ADO-Trastuzumab Emtansine

Announced positive data from the Phase 1 clinical trial of ELVN-001 in CML, reporting a cumulative MMR rate of 44% (8/18) by 24 weeks and showing that ELVN-001 remains well-tolerated with no dose reductions Continued to progress ELVN-002 with a focus on recently initiated combination clinical trials evaluating patients with HER2+ MBC and CRC Strong balance sheet with $292 million in cash, cash equivalents and marketable securities, which is expected to provide cash runway into late 2026 BOULDER, Colo., Nov. 13, 2024 /PRNewswire/ -- Enliven Therapeutics, Inc. (Enliven or the Company) (Nasdaq: ELVN), a clinical-stage biopharmaceutical company focused on the discovery and development of small molecule therapeutics, today reported financial results for the third quarter ended September 30, 2024, and provided a business update, including highlights of pipeline progress. "We are thrilled by the progress that we made in the third quarter of 2024. We reported updated clinical data for ELVN-001, which continues to compare favorably to precedent Phase 1 trials of approved BCR::ABL1 TKIs despite a more heavily pre-treated patient population. Since our data release, we have seen strong enrollment and momentum for the program," said Sam Kintz, Co-founder and Chief Executive Officer of Enliven. "Additionally, we are encouraged by the recent accelerated approval of Scemblix in 1L CML, which we believe will pave the way for earlier line use of this new treatment option, thereby creating a potentially large, 2L+ opportunity for ELVN-001. It has been an exciting year for Enliven, and I look forward to sharing additional updates in 2025." Pipeline Updates ELVN-001 is a potent, highly selective, potentially best-in-class small molecule kinase inhibitor designed to specifically target the BCR-ABL gene fusion, the oncogenic driver for patients with chronic myeloid leukemia (CML). The Company announced positive updated data from the Phase 1 clinical trial evaluating ELVN-001 in patients with CML that have failed, or are intolerant to or not a candidate for, available therapies known to be active for treatment of their CML (NCT05304377). As of the cutoff date, June 25, 2024, ELVN-001 achieved a cumulative major molecular response (MMR) rate of 44.4% (8/18) by 24 weeks with stable or deepening responses between weeks 12 and 24. ELVN-001 remains well-tolerated, consistent with its selective kinase profile, and there have been no dose reductions or discontinuations at ≥ 40 mg due to treatment-related adverse events (TRAE). These data continued to compare favorably to precedent Phase 1 cumulative MMRs for approved BCR::ABL1 TKIs, particularly given the more heavily pre-treated patient population in the ELVN-001 clinical trial. Further details can be found on the Enliven website. The Company plans to report additional Phase 1 data in 2025 and is expected to include between approximately 60-100 patients across various lines of therapy with significant follow-up. ELVN-002 is a potent, highly selective, central nervous system penetrant and irreversible HER2 inhibitor with activity against wild type HER2 and various HER2 mutations. Enliven continued to progress its Phase 1 trial evaluating ELVN-002 as a monotherapy agent in patients with HER2+ and HER2 mutant tumors and its exploratory cohort in combination with Kadcyla® (an approved HER2 antibody drug conjugate) in patients with HER2+ metastatic breast cancer (MBC) (NCT05650879). Additionally, the Company continues to enroll its Phase 1 trial evaluating ELVN-002 in combination with trastuzumab +/- chemotherapeutic agents in patients with HER2+ MBC and colorectal cancer (CRC) (NCT06328738). Enliven plans to report Phase 1 data from the ongoing trials in 2025. Third Quarter 2024 Financial Results Cash Position: As of September 30, 2024, the Company had cash, cash equivalents and marketable securities totaling $291.8 million, which is expected to provide cash runway into late 2026. Research and development (R&D) expenses: R&D expenses were $21.3 million for the third quarter of 2024, compared to $19.6 million for the third quarter of 2023. General and administrative (G&A) expenses: G&A expenses were $5.8 million for the third quarter of 2024, compared to $4.6 million for the third quarter of 2023. Net Loss: Net loss was $23.2 million for the third quarter of 2024, compared to $20.8 million for the third quarter of 2023. About Enliven Therapeutics Enliven is a clinical-stage biopharmaceutical company focused on the discovery and development of small molecule therapeutics to help people with cancer not only live longer, but live better. Enliven aims to address existing and emerging unmet needs with a precision oncology approach that improves survival and enhances overall well-being. Enliven's discovery process combines deep insights in clinically validated biological targets and differentiated chemistry to design potentially first-in-class or best-in-class therapies. Enliven is based in Boulder, Colorado. Forward-Looking Statements This press release contains forward-looking statements (including within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and Section 27A of the Securities Act of 1933, as amended) concerning Enliven and other matters. These statements may discuss goals, intentions and expectations as to future plans, trends, events, results of operations or financial condition, or otherwise, based on current beliefs of the management of Enliven, as well as assumptions made by, and information currently available to, management of Enliven. 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," "expect," "anticipate," "plan," "likely," "believe," "estimate," "project," "intend," and other similar expressions or the negative or plural of these words, or other similar expressions that are predictions or indicate future events or prospects, although not all forward-looking statements contain these words. Statements that are not historical facts are forward-looking statements. Forward-looking statements in this press release include, but are not limited to, statements regarding the potential of, and plans, market opportunities, and expectations regarding Enliven's programs, including ELVN-001 and ELVN-002; Enliven's pipeline of product candidates; expected milestones for ELVN-001 and ELVN-002, including the expected timing of data from the clinical trials of ELVN-001 and ELVN-002 and the number of patients included in such data; statements relating to Enliven's expected cash runway; and statements by Enliven's Co-founder