ZN-c5

巴菲特喜欢用4美分的价格买入价值1美元的公司，而我更喜欢用1美分的价格买入价值1美元的生物科技公司股票。 为什么呢？因为我发现Biotech的一个特点，它们需要先烧钱推进临床管线，这种依赖融资的商业模式受美债利率影响极大，估值在利率周期内可以波动超十倍。 因此，如果你能看懂管线的内在价值，又愿意承担研发风险，那么利用这种周期波动和资产价值的爆炸性增长，可能在短期内带来几十倍甚至上百倍的回报。 Zentalis的WEE1抑制剂Azenosertib，就是这样一个临床II期资产，它有潜力成为治疗Cyclin E1阳性PROC的FIC和BIC药物，并在一年后获FDA加速批准。 我先在这里做个标记：今天Zentalis的市值还不到1亿美元（2025-12-23），3年内极有可能存在10倍以上的空间。 现在最关键的是，我们是否有足够的能力去评估它的成药性和价值，从而计算风险和收益，毛估估风险收益比。 下面我就简单聊聊Zentalis的背景、Azenosertib治疗PROC的临床需求、赛道演进和竞争格局、疗效和安全性、公司基本面，评估他未来的确定性。 Zentalis——DDR赛道的孤勇者 尽管在Biotech圈剧烈动荡的公司常见，能像Zentalis这样大起大落的公司也不常见。 作为WEE1抑制剂赛道的代表，它的故事可以总结为：偏执、挫败与重生。 公司在质疑和危机中反复横跳，在带着“毒性诅咒”的WEE1靶点上，通过几次断臂求生，艰难地完成了转型。 Zentalis成立于2014年，专注“合成致死”靶点。一开始它并不只盯着一个靶点，而是搭建了一个精准肿瘤学平台。当时的招牌管线是治疗ER+乳腺癌的口服SERD药物ZN-c5，其次才是刚进I期的WEE1抑制剂Azenosertib。公司强调“高选择性”，想通过优化分子结构来降低前代药物的毒性。 2020年4月，疫情之下，Zentalis逆势在纳斯达克IPO。上市时市值18亿美元，2021年一度超过60亿。它还吸引了阿斯利康的投资，以及辉瑞的临床合作，一时风光无两。 表一. IPO招股书中Zentalis所列管线 当时公司的技术亮点是利用肿瘤生物学知识，结合结构设计（SBDD和SAR），快速推进新药。号称平均每个产品不到3年就能进入IND阶段。 不过，Azenosertib是从Recurium IP Holdings, LLC引进的分子（IP: WO2019173082），是在阿斯利康AZD1775（即后面的Adavosertib）的基础上做的专利突破和优化。 转折发生在2022年。作为WEE1赛道领头羊的阿斯利康因无法解决的疗效-副作用平衡问题而放弃Adavosertib的开发。市场顿时对WEE1靶点失去信心，Zentalis也被推上风口浪尖，质疑声如潮水般涌来。 2024年中，FDA因两例败血症死亡病例，对三个Azenosertib的临床试验实施了部分临床搁置。股价瞬间腰斩，现金流告急，公司到了生死边缘，尽管Azenosertib的临床试验在同年9月得到了恢复。 于是Zentalis不得不彻底变革。2024年底，管理层大换血，公司执行“极度聚焦”策略。他们暂停了BCL-2、SERD等所有非核心管线，把所有筹码都押在Azenosertib这一个靶点上。 2025年1月，公司宣布裁员40%，股价再次腰斩。尽管如此，新管理层通过精简架构和加强监管沟通，努力让公司从“平台型”公司转向“准商业化”公司。 2025年1月Zentalis公布了Azenosertib的临床数据，Azenosertib在CCNE1扩增的铂类耐药卵巢癌（PROC）中，客观缓解率ORR接近35%，远超化疗（4-13%）。FDA也为此授予了快速通道资格（FTD）。 但即便如此，公司市值现在还是在1亿美元上下徘徊。从60亿到1亿，堪称价值毁灭。 造成这一动荡的原因，一是2022年的流动性泡沫导致公司估值泡沫化，二是同行挫折让市场走向了另一个极端，三是安全性数据让市场丧失了信心。实际上晚期癌症的临床试验中偶尔出现意外死亡事件是常有的事情，因为病人本身更脆弱，且毒副作用的可接受程度应该与病人的临床需求相平衡。 对投资者而言，机会往往就在这种预期差的时候出现。 WEE1抑制剂生物学原理 WEE1抑制剂是一种合成致死机制，类似于PARP抑制剂。它的目的是在癌细胞里造成足够的DNA损伤，通过DNA损伤应激反应诱导癌细胞凋亡。 WEE1激酶是细胞周期G1/S和G2/M检查点的关键开关。正常细胞在分裂前，必须确保DNA复制完成且损伤修复好。这个过程由CDK1和CDK2控制。WEE1会给CDK添加磷酸基团，让它保持失活状态。 只要WEE1在干活，CDK这个“分裂引擎”就熄火，细胞停在G1/G2期进行自我检查修复。这个过程对癌细胞是刚需，因为癌细胞存在大量的基因突变，比如BRCA突变，造成DNA修复能力不足。同时癌细胞大量增殖和DNA复制产生更多的DNA突变和断裂。因此癌细胞也需要停下来修复自己的基因组。 使用WEE1抑制剂（比如Azenosertib）会强行解除对CDK的抑制。对于有TP53突变或Cyclin E1扩增的癌细胞来说，这很致命。这些癌细胞本来DNA复制压力就大，损伤多。没了WEE1这个刹车，它们会带着大量断裂的DNA进入分裂期。结果就是染色体破碎紊乱，最终触发有丝分裂灾难，走向死亡。这个机制在Cyclin E1高表达的细胞里尤其明显。 其实副作用也跟该机制相关，因为干扰了所有的细胞分裂活动，自然影响造血功能。WEE1抑制剂可以理解为一种更有效的化疗药物，这也是为什么几大MNC都来寻求药物联用的原因。 WEE1抑制剂的临床开发 Azenosertib的进展很大程度上站在了阿斯利康adavosertib的肩膀上。 2013到2015年，阿斯利康从默克买下adavosertib，启动了多项I期临床。 2016到2021年，它在一些II期试验中显示出疗效信号，尤其在子宫浆液性癌（USC）中单药有效率约29.4%。 但2022年，阿斯利康因为无法平衡疗效和毒性，终止了这款药的开发。 根据2021年ASCO的数据，adavosertib单药治疗PARP耐药的乳腺癌（其中64%是PROC），客观缓解率23%。联合PARP抑制剂奥拉帕利Olaparib的话，有效率29%。 但毒性不小。单药组51%出现3/4级毒性，联合组这个比例是76%。耐受性也极差，单药治疗组中72%的病人需要剂量中断，51%的病人需要降低剂量。 不仅阿斯利康，另一家拥有WEE1抑制剂的Nuvation Bio也在2022年宣布不再重点推进其产品。 Azenosertib是第二个进入临床的WEE1抑制剂，可以说是adavosertib的fast follower。它在设计时就力求提高选择性，以降低临床毒性。 2020年3月，它启动I期临床。