数据发现：肺癌和乳腺癌对骨髓的影响非常持久，甚至在肿瘤切除后的第40周仍存在[1]。他们认为，这种持久的免疫抑制现象在一定程度上也解释了为何有些患者术后会复发。 让人欣喜的是，他们还找到了破除肿瘤持久免疫抑制、加速患者免疫恢复的方法。贝勒医学院郝晓鑫和沈一超为论文的共同第一作者。 论文首页截图 在免疫治疗时代，大家对肿瘤的免疫抑制都不陌生了。 近年来，科学家逐渐发现，肿瘤对免疫细胞的打压不仅限于肿瘤内。2018年，宾夕法尼亚大学的华人科学家Xu Xiaowei和Guo Wei团队发现，癌细胞会释放携带PD-L1的外泌体，远程压制全身T细胞[2]；一年后，加州大学旧金山分校Robert Blelloch教授团队，又在肿瘤引流淋巴结和脾脏中发现了携带PD-L1的肿瘤外泌体[3]。 这些研究都是围绕PD-1/PD-L1这条通路，寻找肿瘤造成系统性免疫抑制的原因。张翔团队一直专注于癌症的骨转移以及癌症微环境。他们2021年发表的一项研究成果显示，早期的骨转移可上调乳腺癌细胞的干性特征，进而赋予这些癌细胞更强的转移能力[4]。 这一次，张翔团队将研究重点放在了骨髓来源的免疫抑制细胞上。 众所周知，肿瘤微环境中聚集了大量的髓源免疫抑制细胞。究其背后原因，主要是在肿瘤的影响下，骨髓的造血功能偏向于髓系，进而导致骨髓系细胞的积累[5]。然而，肿瘤究竟是如何远距离调控骨髓的分化方向，以及这种影响究竟有多持久，目前仍知之甚少。 张翔团队首先研究了7种乳腺癌模型和1种肺癌模型对骨髓造血的影响，发现肺癌细胞系（LLC）和富集中性粒细胞的乳腺癌亚型（例如PyMT-N）对小鼠的骨髓和外周血中髓系细胞的影响较大，因此以LLC和PyMT-N为研究对象，探索了癌细胞对骨髓的影响。 我们都知道，造血干细胞和祖细胞（HSPCs）的分化受到周围环境的严格调控。然而，在PyMT-N和LLC小鼠模型中，张翔团队发现造血干细胞错位，没有待在它该待位置，而且它的位置被CD41阴性的粒细胞-单核细胞祖细胞（GMPs）入侵，甚至完全被CD41阴性GMP取代。基于此，他们认为，这种现象就是异常造血的根源。 CD41阴性GMP的分布（黄色箭头） 至于CD41阴性GMP大规模扩张的机制，张翔团队也做了深入的研究。 简单来说，癌细胞释放的含HTRA1外囊泡进入骨髓之后，会被骨祖细胞（OPs）吞噬，导致骨祖细胞的MMP-13表达上调，骨祖细胞的成骨分化和增殖同时增加，破坏骨髓微环境，导致造血干细胞分化成CD41阴性GMP和髓细胞过度产生。 机制示意图 值得注意的是，张翔团队注意到，即使在PyMT-N或LLC形成的肿瘤体积小于0.2cm³的时候，也能观察到骨祖细胞的扩张。在肿瘤体积为0.2-0.3cm³时，就能观察到骨髓中存在CD41阴性GMP的扩张。 这说明，在肿瘤的早期，癌细胞就开始远程调控骨髓微环境，制造全身免疫抑制。 在肿瘤很小的时候，影响就产生了 让人感到毛骨悚然的是，肿瘤对骨髓的这种影响不仅早，而且能持续很久，哪怕肿瘤已经被切除。 张翔团队发现，即使是在小鼠接收手术切除肿瘤的45天之后，编码MMP-13的Mmp13基因仍然是骨祖细胞中上调最多的基因，而且短期造血干细胞（ST-HSCs）、多潜能祖细胞（MPPs）、GMPs和中性粒细胞仍然明显高于无瘤小鼠。 为了了解癌症患者体内是否存在类似的情况，张翔团队分析了临床样本的数据，发现与非癌症受试者相比，癌症患者（切除前）的中性粒细胞和单核细胞有所增加。让人震惊的是，乳腺癌和女性肺癌患者的中性粒细胞和单核细胞水平在肿瘤切除后长达40周的时间里处于较高的水平，不过髓系细胞没有升高；而且这种持久的效果在女性肺癌患者中似乎更为明显。 不难看出，肿瘤对骨髓微环境的破坏，不仅深刻，而且持久。 人体数据呼应小鼠研究 张翔团队既然发现了这个现象，就不可能眼睁睁看着肿瘤为非作歹而无动于衷。 好消息是，他们发现术后用MMP-13抑制剂（CL-82198）干预，就可以恢复抗肿瘤免疫。在与免疫检查点抑制剂联用的情况下，可以降低自发性肺转移发生率，并明显改善肿瘤切除后小鼠的生存率。 小鼠的复发转移和生存都改善了 “我们的发现提出了一种新的治疗方式，与目前的策略非常不同。它不是针对癌细胞，也不是针对T细胞，它是针对整个机体。这种方式试图消除肿瘤投在整个免疫系统上的阴影。”张翔说[6]。 鉴于转移复发是癌症患者的主要死亡原因，期待张翔团队在这个研究的基础上，取得更大的突破。 参考文献： [1].Hao X, Shen Y, Chen N, et al. Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal. Cell Stem Cell. 2023;30(5):648-664.e8. doi:10.1016/j.stem.2023.04.005 [2].Chen G, Huang AC, Zhang W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560(7718):382-386. doi:10.1038/s41586-018-0392-8 [3].Poggio M, Hu T, Pai CC, et al. Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory. Cell. 2019;177(2):414-427.e13. doi:10.1016/j.cell.2019.02.016 [4].Zhang W, Bado IL, Hu J, et al. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell. 2021;184(9):2471-2486.e20. doi:10.1016/j.cell.2021.03.011 [5].Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19(2):108-119. doi:10.1038/s41590-017-0022-x [6].https://www.bcm.edu/news/breast-cancer-tumors-disrupt-the-immune-system-remotely-favoring-their-own-growth

PALO ALTO, Calif., April 21, 2023 /PRNewswire/ -- Kodiak Sciences Inc. (Nasdaq: KOD), a biopharmaceutical company committed to researching, developing and commercializing transformative therapeutics to treat high prevalence retinal diseases, announced today that multiple scientific presentations on its clinical and research pipeline programs will be made at the Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting, being held from April 23 – 27 in New Orleans, United States. "We look forward to sharing data across our pipeline of investigational medicines at this year's ARVO Annual Meeting," said Victor Perlroth, M.D., Chief Executive Officer of Kodiak Sciences. "Our efforts encompass Phase 3 clinical studies with our lead tarcocimab tedromer, a Phase 1 clinical study with our new bispecific