RLY-5836

Completed enrollment in initial RLY-2608 600mg + fulvestrant dose expansion cohort & initiated additional dose expansion cohorts with RLY-2608 400mg & 600mg Initiated RLY-2608 + fulvestrant + ribociclib triplet combination in PI3Kα-mutated HR+/HER2- metastatic breast cancer Approximately $750 million in cash, cash equivalents and investments at end of Q4 2023, expected to fund operations into second half of 2026 CAMBRIDGE, Mass., Feb. 22, 2024 (GLOBE NEWSWIRE) -- Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, today reported fourth quarter and full year 2023 financial results and corporate highlights. “We made important progress across our portfolio during 2023, advancing multiple clinical programs and continuing to invest significantly in our research engine – the Dynamo platform,” said Sanjiv Patel, M.D., President and Chief Executive Officer of Relay Therapeutics. “We are very pleased with the RLY-2608 data disclosed to-date and how its clinical pro to mature throughout last year. Our clinical team is focused on advancing this program in the near term in both a doublet and a triplet combination, and we look forward to sharing additional data in the second half of 2024. Our Dynamo platform continues to demonstrate precision and productivity with each target we’ve chosen to-date, and we are excited to disclose at least one new program that has come out of it later this year, which is being designed to have first-in-class potential.” Recent Corporate Highlights PI3Kα RLY-2608 doublet Completed enrollment in initial dose expansion cohort of RLY-2608 600mg BID + fulvestrant in patients with PI3Kα-mutant, HR+, HER2- locally advanced or metastatic breast cancer Initiated two additional dose expansion cohorts of RLY-2608 in combination with fulvestrant – a second 600mg BID cohort as well as one at 400mg BID Published RLY-2608 preclinical pro clinical proof-of-concept in Cancer Discovery (Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia) with vignettes from two patients with advanced HR+ breast cancer with kinase or helical mutations, with no observed wildtype PI3Kα-related toxicities RLY-2608 triplet Initiated RLY-2608 + fulvestrant + ribociclib triplet combination in patients with PI3Kα-mutant, HR+, HER2- locally advanced or metastatic breast cancer RLY-5836 Deprioritized further clinical development Lirafugratinib (RLY-4008) Presented initial clinical data in patients with FGFR2-altered solid tumors at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics As previously disclosed, the company will minimize resource allocation in 2024 to allow data to mature and inform future clinical development decisions Anticipated 2024 Milestones RLY-2608 RLY-2608 + fulvestrant data update in the second half of 2024 RLY-2608 + fulvestrant + ribociclib initial safety data in the second half of 2024 Lirafugratinib: tumor agnostic data and regulatory update in the second half of 2024 Pre-clinical: disclose new program(s) in 2024 Fourth Quarter and Full Year 2023 Financial Results Cash, Cash Equivalents and Investments: As of December 31, 2023, cash, cash equivalents and investments totaled $750.1 million compared to approximately $1 billion as of December 31, 2022. The company expects its current cash, cash equivalents and investments will be sufficient to fund its current operating plan into the second half of 2026. Revenue: There was no material revenue for the fourth quarter of 2023 or 2022. Revenue was $25.5 million for the full year 2023, as compared to $1.4 million for the full year 2022. The increase was primarily due to the recognition of previously received milestone payments under the company’s Collaboration and License Agreement with Genentech, Inc. R&D Expenses: Research and development expenses were $77.5 million for the fourth quarter of 2023, as compared to $67.3 million for the fourth quarter of 2022. The increase was primarily due to additional clinical trial expenses and employee-related costs, which were offset by a decrease in other external research costs. Research and development expenses were $330.0 million for the full year 2023, as compared to $246.4 million for the full year 2022. The increase was primarily due to $50.0 million of additional external costs in connection with our clinical trials and $32.4 million of additional employee costs from increased headcount in our research and development functions, which includes $17.7 million of additional stock compensation expense. G&A Expenses: General and administrative expenses were $16.8 million for the fourth quarter of 2023, as compared to $16.4 million for the fourth quarter of 2022. The increase was primarily due to additional stock compensation expense. General and administrative expenses were $75.0 million for the full year 2023, as compared to $66.0 million for the full year 2022. The increase was primarily due additional stock compensation expense. Net Loss: Net loss was $83.5 million for the fourth quarter of 2023, or a net loss per share of $0.67, as compared to a net loss of $67.5 million for the fourth quarter of 2022, or a net loss per share of $0.56. Net