有意思的是，在做完连续给药爬坡后，很快也转向了间隔给药，可能是观察到了较高的副作用和借鉴了adavosertib的临床开发经验。 2021到2023年，它在PROC和子宫浆液性癌中验证疗效，并确立了Cyclin E1这个关键生物标志物。这个发现促使公司把后续研究升级为针对FDA加速批准的注册性试验。 2021年下半年，它还和GSK合作，探索与PARP抑制剂或化疗联用的效果。2022年在AACR上公布了Ib PROC的数据，联合疗法取得了30.2%的ORR和86%的DCR，疗效与adavosertib单药相当。 但是也有意外，就是azenosertib与PLD连用的ORR仅为12.5%，市场似乎不买账，股价又跌了30%。 十几天后，辉瑞以2500万美元股权合作介入，共同推进azenosertib的临床开发。Blackwell也在后来募集了2亿美元，支持公司开发这款WEE1抑制剂用于子宫浆液性癌和实体瘤的治疗。 2024年6月，公司在ASCO公布了联合化疗治疗骨肉瘤的I期数据，安全性数据较好。 同月18日，FDA因两例败血症死亡病例，暂停了其三项临床研究。股价再次腰斩。 2024年底公司重组，2025年1月宣布全力聚焦azenosertib，裁员40%，股价又跌一轮。 1月29日，公司公布了最新的单药临床数据，并分享了Cyclin E1+ PROC 患者未来临床开发和潜在注册计划的详细信息，基于优异的疗效，随后获得了FDA的FTD认证。MAMMOTH 和 ZN-c3-016 结直肠癌联合队列的结果也在当天披露。 Azenosertib 临床结果速览 Azenosertib到底有没有效？安不安全？咱们直接看几项关键研究的结果。 首先是ZN-c3-001研究，这是一项早期的剂量探索试验。 在那些间歇给药、且携带Cyclin E1生物标志物的PROC患者里（23人），有34.8%的人肿瘤明显缩小，中位缓解时间保持了5.2个月。 更关键的是安全性。在每日剂量超过300mg的所有患者中（193人），没有出现3级以上的严重胃肠道副作用。大家最担心的血液毒性，3级以上的发生率在11%左右，而且多数是3级。因为副作用停药的比例只有5.2%。当然，研究中发生过1例致命的5级不良事件。 接着看MAMMOTH研究，它专门针对PARP抑制剂已经耐药的难治性PROC患者。 在这个更棘手的群体里，使用400mg剂量方案的Cyclin E1阳性PROC患者（16人），客观缓解率是31.3%。 安全性数据和001研究类似，3级血液毒性可控，400mg组因副作用中断治疗的比例是5.6%。同样，这项61人研究也报告了1例致命的5级事件。 不过，这个研究里尝试与PARP抑制剂尼拉帕利联用的方案，效果不理想，没能让Azenosertib在体内达到有效的暴露水平，所以公司已经放弃这个联合路线了。 然后是DENALI研究，这部分数据可能最接近未来的注册申报。 在Cyclin E1阳性的PROC患者中，经评估的ORR是34.9% (N=48)。如果按所有用药患者的意向治疗分析，有效率是31.3%。中位缓解时间还在观察中，目前看大概是5.5个月。 安全性特征和前面两项研究基本一致，没有出现新的意外死亡事件。 最后还有个ZN-c3-016研究，是和辉瑞合作，探索在BRAF突变肠癌中三联用药的。 剂量探索阶段的结果看起来不错，联用时Azenosertib的MTD剂量是300mg，但公司决定不继续推进扩展研究了。理由是资源要优先用在更核心的卵巢癌项目上，而且肠癌的治疗格局变化太快。 简单总结一下这些数据： 在精心筛选的1-3线Cyclin E1阳性PROC患者里，Azenosertib单药能带来30%-40%的客观缓解率，效果是传统化疗的好几倍。 未来公司准备申报的适应症是1-3线PROC，在这个群体的ORR是40%。 安全性方面，最令人担心的血液毒性相比Adavosertib有了质的改善，严重的胃肠道副作用很少见。当然，致命的毒副作用风险并未完全杜绝，这也是所有这类药物必须面对的挑战。 至于和其他药物联用，目前看来策略还不明朗，单药冲刺可能是更现实的策略。 PROC的竞争格局 下面我们来看看Azenosertib在卵巢癌治疗中处于一个什么样的生态位。 全球每年新增卵巢癌约31万至33万例。铂类耐药卵巢癌（PROC）作为疾病演进的终末阶段，仍是妇科肿瘤中预后最差、难治性最高的挑战。约 70%–80% 的晚期患者在接受一线含铂化疗后会面临复发。复发患者根据生物标志物检测结果，可采用贝伐珠单抗联合化疗或 PARP 抑制剂进行维持治疗。 尽管铂敏感复发患者可继续从二线含铂方案中获益，但随着耐药性的累积，几乎所有患者最终都将进展为铂类耐药阶段（PROC）。PROC现在已按生物标志物进行分型。主要亚型包括FRα高表达型（~55%）和预后极差的CCNE1扩增型（~70%）。 目前的治疗是“双轨制”：FRα高表达PROC患者可以用FRα-ADC药物Elahere；没有特定标志物的患者，还是靠老的非铂类化疗药，疗效很差。传统非铂类化疗的ORR长期在4%-13%之间，mPFS只有3-4个月，mOS往往不到16个月。临床需求远未满足，尤其是CCNE1扩增的患者，目前根本没有获批的靶向药，这里美国大约每年有1-2.1万人。 另外，随着PARP抑制剂在一线治疗中的普及，如何解决PARP耐药，以及开发毒性更低的新机制药物，成了迫切的需求。 所以在PROC这个“决赛圈”里，目前唯一获批的靶向药Elahere只覆盖了大约一半的患者（FRα高表达）。而Zentalis的Azenosertib，针对的是另一个主要群体（Cyclin E1阳性占PROC的~70%）。这两个人群大约有20%的重叠，但理论上Cyclin E1阳性的人群规模更大。这，就是它的市场空间。 和“前辈”Adavosertib比，Azenosertib的疗效旗鼓相当，ORR都在30-40%左右。 和已获批的Elahere比，在各自的优势人群中，Elahere的客观缓解率更高一些（约42%），但两者中位无进展生存期相差不大。 至于PARP抑制剂（像奥拉帕利、尼拉帕利），它们主要用于早期对铂类化疗更敏感的患者，是发生在PROC之前的治疗。很多患者是在PARP抑制剂失效后，才进展到需要Azenosertib来救场的阶段。 表二. 横向对比以获批和临床开发阶段的卵巢癌药物疗效数据 对于WEE1抑制剂来说，安全性可能比疗效更能决定生死。我们来看看具体数据： Adavosertib：它的血液毒性非常严重。3级以上贫血、血小板减少、中性粒细胞减少的发生率动不动就超过20%，甚至到60%。这导致超过一半的患者需要中断或减少用药，还有近4%的死亡风险。这正是它被放弃的主要原因。 已上市药物Elahere：它的主要问题是眼部毒性（有黑框警告），3级以上不良事件发生率约42%-44%，与化疗相当，因毒性停药率9%，治疗相关死亡率为~2%。 