KSI-501, and earlier discovery efforts. We believe the data being presented will demonstrate the robust retina-focused research and development engine at Kodiak. We remain committed to our mission of bringing new science to the prevention and treatment of high prevalence retinal diseases." The following data will be presented at the meeting: Presentation on tarcocimab tedromer (KSI-301): Abstract Title: Nonclinical Pharmacokinetics, Distribution and Excretion of 125I-KSI-301 after Intravenous Administration in Rats Session Title: Retina / RPE: New drugs, mechanisms of action and toxicity Session Date and Time: April 25, 2023; 8:45 – 10:45 AM CT Presentation Type: Poster Session Poster Number: 2606 - B0319 Presentations on KSI-501: Abstract Title: KSI-501 is a novel anti-VEGF and anti-IL-6 bispecific biopolymer conjugate to simultaneously address neovascularization and inflammation in retinal diseases Session Title: AMD New drugs, delivery systems and mechanisms of action 2 Session Date and Time: April 23, 2023; 3:45 – 5:45 PM CT Presentation Type: Poster Session Poster Number: 1153 - C0308 Abstract Title: Biological benefits of KSI-501: Novel bispecific anti-inflammatory and anti-angiogenic therapy for the treatment of both retinal vascular and inflammatory diseases Session Title: AMD anti-VEGF Session Date and Time: April 24, 2023; 3:15 – 5:00 PM CT Presentation Type: Poster Session Poster Number: 2215 - C0168 Presentations on research pipeline: Abstract Title: Development and characterization of an anti-HTRA1 antibody for dry AMD treatment Session Title: AMD New drugs, delivery systems and mechanisms of action 2 Presentation Date and Time: April 23, 2023; 3:45 – 5:45 PM CT Presentation Type: Poster Session Poster Number: 1151 - C0306 Abstract Title: Development of a modular IL-1 trap and anti-HTRA1 bispecific for the treatment of dry AMD Session Title: AMD New drugs, delivery systems and mechanisms of action 2 Presentation Date and Time: April 23, 2023; 3:45 – 5:45 PM CT Presentation Type: Poster Session Poster Number: 1152 - C0307 About tarcocimab tedromer (tarcocimab, KSI-301) Tarcocimab is an investigational anti-VEGF therapy built on Kodiak's Antibody Biopolymer Conjugate ("ABC") Platform and is designed to maintain potent and effective drug levels in ocular tissues for longer than existing available agents. Kodiak's objective with tarcocimab is to enable earlier treatment and prevention of vision loss for patients with diabetic eye diseases and to develop a new first-line agent to improve outcomes for patients with retinal vascular diseases as a whole. The tarcocimab clinical program is designed to explore 6-month durability in the majority of patients with diabetic eye disease through the GLEAM and GLIMMER Phase 3 studies in diabetic macular edema ("DME") and the GLOW Phase 3 study in non-proliferative diabetic retinopathy ("NPDR") without DME. The tarcocimab clinical program is also exploring the product's durability, efficacy and safety in retinal vein occlusion ("RVO") via the BEACON Phase 3 study and in wet age-related macular degeneration ("wet AMD") via the on-going DAYLIGHT Phase 3 study. The BEACON study met its primary endpoint in 2022, and four Phase 3 clinical studies are expected to announce topline data in 3Q2023. If successful, Kodiak plans to file a single Biologics Licensing Applications ("BLA") for tarcocimab in the four major retinal vascular disease indications. The global tarcocimab