loss was $342.0 million for the full year 2023, or a net loss per share of $2.79, as compared to a net loss of $290.5 million for the full year 2022, or a net loss per share of $2.59. About Relay Therapeutics Relay Therapeutics (Nasdaq: RLAY) is a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies with the goal of bringing life-changing therapies to patients. As the first of a new breed of biotech created at the intersection of complementary techniques and technologies, Relay Therapeutics aims to push the boundaries of what’s possible in drug discovery. Its Dynamo™ platform integrates an array of leading-edge computational and experimental approaches designed to drug protein targets that have previously been intractable or inadequately addressed. Relay Therapeutics’ initial focus is on enhancing small molecule therapeutic discovery in targeted oncology and genetic disease indications. For more information, please visit or follow us on Twitter. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding Relay Therapeutics’ strategy, business plans and focus; the progress and timing of the clinical development of the programs across Relay Therapeutics’ portfolio, including the expected therapeutic benefits of its programs, potential efficacy and tolerability, and the timing and success of interactions with and approval of regulatory authorities; the timing of a clinical data update for the PI3Kα franchise, the progress of doublet and triplet combinations for RLY-2608, the timing of clinical updates for RLY-2608, the timing of a clinical data and regulatory update for lirafugratinib, and the timing of disclosure of additional pre-clinical programs; expectations regarding Relay Therapeutics’ pipeline, operating plan, use of capital, expenses and other financial results; and Relay Therapeutics’ cash runway projection. The words “may,” “might,” “will,” “could,” “would,” “should,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions, or the negative thereof, are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: the impact of global economic uncertainty, geopolitical instability and conflicts, or public health epidemics or outbreaks of an infectious disease on countries or regions in which Relay Therapeutics has operations or does business, as well as on the timing and anticipated results of its clinical trials, strategy, future operations and profitability; the delay or pause of any current or planned clinical trials or the development of Relay Therapeutics’ drug candidates; the risk that the preliminary results of its pre-clinical or clinical trials may not be predictive of future or final results in connection with future clinical trials of its product candidates; Relay Therapeutics’ ability to successfully demonstrate the safety and efficacy of its drug candidates; the timing and outcome of its planned interactions with regulatory authorities; and obtaining, maintaining and protecting its intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Relay Therapeutics’ most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Relay Therapeutics' views only as of today and should not be relied upon as representing its views as of any subsequent date. Relay Therapeutics explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Contact: Megan Goulart 617-545-5526 mgoulart@relaytx.com Media: Dan Budwick 1AB 973-271-6085 dan@1abmedia.com Relay Therapeutics, Inc. Condensed Consolidated Statements of Operations and Comprehensive Loss (In thousands, except share and per share data) (Unaudited) Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 Revenue: License and other revenue $ — $ 253 $ 25,546 $ 1,381 Total revenue — 253 25,546 1,381 Operating expenses: Research and development expenses $ 77,496 $ 67,277 $ 330,018 $ 246,355 Change in fair value of contingent consideration liability (2,066 ) (10,544 ) (6,422 ) (11,677 ) General and administrative expenses 16,766 16,371 74,950 65,978 Total operating expenses 92,196 73,104 398,546 300,656 Loss from operations (92,196 ) (72,851 ) (373,000 ) (299,275 ) Other income: Interest income 8,700 5,372 31,045 8,786 Other income (expense) 1 (24 ) (18 ) (20 ) Total other income, net 8,701 5,348 31,027 8,766 Net loss $ (83,495 ) $ (67,503 ) $ (341,973 ) $ (290,509 ) Net loss per share, basic and diluted $ (0.67 ) $ (0.56 ) $ (2.79 ) $ (2.59 ) Weighted average shares of common stock, basic and diluted 124,752,843 120,966,401 122,576,527 112,233,649 Other comprehensive loss: Unrealized holding gain (loss) 3,210 (2,969 ) 10,224 (9,332 ) Total other comprehensive gain (loss) 3,210 (2,969 ) 10,224 (9,332 ) Total comprehensive loss $ (80,285 ) $ (64,534 ) $ (331,749 ) $ (299,841 ) Relay Therapeutics, Inc. Selected Condensed Consolidated Balance Sheet Data (In thousands) (Unaudited) December 31, 2023 December 31, 2022 Cash, cash equivalents and investments $ 750,086 $ 998,917 Working capital (1) 739,834 955,796 Total assets 843,980 1,099,771 Total liabilities 91,977 149,553 Total stockholders’ equity 752,003 950,218 Restricted cash 2,707 2,578 (1) Working capital is defined as current assets less current liabilities.