已上市PARP抑制剂：奥拉帕利Olaparib和尼拉帕利Niraparib的主要毒性也是血液学方面的，3级以上贫血很常见，剂量中断率很高（50%-80%），但停药的比例相对低一些（7-17%）。 主角Azenosertib：它的3级血液学毒性发生率控制在了10%左右，这比Adavosertib有了巨大改进，也优于PARP抑制剂，是一个关键优势。在400mg剂量下，有超过40%的患者需要减量，近60%需要中断用药，因副作用停药的比例超过20%，还有2%的死亡风险。这些数字提示，400mg的剂量方案可能还是太“猛”了。相比之下，300mg剂量的耐受性看起来要好很多，与已上市的Elahere和PARP抑制剂处在同一水平。所以，未来选择更合适的剂量（比如300mg或350mg），可能是平衡疗效与毒性的关键。 表三. 横向对比以获批和临床开发阶段的卵巢癌药物安全性数据 简单总结一下竞争格局：Azenosertib在一个尚未被满足的细分市场（Cyclin E1阳性PROC）跑在了最前面。它的疗效得到了验证，更在安全性上迈出了关键一步，虽然仍未完美。接下来的剧本，就看它能否在更大规模的临床试验中，用一个“刚刚好”的剂量，把疗效和副作用的平衡做到极致了。 Azenosertib的未来潜力 Azenosertib的未来，到底能有多大的想象力？一句话：潜力不小，路径很清晰，就等关键数据来一锤定音。 首先，Azenosertib在安全性上，已经和那些获批上市的前辈们站在了同一个水平线上。特别是300mg的剂量方案，耐受性看起来相当不错。 疗效上，它面对传统化疗有压倒性优势。预期超过30%的客观缓解率，是化疗好几倍。单凭这一点，获批的确定性高。 但真正的想象力，来自市场格局。Elahere只能覆盖大约55%的PROC患者，而Azenosertib瞄准的Cyclin E1阳性PROC人群，理论上占PROC的75%（这里由Zentalis的IHC实验界定）。虽然两者有大约20%的重叠，但Azenosertib的潜在适用人群显然更大。 2025年Elahere销售额就有望冲到7.5亿美元（上市第三年），分析师预测期峰值销售更是看到60亿。它凭这个表现，让艾伯维掏了101亿美元来收购。那么，如果Azenosertib能成功拿下自己那块更大的蛋糕，它的峰值销售冲到数十亿美元级别，是不是听起来就合理多了？ 这还不是全部。Azenosertib和Elahere同时都在开发子宫浆液性癌（USC），2025年处于未开发状态的USC市场约30亿美金。Azenosertib的这个适应症也拿了快速通道资格，早期数据ORR 26-36%。虽然公司目前集中火力主攻卵巢癌而搁置了该管线，但这无疑是个充满潜力的后备适应症。 FDA的快速通道资格正是为了填补巨大的未满足临床需求，加上有说服力的初期数据，让Azenosertib的获批前景看起来偏乐观。 从时间线上看，针对核心适应症的关键二期临床DENALI，顶线数据预计在2026年底出炉。如果数据漂亮，新药申请最快可能在2026年年底提交，那么2027年上半年，我们或许就能看到它获批上市了。 在Azenosertib完全获批后，只需50%的美国Cyclin E1阳性PROC患者年治疗费用10万美元，销售峰值可超过10亿美元，则公司估值指向50亿以上，这个画面是不是很有吸引力？ Zentalis基本情况 说完药物，我们看看公司本身。Zentalis现在的家底怎么样？ 现金充足，这是活下去的根本。据公司Q3财报，截至去年11月，账上躺着2.8亿美元，足够他们烧到2027年底。公司还精打细算，通过裁员和暂停非核心管线把费用降了三四成。 团队方面，CEO Julie Eastland，一位在行业里摸爬滚打了三十年的老将。她最擅长的不是做科研，而是Biotech临床开发、交易和资本运作。 她之前的战绩赫赫，成功把两家公司卖给了巨头：18年Cascadian Therapeutics以6.14亿美金被Seagen/辉瑞收购，主打产品Tucatinib于20年被FDA获批用于脑转移的HER2 阳性乳腺癌；24年开发TCE的Harpoon被默克以6.8亿美金收购，主打产品是一款处于临床I期的DLL3 TCE HPN328。由她来掌舵Zentalis的最后注册临床冲刺和潜在的商业化甚至并购，应该算专业对口。 CMO Ingmar Bruns则是临床开发的老手，前任公司也是被辉瑞收购。他是毕业于杜塞尔多夫大学医学博士学位的内科医生，在全球多中心临床试验的监管沟通与策略执行方面有超过10年的经验。他在拜耳负责过包括实体瘤及血液系统恶性肿瘤在内的多项重点肿瘤项目的全球开发。 结语 分析到这里，是时候给Zentalis这张“期权”做个总结了。 它的目标非常简单：把那个叫Azenosertib的药成功推上市。这个药正处于关键的注册二期阶段，拿到了FDA的快速通行证，在WEE1这个新赛道上跑在了最前面。它的疗效和安全性已经有三百多位患者帮忙验证过了，预期效果比现在的标准疗法要好。 它面对的市场，是一个巨大的空白。卵巢癌患者一旦对铂类化疗耐药，选择就非常少。目前唯一获批的靶向药Elahere，只针对其中一部分特定患者。而Azenosertib瞄准的Cyclin E1阳性人群，范围要更大。这就给了它足够的想象空间。 想象空间有多大呢？我们找到了个参照物，就是前面提到的Elahere，今年是上市第三年，销售额就有望达到7.5亿美元，分析师预测它的峰值能冲到60亿，它也因此被艾伯维用101亿美元收购了。这么一比，Azenosertib未来的市场价值，理论上完全有理由看齐。 除了药物本身，公司别的方面也挺给力。 首先，公司有很多“option”，但市场好像还没完全意识到。最近公司用每股1.33美元的价格，从大股东手里回购了10%的股份，这个动作很说明问题。在生物科技领域，现金为王，而他们的现金储备足够支撑到关键数据出炉。 其次，算算他们的现金消耗。每季度大约烧2000万到3000万美元，加上这次回购，到2026年底，他们每股对应的净现金可能就有2美元。这相当于为股价铺了一层厚实的安全垫。就算最坏的情况发生，公司按现金价值出售，下行风险也被保护得很好。 再者，CEO和CMO的履历都很漂亮。尤其是这位CEO，在我看来算是生物科技圈的明星人物了。她难得地把药物研发的专业知识和为股东创造价值的意识结合在了一起。最近这次低价回购股份，就是一个很好的例子。财务出身的CEO是个资本运作的老手，CMO是临床开发的专家，这个组合非常契合公司现阶段背水一战、寻求突破的需求。 最后，所有的乐观都需要数据支撑。今年1月那场数据发布会，包括临床首席研究员那句直白的“这药管用”，都传递出积极的信号。 把所有条件摆在一起，就看到了一个巨大的反差：重组后的管理层非常优秀，公司拥有2.8亿现金流，有非常大的概率可以维持到一个潜在重磅产品获批，还包括其他临床资产组合，但现在市值只有1亿美元。大概率算未来三年能有30到50倍的上行空间。 当然，高赔率意味着高风险。风险主要集中在两点。第一是安全性，尤其是400mg的剂量会不会太高。我猜团队很可能会为了稳妥，选择300mg的用量。第二是疗效，虽然在86名患者中看到了20%到40%的有效率，但在更大规模的人群里，这个数字会不会掉到20%以下？总存在一些不确定性。 正是因为这些风险存在加上极致的市场低预期，才有了现在1亿美元的地板价。考虑到极高的赔率，我会保持关注，并考虑在股价1到1.1美元区间行动，在未来一年里慢慢收集筹码。 到底Zentalis是价值毁灭还是被市场忽略的黄金，我们一年后就能有答案。