clinical program is being conducted at 150+ study sites in more than 10 countries. Kodiak is developing and owns global rights to tarcocimab. About KSI-501 Also built on Kodiak's ABC Platform, KSI-501 is an investigational, first-in-class bispecific ABC that is designed to inhibit two mechanisms implicated in retinal diseases: vascular endothelial growth factor ("VEGF") and interleukin-6 (IL-6). IL-6 is a pro-inflammatory cytokine and growth factor implicated in the pathophysiology of multiple retinal diseases and, in conditions for which anti-VEGF treatment is used, elevated levels of ocular IL-6 have been associated with poor anti-VEGF treatment response. KSI-501 is a trap-antibody fusion biopolymer conjugate designed to provide potent inhibition of (i) VEGF-mediated angiogenesis and vascular permeability through a soluble decoy receptor inhibiting the binding of VEGF-A and PLGF to their cognate receptors and (ii) IL-6 mediated inflammation through an antibody that binds soluble interleukin-6, inhibiting its binding to both soluble and membrane-bound IL-6 receptors. In cell-based assays, KSI-501 inhibits angiogenesis and also normalizes inner and outer blood retinal barriers; dual inhibition of VEGF and IL-6 by KSI-501 confers superior normalization of cell morphology and junctional biology compared to either anti-VEGF or anti-IL-6 monotherapy. We believe KSI-501 has the potential to become a new category of retinal medicines with greater therapeutic efficacy than existing therapies while also benefiting from the promising long-interval durability of Kodiak's ABC Platform. A Phase 1 study of KSI-501 is currently dosing patients in the United States to evaluate the safety, tolerability and bioactivity of KSI-501 in DME patients. About Kodiak Sciences Inc. Kodiak (Nasdaq: KOD) is a biopharmaceutical company committed to researching, developing and commercializing transformative therapeutics to treat high prevalence retinal diseases. We are focused on bringing new science to the design and manufacture of next generation retinal medicines to prevent and treat the leading causes of blindness globally. Our antibody biopolymer conjugate platform, or ABC Platform™, uses molecular engineering to merge the fields of antibody-based and chemistry-based therapies and is at the core of Kodiak's discovery engine. Kodiak's lead investigational medicine, tarcocimab tedromer, is a novel anti-VEGF antibody biopolymer conjugate being developed for the treatment of retinal vascular diseases including diabetic eye diseases, the leading cause of blindness in working-age patients in the developed world, and wet age-related macular degeneration, the leading cause of blindness in elderly patients in the developed world. The tarcocimab clinical program is designed to assess the product candidate's durability, efficacy and safety in major retinal vascular diseases in parallel, through the GLEAM and GLIMMER studies in diabetic macular edema, the BEACON study in retinal vein occlusion, the GLOW study in non-proliferative diabetic retinopathy and the DAYLIGHT study in wet age-related macular degeneration. Phase 3 data across the tarcocimab clinical program are expected in 3Q2023. Kodiak has leveraged its ABC Platform to build a pipeline of product candidates in various stages of development. KSI-501 is our dual inhibitor antibody biopolymer conjugate targeting both VEGF (VEGF-trap) and IL-6 (anti-IL-6 antibody) and is being investigated in