曾几何时，AI制药概念风靡，第一批先驱们希望可以利用人工智能技术、更短的时间、更低的成本创造出质量更高的药物。然而，多年过去后，第一批进入临床的AI设计药物接连受挫。AI制药公司正在经历前所未有的压力和磨难，但他们积极调整管线，断舍离，急转头，快速推进新的管线进临床，逆境生存。本文，我们走进四家AI制药先驱公司，看看他们经历了怎样的挫折和战略调整，未来又有哪些管线带来新的希望。AI制药先驱Exscientia临床管线大换血Exscientia是一家成立于2012年的英国老牌AI制药企业，为了实现药物设计自动化的理念，Exscientia搭建了三大技术模块，包括CentaurAI、Centaur Biologist、Centaur Chemist，通过这三大技术模块，Exscientia能够实现更快速、更高效的开发药物[1]。2023年10月份，Exscientia公司宣布因疗效达不到预期即将终止癌症候选药物EXS-21546的I/II期研究[2]。EXS-21546是由Exscientia利用其人工智能驱动的平台和Evotec公司提供的生物学和化学能力共同发明和开发的A2A受体拮抗剂。此前，EXS-21546在健康志愿者1a期研究的顶线数据表明：EXS-21546可靶向抑制A2A受体信号传导，是一种高效价、选择性、中枢神经系统(CNS)暴露量低的A2AR拮抗剂。然而，这并不是Exscientia公司第一次终止药物临床研究。DSP-0038是Exscientia和住友制药共同开发一款5-HT1A受体激动剂和5-HT2A受体拮抗剂，用于治疗阿尔兹海默症，也因临床疗效达不到而被终止临床。DSP-1181是由Exscientia和住友制药共同开发的一款用于治疗强迫症(OCD)的长效血清素5-HT1A受体激动剂，于2020年1月在日本启动了I期临床研究，是全球首个由人工智能设计进入临床的药物。然而，2022年，因为临床I期的研究并未达到预期标准，DSP-1181已被Exscientia和住友制药停止开发。这些年，Exscientia的管线已经被“大换血”，从最初的EXS-21546、DSP-0038以及DSP-1181换到现在的CDK7抑制剂GTAEXS617、PKCd抑制剂EXS4318、LSD1抑制剂EXS74539和MALT1抑制剂EXS73565等（图1）。目前，Exscientia管线中进展最快的药物是GTAEXS617。GTAEXS617是由Exscientia与GT Apeiron合作设计，具有高效力、选择性、口服生物利用度的新型CDK7抑制剂。2023年7月份，Exscientia宣布GTAEXS617的1/2期ELUCIDATE研究招募了首位患者，目前正在一项名为ELUCIDATE的1/2期试验中进行测试，用于治疗晚期实体瘤，包括头颈癌、乳腺癌、非小细胞肺癌等癌症。 图1. Exscientia的研发管线虽困难重重，但Exscientia还是受到很多大药企的青睐，建立了多项合作伙伴关系，包括与赛诺菲和默克达成的出色交易。Exscientia与赛诺菲的合作始于2017年，两家公司达成了一项价值2.73亿美元的许可协议，专注于发现治疗代谢疾病的双特异性小分子药物。2022年，Exscientia和赛诺菲还达成了一项研究和许可协议，以开发多达15种肿瘤学和免疫学领域的小分子候选药物。与此同时，Exscientia宣布与默克公司达成一项价值6.74亿美元的新协议，专注于发现肿瘤学、神经炎症和免疫学领域的新型小分子候选药物[3]。股价下跌超90%，BenevolentAI急需充血BenevolentAI是一家于2013年在伦敦成立的老牌AI制药公司，拥有独特的BenAI Engine技术，该技术成为他们端到端药物发现产品和知识探索的基础工具。BenevolentAI通过整合尽可能多的跨领域和不同数据类型的数据，包括组学、分子、实验数据、文献、病理学和生物系统，将这些不同的复杂数据源整合在一起，从而使疾病、基因和药物之间组成关联信息（图2）。 图2. BenevolentAI的数据库来源基于此，BenevolentAI专注于药物发现和开发的人工智能平台可以分为四个子模块，包括知识图谱、目标识别、分子设计和精准医学，使用机器学习来释放庞大且不断扩展的生物医学数据领域的力量，以产生对疾病根本原因的新见解。