Azenosertib monotherapy achieved an ORR of 36.8% in heavily pretreated platinum-resistant ovarian cancer and USC patients who received intermittent dosing Identified azenosertib monotherapy RP2D, which more than doubles exposure levels, maintains safety and improves tolerability with no treatment-related discontinuations Presented positive Phase 1b azenosertib + chemotherapy data in ovarian cancer at ASCO, demonstrating encouraging anti-tumor activity and strong tolerability pro intermittent dosing Raised approximately $250.0 million in gross proceeds from recent follow-on offering, extending cash runway into 2026 NEW YORK and SAN DIEGO, Aug. 09, 2023 (GLOBE NEWSWIRE) -- Zentalis® Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers, today announced financial results for the quarter ended June 30, 2023, and highlighted recent corporate accomplishments. “We have strong azenosertib data that creates the potential to build a meaningful franchise around this exciting product candidate with the possibility of near-, mid- and long-term opportunities across multiple tumor types,” said Kimberly Blackwell, M.D., Chief Executive Officer of Zentalis. “As a monotherapy, azenosertib achieved an objective response rate of 36.8% in ovarian cancer and uterine serous carcinoma patients who received intermittent dosing. Azenosertib plus chemotherapy combinations also demonstrated positive results in women facing heavily pretreated ovarian cancer. Taking these results together, we believe there is the potential for azenosertib to transform the standard of care for patients with ovarian and uterine cancers, and ultimately other solid tumors. We are well positioned to advance this program with a strong cash position resulting from our recent offering that extended our cash runway and will sustain our corporate and clinical strategy for the next several years.” WEE1 Inhibitor (Azenosertib) Program Highlights Identified monotherapy recommended Phase 2 dose (RP2D) and reported positive safety and efficacy data. Based on encouraging Phase 1 dose optimization clinical data, the Company identified 400 mg daily (QD) on a 5 days on 2 days off (5:2) administration schedule as the monotherapy RP2D. Intermittent dosing more than doubled steady state drug exposure to achieve an objective response rate (ORR) of 36.8% in ovarian cancer and uterine serous carcinoma (USC) patients, while maintaining safety and improving tolerability in comparison to continuous dosing. For a more detailed summary of the Phase 1 monotherapy dose optimization