and Chief Executive Officer. Forward-looking statements are based on current beliefs and assumptions that are subject to risks and uncertainties and are not guarantees of future performance. Actual results could differ materially from those contained in any forward-looking statement as a result of various risks and uncertainties, including, without limitation: the limited operating history of Enliven; the ability to advance product candidates through preclinical and clinical development; the ability to obtain regulatory approval for, and ultimately commercialize, product candidates; the outcome of preclinical testing and early clinical trials for product candidates and the potential that the outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials; Enliven's limited resources; the risk of failing to demonstrate safety and efficacy of product candidates; Enliven's limited experience as a company in designing and conducting clinical trials; the potential for interim, topline, and preliminary data from Enliven's preclinical studies and clinical trials to materially change from the final data; potential delays or difficulties in the enrollment or maintenance of patients in clinical trials; developments relating to Enliven's competitors and its industry, including competing product candidates and therapies; the decision to develop or seek strategic collaborations to develop Enliven's current or future product candidates in combination with other therapies and the cost of combination therapies; the ability to attract, hire, and retain highly skilled executive officers and employees; the ability of Enliven to protect its intellectual property and proprietary technologies; the scope of any patent protection Enliven obtains or the loss of any of Enliven's patent protection; reliance on third parties, including contract manufacturing organizations, contract research organizations and strategic partners; general market or macroeconomic conditions; Enliven's ability to obtain additional capital to fund Enliven's general corporate activities and to fund Enliven's research and development; and other risks and uncertainties, including those more fully described in Enliven's filings with the Securities and Exchange Commission (SEC), which may be found in the section titled "Risk Factors" in Enliven's Annual and Quarterly Reports on Form 10-K and 10-Q filed with the SEC and in Enliven's future reports to be filed with the SEC. Except as required by applicable law, Enliven undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. This press release contains hyperlinks to information that is not deemed to be incorporated by reference into this press release. SOURCE Enliven Therapeutics, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

康宁杰瑞过去多个项目的失败，让整个市场都见识到了创新药研发残酷的一面。在2024年以前，中国的Biotech甚少传出研发失败的声音，主要原因在于此前整个研发领域充斥着各种me-too。而如今，低垂的果实已经被采摘完毕，创新药研发开始进入深水区。而康宁杰瑞的数次失败也说明了这些项目是真正的First-in-class项目，没办法耍小聪明，前路尽是未知。 往往在这种时刻，更能体现一家具有真正创新精神Biotech的韧性。在资本市场逐渐火热的氛围下，康宁杰瑞已经悄悄地从低谷爬起，短时间内实现了市值翻倍。 1 倚仗ADC 从底部浮出水面喘上一口气，康宁杰瑞要感谢石药集团。 在国庆前一天，康宁杰瑞发布公告称，与石药集团子公司津曼特生物订立了一项许可协议。根据许可协议的条款，津曼特生物将获得在大中华区开发、销售、许诺销售及商业化JSKN003（一种靶向HER2双表位ADC）的独家许可及再权限，并成为该地区的唯一上市许可持有人。 康宁杰瑞有权收取最高合共30.8亿元的预付款及里程碑付款，其中包括收取4亿元的预付款，与开发里程碑付款3亿元，以及产品销售净额两位数百分比的特许权使用费。 这不是康宁杰瑞与津曼特生物的首次合作，此前的2021年，双方就KN026的权益达成过合作。 