此前，用于治疗特应性皮炎（AD）的药物的BEN-2293一直是BenevolentAI管线中进展最快也最受期待的，然而2023年4月，BEN-2293的II期试验未达到预期治疗效果，减少瘙痒和炎症的次要疗效终点未达到，随后，BenevolentAI也终止了该药物的开发。BenevolentAI的管线也进行了调整，目前其管线中BEN-8744进展最快（图3）。BEN-8744是一种潜在的同类首创靶向PDE10的外周限制性小分子药物，用于治疗溃疡性结肠炎，BenevolentAI于2023年8月启动了BEN-8744 的I期研究，这项研究的顶线数据预计将于2024年第一季度公布[4]。图3. BenevolentAI的研发管线迅速调整战略，Relay多条管线齐发Relay Therapeutics是一家成立于2016年的以计算为特色的药物发现公司，基于对蛋白质运动与其功能之间无与伦比的洞察力，整合业内前沿的实验和计算方法，建立了独有的Dynamo平台。Dynamo平台结合实验和计算两部分，实验部分包括X-ray crystallography、Cyro-EM等解析结构的技术，计算部分中以分子动力学为主（图4）[5]。 图4. Dynamo平台Relay的研发管线中也有很多被终止或降低优先级，如2023年Relay在公布第三季度时宣布暂停CDK2抑制剂RLY-2139的进一步开发工作，而且Relay也下调了PI3Ka突变抑制剂RLY-2608和RLY-5836的优先级。2023 AACR会议上，Relay揭露了RLY-2608初步临床有效性数据，研究结果表明：24例可评估患者，仅出现1例unconfirmed PR，临床有效性未达到[6]。随着RLY-2608和RLY-5836的临床达不到预期结果，Relay也调整了策略，同时开发用于治疗乳腺癌的靶向PI3Ka特定突变如H1047R的抑制剂，该项目还在临床前开发阶段（图5）。 图5. Relay开发用于治疗乳腺癌的PI3Ka突变抑制剂目前Relay的研发管线中进展最快的是RLY-4008（图6）。 图6. Relay的研发管线RLY-4008（lirafugratinib）是一种有效的、选择性的口服小分子 FGFR2 抑制剂，FGFR2 是一种受体酪氨酸激酶，在某些癌症中经常发生改变。在临床前，RLY-4008在癌细胞系中显示出 FGFR2 依赖性杀伤，并在体内模型中诱导消退，同时观察到对其他靶点（包括 FGFR 家族的其他成员）的选择性。2023年AACR-NCI-EORTC分子靶点和癌症治疗国际会议上，Relay公布了 RLY-4008在FGFR2 突变的实体瘤患者的初步临床数据，该会议显示了多个亚组的活性，包括 FGFR2 融合肿瘤患者和 FGFR2 突变的 HR+/HER2- 乳腺癌患者。研究结果表明：截止2023年8月23日，在26例FGFR2融合肿瘤患者中有9例出现确认部分缓解（PR）（ORR为35%），63%的患者缓解持续时间至少为6个月，在10名FGFR2突变HR+/HER2- 乳腺癌患者中有4名达到 PR（ORR为40%），所有反应者的反应持续时间至少为6个月，最长反应持续时间为 72 周，在34名FGFR2扩增患者中有8名出现PR（ORR为24%），43%的反应者反应持续时间至少为6个月[7,8]。姜还是老的辣Recursion股价已从低谷回升近100%Recursion Pharmaceuticals是一家成立于2013年的结合使用先进的成像技术和人工智能技术的生物制药公司，通过运用计算机视觉技术来处理细胞图像，分析细胞特征来评估疾病细胞药后反应。Recursion拥有专有的AI驱动药物发现平台Recursion OS，Recursion OS由三部分组成：基础设施层（The Infrastructure Layer）、Recursion数据宇宙（Recursion Data Universe）、Recursion映射（Recursion Map），采用先进的成像技术和人工智能技术进行高通量的细胞模型实验，提高效率。