data, click here. To listen to a replay of the call, click here. Presented positive azenosertib + chemotherapy combination data at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. The Company presented positive data from its Phase 1b chemotherapy combination trial in platinum-resistant ovarian cancer at the ASCO Annual Meeting in Chicago on June 5, 2023. Azenosertib was well tolerated in combination with multiple types of chemotherapy and demonstrated strong anti-tumor activity, with noteworthy improvements in ORRs and median progression free survival (mPFS) in all patients, especially those with Cyclin E1+ tumors, a subgroup recognized to have a poor prognosis and relatively poor outcomes following chemotherapy. Azenosertib combined with paclitaxel resulted in an ORR of 50.0% and mPFS of 7.4 months. An ORR of 35.7% and mPFS of 10.4 months was observed in azenosertib combined with carboplatin. Zentalis is preparing for a Phase 3 trial of azenosertib using intermittent dosing in combination with chemotherapy in Cyclin E1+ platinum-sensitive ovarian cancer. To review the Phase 1b results in more detail, click here. Biomarker enrichment strategies. Zentalis is exploring biomarker enrichment strategies for azenosertib targeting tumors of high genomic instability, such as Cyclin E1+ tumors and homologous recombination deficient tumors. In April 2023, the Company presented preclinical data supporting the rationale for the Cyclin E1 enrichment strategy at the American Association for Cancer Research (AACR) Annual Meeting 2023. Corporate Highlights In August 2023, the Company announced the appointment of Kimberly Freeman as Chief Strategy Officer. In this role, she will support and implement Zentalis’ long-term portfolio strategy. Ms. Freeman joins Zentalis with over 25 years of clinical development and strategic leadership experience, including deep expertise in oncology, particularly in gynecologic malignancies and the DNA damage response (DDR) pathway. Ms. Freeman brings an outstanding track record of building and executing drug development and franchise strategies that will be invaluable to the Company as it seeks to capitalize on the significant opportunity with azenosertib across a broad array of tumor types. In June 2023, the Company closed an underwritten public offering of 11,032,656 shares of its common stock at a public offering price of $22.66 per share. The total gross proceeds were approximately $250.0 million. In May 2023, the Company appointed Diana Hausman, M.D., to its Board of Directors. Dr. Hausman is an oncologist with extensive experience in all aspects of drug development, including development and implementation of clinical strategy. Dr. Hausman is currently serving as Chief Medical Officer of Link Immunotherapeutics. Dr. Hausman previously served as Chief Medical Officer of Lengo Therapeutics, Zymeworks