a Phase 1 clinical study initially in patients with diabetic macular edema. We are expanding our early research pipeline to include ABC Platform based triplet inhibitors for multifactorial retinal diseases. Kodiak is based in Palo Alto, CA. For more information, please visit . Kodiak®, Kodiak Sciences®, ABC™, ABC Platform™ and the Kodiak logo are registered trademarks or trademarks of Kodiak Sciences Inc. in various global jurisdictions. Forward-Looking Statements This release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. These forward-looking statements are not based on historical fact and include statements regarding: the expected timing and presentation of clinical study readouts; our robust retina-focused research and development engine; the potential of the ABC Platform to maintain potent and effective drug levels in ocular tissues for longer than existing available agents; the potential for KSI-501 to achieve a greater therapeutic benefit for certain patients and to provide potent inhibition of both VEGF-mediated vascular permeability and IL-6 mediated inflammation; future development plans; the objectives and potential benefits of our tarcocimab clinical program, including its potential to enable earlier treatment and prevention of vision loss for patients with diabetic eye diseases; the objectives and potential benefits of KSI-501, including its potential to be a first-in-class bispecific ABC inhibiting VEGF and IL-6 and its potential to provide extended durability; and the potential for a single BLA submission in four major retinal vascular disease indications. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as "may," "will," "should," "would," "could," "expect," "plan," "believe," "intend," "pursue," and other similar expressions among others. Any forward-looking statements are based on management's current expectations of future events and are subject to a risks and uncertainties that could cause actual results to differ materially and adversely from those in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: cessation or delay of any clinical studies and/or development of tarcocimab and/or KSI-501 may occur; the risk that KSI-501 may not inhibit VEGF and IL-6, provide extended durability or have an impact on the treatment of patients as expected; the risk that tarcocimab may not enable earlier treatment and prevention of vision loss for patients with diabetic eye diseases as expected; future potential regulatory milestones of tarcocimab/KSI-501, including those related to current and planned clinical studies, may be insufficient to support regulatory submissions or approval; adverse economic conditions may significantly impact our business and operations, including our clinical trial sites, and those of our manufacturers, contract research organizations or others with whom we conduct business; as well as the other risks identified in our filings with the Securities and Exchange Commission (SEC). For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our most recent Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the SEC. These forward-looking statements speak only as of the date hereof and Kodiak undertakes no obligation to update forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements. Kodiak®, Kodiak Sciences®, ABC™, ABC Platform™ and the Kodiak logo are registered trademarks or trademarks of Kodiak Sciences Inc. in various global jurisdictions. SOURCE Kodiak Sciences Inc.