来源：公告 JSKN003是一款靶向HER2双表位ADC，通过糖基定点偶联将拓扑异构酶I抑制剂连接至抗体KN026（重组人源化抗HER2双特异性抗体）的N糖基化位点处。点击反应偶联物较马来酰亚胺－迈克尔反应的偶联物具有更好的血清稳定性。双表位HER2靶向性使JSKN003具有更强的内吞诱导及旁观者杀伤效应，使其在HER2表达肿瘤中具有较强的抗肿瘤活性。 目前正在澳大利亚进行JSKN003的I期临床试验，并在中国开展I/II期和III期临床试验。研究结果显示JSKN003在既往经多线治疗的晚期/转移性实体瘤患者中耐受性、安全性良好，显示出令人鼓舞的初步抗肿瘤活性。于2024年6月在ASCO年会上展示的数据显示，JSKN003在2.1mg/kg至8.4mg/kg的剂量范围耐受性良好，且在既往接受过深度治疗的患者中显示出令人鼓舞的抗肿瘤活性。 以JSKN003为基础的复方制剂JSKN033的临床数据也在近期于2024年SITC年会上发布。 JSKN033是一款康宁杰瑞自主研发的全球首个皮下注射ADC复方制剂，由JSKN003和KN035组成。一项开放、多中心及首次人体的I/II期临床试验JSKN033-101数据表明，安全性方面，最常见的TRAEs是注射部位反应，均为1级，且通常在无需任何治疗、或仅接受抗组胺药物后的2周内自行缓解，未观察到DLT，不同剂量组之间的安全性无显著差异；有效性方面，10例疗效可评估患者中，3例患者出现PR，5例患者SD，DCR达80%，在4.5mg/kg剂量下即对患者表现出抗肿瘤活性。 在以往的方案中，以复方制剂这种形式进行的药物联用较为少见，JSKN033具有探索性意义。更进一步细究之下，JSKN033是以KN026（HER2双抗）为基础的ADC，此等环环相扣的产品设计可以说在国内Biotech中绝无仅有。 2 环环相扣 KN026是目前康宁杰瑞最具战略意义的在研产品。 这是一款HER2双抗，可以同时结合两种不同的HER2表位。在中国及美国的I期及II期临床试验中，KN026对于经多线治疗的HER2表达癌症患者，显示出良好的初步疗效及安全性。目前，KN026正在中国进行数项临床试验，正在开展KN026联合多西他赛（白蛋白结合型）一线治疗HER2阳性BC（乳腺癌）及KN026联合化疗二线及以上治疗HER2阳性GC/GEJ（胃癌/胃食管结合部癌）的III期临床试验。KN026联合化疗用于一线标准治疗（曲妥珠单抗联合化疗）失败的HER2阳性GC（包括GEJ）患者已获国家药监局CDE授予突破性疗法认定。 HER2作为肿瘤领域热门靶点，已有多个不同类型的药物相继上市。 罗氏的曲妥珠单抗是全球第一个获批上市的HER2靶向药物；GSK/诺华的拉帕替尼是全球第一个获批上市的HER2小分子靶向抑制剂药物；罗氏的恩美曲妥珠单抗（T-DM1）是全球第一个获批上市的HER2靶向ADC药物。 这些产品都已经非常成熟，经过了时间的严格考验。 曲妥珠单抗已不必赘述，目前光在国内获批的生物类似药就有复宏汉霖的汉曲优、齐鲁制药的安曲妥、安科生物的安赛汀等多款；恩美曲妥珠单抗在全球首次获批上市到现在的二十年多中，从二线到一线，从辅助治疗到新辅助，从联合内分泌治疗到联合小分子药物，其在乳腺癌领域的探索实现全面开花，并展现出多维的临床应用潜力。 值得注意的是，靶向HER2的ADC药物当下的主角已不再是恩美曲妥珠单抗，而是来自阿斯利康和第一三共联合开发的DS-8201（Enhertu）。国内也已经有获批上市的HER2 ADC，即来自荣昌生物的维迪西妥单抗。 根据药渡数据不完全统计，目前全球范围内涉及HER2靶点的药物已超600款，其中，ADC超130款，其次为单抗和小分子化药各超100款、双抗超40款等。康宁杰瑞的这一套HER2靶点的连环设计的竞争压力可想而知。 康宁杰瑞主要研发管线 来源：2024年半年报 除了KN026，康宁杰瑞此前的王牌KN046虽然遭遇了些许挫折，但依然是其管线中最具商业化前景的双抗。今年2月和3月KN046的一线三阴性乳腺癌和一线非小细胞肺癌（NSCLC）的II期临床试验结果分别在《Nature Communications》及《Cell Reports Medicine》上发表；2024年9月，完成了KN046治疗晚期sq NSCLC的III期临床试验的最终OS分析，试验结果具有统计学差异的OS获益。此外，对于PFS的最终分析显示KN046联合含铂化疗组显著获益。 在过去的两年里，ADC大放异彩，但进入2024年，双抗的光芒似乎正在逐渐绽放，国内Biotech的双抗出海频率开始加快。 3 双抗赛道即将爆发 双特异性抗体，简称双抗，是指拥有两个不同的抗原结合位点，能同时靶向两个抗原或同一抗原两个不同表位的人工抗体。 双抗靶向两种抗原或抗原表位，可以同时阻断或激活其介导的生物学功能，或使表达两种抗原的细胞相互接近，从而增强两者间的相互作用，并以不同的作用机制介导多种特定的生物学效应。目前普遍认为双抗的药效学或生物学作用机制主要包括空间重排和背负式运输，在研的大部分双抗药物采用空间重排（桥联细胞、桥联受体、桥联因子）的方式起效。 双抗作用机制分类及其代表案例 来源：东吴证券研报 因其具有潜在的优效和安全性优势，国内外企业纷纷布局双抗领域，成为仅次于ADC的热点领域。 根据药渡数据，截至2024年10月，全球双抗药物共获批上市17款（其中首款商业化药物Catumaxomab已退市），进入临床阶段超460款。主要适应症集中在肿瘤领域，自免领域相关临床也在逐步推进。 随着双抗药物逐步上市，双抗市场规模也来到了新的高度，于2023年上市的12款双抗药物的全年销售额达到了83亿美元。 今年以来，国内Biotech的双抗（多抗）出海开始走上快车道，诞生了多项价值巨大的交易。 7月，康诺亚与Belenos合作，授权两款双抗产品，将获得1500万美元首付款和近期里程碑付款，最高1.7亿美元里程碑款，及分层特许权使用费，并持有Belenos约30.01%的股权；8月，嘉和生物宣布采用NewCo模式将其GB261（CD3×CD20）授权给TRC2004，获得数千万美元首付款、4.43亿美元里程碑付款及分层特许权使用费，并持有TRC2004一定股权；9月，岸迈生物宣布与Vignette Bio就开发BCMA×CD3双特异性抗体EMB-06达成了战略合作，岸迈生物以现金和Vignette股权的形式收取总计6000万美元的首付款对价，并将有权收取最多5.75亿美元的里程碑付款；10月，葛兰素史克（GSK）宣布和恩沐生物达成合作，将以3亿美元的首付款从恩沐生物拿下CMG1A46（CD3/CD19/CD20三抗），后者将有资格获得总计5.5亿美元的开发和商业化里程碑付款。 据不完全数据统计，全球目前有超过上千款双抗在研药物，其中近400款已进入临床阶段，这其中，将近一半的管线来自中国企业，康方生物、百利天恒、宜明昂科、康宁杰瑞、科望医药、普米斯、友芝友生物等都是个中翘楚。 4 结语 作为国内最早涉足双抗研发的Biotech，康宁杰瑞追求创新的精神令人敬佩，不论是挑战“癌王”胰腺癌，还是双抗ADC的探索，都极具勇气。从在研产品的布局上看，连环扣式的研发布局风险性极高，但好在瞄准的是成熟靶点。因此，一旦连环扣中有一项突破，有望将带来连带效应，实现全线在研的前景重塑。后续发展如何，药渡还将持续关注。 参考资料 康宁杰瑞官网、公告、年报等 东吴证券、国盛证券、中信建投研报等 《一年“闪崩”三次，康宁杰瑞的“癌王”适应症还是失败了》，华尔街见闻，2024-05-29 《国产ADC“硬刚”罗氏T-DM1！复星、科伦会否复制DS-8201完胜？》，医药经济报，2023-06-20 《天堂和地狱！上市、在研和失败的Her2 ADC们》，胖猫的生命医学札记，2024-06-26