and Oncothyreon. Prior to Oncothyreon, Dr. Hausman held positions of increasing responsibility at ZymoGenetics, Berlex Laboratories and Immunex. Dr. Hausman currently serves on the Board of Directors of Immuneering. In May 2023, the Company announced that it had appointed Funda Meric-Bernstam, M.D., a widely recognized Phase 1 trial expert and experimental therapeutics researcher in oncology, to its Scientific Advisory Board. Dr. Meric-Bernstam is the Chair of the Department of Investigational Cancer Therapeutics -- the Phase 1 Program at The University of Texas MD Anderson Cancer Center. Her clinical research is focused on novel therapeutics, novel combination therapies and biomarkers to predict and monitor drug response. Second Quarter 2023 Financial Results Cash and Marketable Securities Position: As of June 30, 2023, Zentalis had cash, cash equivalents and marketable securities of $553.0 million. The Company believes that its existing cash, cash equivalents and marketable securities as of June 30, 2023 will be sufficient to fund its operating expenses and capital expenditure requirements into 2026. Research and Development Expenses: Research and development (R&D) expenses for the three months ended June 30, 2023 were $42.7 million, compared to $43.8 million for the three months ended June 30, 2022. The decrease of $1.1 million was primarily due to $1.7 million in decreased collaboration costs, a $1.1 million decrease related to clinical trials and R&D supplies, and a $0.6 million reduction in personnel and related expense. These decreases were partially offset by a $1.5 million increase in Zentera Therapeutics cost sharing and a $0.8 million increase in consulting and other expense. General and Administrative Expenses: General and administrative expenses for the three months ended June 30, 2023 were $15.7 million, compared to $19.6 million during the three months ended June 30, 2022. This decrease of $3.9 million was primarily attributable to a $4.2 million decrease in non-cash, stock-based compensation expense and a $0.8 million decrease related to other personnel expenses. These decreases were partially offset by an increase of $0.8 million in allocated overhead expenditures and a $0.3 million increase in outside services and other costs. Zentera-Related Expenses: On June 15, 2023, the Company announced that it had regained worldwide development and commercialization rights to azenosertib, ZN-d5 and ZN-c5 as a result of the termination of its collaboration with Zentera Therapeutics in certain Asian countries, including China. In connection with the Zentera termination, the Company incurred one-time expenses totaling $45.6 million. About Azenosertib Azenosertib is a potentially first-in-class and best-in-class small molecule WEE1 inhibitor in development for the treatment of cancer. Inhibition of WEE1, a DNA damage