2022年10月，Recursion在提交给美国证券交易委员会（SEC）的文件中表示将结束REC-3599的开发，这是一种用于治疗GM2神经节苷脂沉积症的候选药物。REC-3599是口服的具有CNS渗透性的靶向PKC-β和GSK3β的小分子抑制剂，它的前身为礼来的Ruboxistaurin，2015年，Chromaderm从礼来获得了Ruboxistaurin的权利，而 2019年12月Chromaderm将Ruboxistaurin全球开发许可转让给了Recursion，Recursion开发成REC-3599。Recursion基于核心技术平台Recursion OS开发了多个项目，专注于罕见病和肿瘤领域。除了REC-3599之外，Recursion还有几款药物在临床开发阶段，如用于治疗家族性腺瘤息肉症（Familial Adenomatous Polyposis，FAP）的REC-4881、用于治疗2型神经纤维瘤病（Neurofibromatosis Type 2）的REC-2282以及用于治疗脑海绵状畸形（Cerebral Cavernous Malformation）的REC-9942（图7）。图7. Recursion的研发管线REC-4881是Recursion于2020年5月从武田制药公司获得的一款口服的、非ATP竞争性的MEK1和MEK2的变构小分子抑制剂，Recursion通过利用其专有的人工智能药物发现平台Recursion OS，发现了REC-4881作为治疗FAP的潜在候选药物。REC-4881于2022年7月份获得欧盟委员会授予的用于潜在治疗FAP的孤儿药资格认定。在资本寒冬里，2023年7月，Recursion获得了英伟达5000万美元的投资，消息公布后，Recursion的股价飙升了80%。达成协议后，两家公司计划加速开发 Recursion的生物和化学AI基础模型，并利用英伟达的云服务对模型进行优化，为生物技术和制药公司提供AI驱动的药物发现服务。近期，Recursion与拜耳达成一项合作协议，获得新靶点许可的潜在同类首创新分子，用于治疗纤维化疾病[9]。小结任何一项新技术或者新领域的突破都是曲折的，AI制药亦如此，在披荆斩棘的路上总有人在前行，在行动，希望往往诞生于绝望之间，虽然现在很多AI制药药物折戟于临床，但是还是有很多后继者在补位，未来仍有希望。参考文献1.智药邦：AI药物研发公司Exscientia的理念、技术与特点2.After years of hype, the first AI-designed drugs fall short in the clinic3.Five AI drug discovery companies you should know about4.BEN-8744 is a potential first-in-class peripherally restricted small molecule for the treatment of Ulcerative Colitis currently in a Phase I study.5.Relay Therapeutics JPM Presentation January 20236.Relay Therapeutics Announces Initial Clinical Data Demonstrating that RLY-2608 Selectively Targets Multiple PI3Kα Mutations7.Relay Therapeutics Reports Third Quarter 2023 Financial Results and Corporate Highlights8.Relay Therapeutics Announces Initial RLY-4008 (lirafugratinib) Data Demonstrating Durable Responses Across Multiple FGFR2-Altered Solid Tumors9.Recursion Adds New Chemical Entity Targeting Fibrotic Diseases to Late Discovery Pipeline