response kinase, drives cancer cells into mitosis without being able to repair damaged DNA, resulting in cell death. Currently, there are no FDA-approved WEE1 inhibitors, and azenosertib has been designed for superior selectivity and pharmacokinetic properties. Azenosertib is being developed in therapeutic areas of high unmet need and is being evaluated as a monotherapy, in combination with chemotherapy, and in combination with molecularly targeted agents. About Zentalis Pharmaceuticals Zentalis® Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers. Utilizing its Integrated Discovery Engine, the Company is developing a focused pipeline of potentially best-in-class oncology candidates, which include azenosertib (ZN-c3), a WEE1 inhibitor for advanced solid tumors, ZN-d5, a BCL-2 inhibitor for hematologic malignancies and related disorders, and a heterobifunctional degrader of BCL-xL for solid and hematological malignancies. The Company is also leveraging its extensive experience and capabilities across cancer biology and medicinal chemistry to advance its research on protein degraders. Zentalis has operations in both New York and San Diego. For more information, please visit . Follow Zentalis on Twitter at @ZentalisP and on LinkedIn at . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the U.S. 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 statements regarding the potential to build a meaningful franchise around azenosertib; opportunities with azenosertib across multiple tumor types; the potential for azenosertib to transform the standard of care for patients with ovarian and uterine cancers, and potentially other solid tumors; the potential benefits of azenosertib, including the potential benefits of the design thereof; and the Company’s cash runway. The terms “believe,” “designed,” “opportunity,” “potential,” “will” and similar references are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our limited operating history, which may make it difficult to evaluate our current business and predict our future success and viability; we have and expect to continue to incur significant losses; our need for additional funding, which may not be available; our plans, including the costs thereof, of development of any diagnostic tools; our substantial dependence on the success of our lead product candidates; the outcome of preclinical testing and early trials may not be predictive of the success of later clinical trials; failure to identify additional product candidates and develop or commercialize marketable products; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the regulatory approval process or ongoing regulatory obligations; failure to obtain U.S. or international marketing approval; our product candidates may cause serious adverse side effects; inability to maintain our collaborations, or the failure of these collaborations; our reliance on third parties; effects of significant competition; the possibility of system failures or security breaches; risks relating to intellectual property; our ability to attract, retain and motivate qualified personnel, and risks relating to management transitions; significant costs as a result of operating as a public company; and the other important factors discussed under the caption “Risk Factors” in our most recently filed periodic report on Form 10-K or 10-Q and subsequent filings with the U.S. Securities and Exchange Commission (SEC) and our other filings with the SEC. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. ZENTALIS® and its associated logo are trademarks of Zentalis and/or its affiliates. All website addresses and other links in this press release are for information only and are not intended to be an active link or to incorporate any website or other information into this press release. Dr. Meric-Bernstam receives compensation as a member of the Zentalis Scientific Advisory Board, and this financial relationship has been disclosed to MD Anderson’s Conflict of Interest Committee in accordance with its institutional policy. Contact: Katie Beach Oltsik Evoke Canale Katherine.Beach@evokegroup.com Zentalis Pharmaceuticals, Inc. Condensed Consolidated Statements of Operations (Unaudited) (In thousands, except per share amounts) Three Months Ended June 30, Six Months Ended June 30, 2023 2022 2023 2022 Operating Expenses Research and development $42,684 $43,825 $91,268 $89,937 Zentera in-process research and development 45,568 — 45,568 — General and administrative 15,664 19,636 32,033 31,403 Total operating expenses 103,916 63,461 168,869 121,340 Operating loss (103,916 ) (63,461 ) (168,869 ) (121,340 ) Other Income (Expense) Investment and other income, net 4,451 424 8,560 850 Net loss before income taxes (99,465 ) (63,037 ) (160,309 ) (120,490 ) Income tax expense (benefit) (605 ) 17 (497 ) 50 Loss on equity method investment 13,704 5,338 16,014 7,089 Net loss (112,564 ) (68,392 ) (175,826 ) (127,629 ) Net loss attributable to noncontrolling interests (37 ) (35 ) (80 ) (195 ) Net loss attributable to Zentalis $(112,527 ) $(68,357 ) $(175,746 ) $(127,434 ) Net loss per common share outstanding, basic and diluted $(1.85 ) $(1.34 ) $(2.93 ) $(2.64 ) Common shares used in computing net loss per share, basic and diluted 60,790 51,117 60,038 48,197 Zentalis Pharmaceuticals, Inc. Selected Condensed Consolidated Balance Sheet Data (Unaudited) (In thousands) As of June 30, As of December 31, 2023 2022 Cash, cash equivalents and marketable securities $552,986 $437,371 Working capital (1) 512,170 395,286 Total assets 621,444 539,310 Total liabilities 98,162 105,286 Total Zentalis equity $523,282 $434,024 (1) The Company defines working capital as current assets less current liabilities.