NVL-330

▎药明康德内容团队编辑日前，Nuvalent公司宣布，美国FDA已授予其在研脑渗透性ALK抑制剂NVL-655突破性疗法认定（BTD），用于治疗先前接受过两种或两种以上ALK酪氨酸激酶抑制剂（TKI）治疗的局部晚期或转移性ALK阳性非小细胞肺癌（NSCLC）患者。ALK重排在转移性NSCLC中发生率高达约5%，而在这类患者中，有多达40%在确诊时发现伴有脑转移。约50%的患者在接受目前可用的第一代或第二代ALK TKI治疗后出现耐药突变。对于之前接受过两种或两种以上ALK TKI治疗的患者，目前尚无明确的标准治疗方案。NVL-655获授予BTD主要是基于NVL-655在1/2期临床试验ALKOVE-1的1期部分中，对接受过大量治疗的晚期ALK阳性NSCLC患者的初步安全性和活性积极结果。▲NVL-655疗效结果摘要（图片来源：参考资料[2]）截至2023年8月8日，共有93名患者接受了每日一次的NVL-655治疗，剂量从15 mg到200 mg不等，其中应答可评估的ALK阳性NSCLC患者共51位。接受所有剂量治疗的ALK阳性NSCLC患者的客观缓解率（ORR）达39%（n=20/51），其中具有中枢神经系统（CNS）转移史患者的ORR达到52%（n=15/28）。值得一提的是，肿瘤带有任何ALK耐药突变患者的ORR达54%（n=15/28），其中肿瘤带有常见ALK耐药突变G1202R患者的ORR高达71%（n=12/17）。此外，还观察到了NVL-655具有CNS活性的早期指标。▲带有ALK耐药突变患者对NVL-655应答较佳（图片来源：参考资料[2]）安全性方面，NVL-655的耐受性良好，治疗相关不良事件一般较轻。仅有2%患者因治疗伴发不良事件（TRAE）停止接受治疗。▲NVL-655在TKI耐药ALK阳性NSCLC患者中产生颅内应答（图片来源：参考资料[2]）ALKOVE-1试验2期部分的招募工作正在进行中，该公司预计将在2024年下半年的医学会议上分享该试验的最新数据。NVL-655是一种新型、具有脑部渗透性的潜在“best-in-class”ALK选择性抑制剂，旨在克服目前可用ALK抑制剂所观察到的局限性。NVL-655被设计用于对抗已对第一代、第二代及第三代ALK抑制剂产生耐药的肿瘤，包括具有单一或复合治疗后出现的ALK突变（如G1202R）的肿瘤。此外，NVL-655针对CNS的渗透性进行了设计，以改善脑转移患者的治疗选择，并避免抑制结构相关的肌球蛋白受体激酶（TRK）家族。这些特性有可能避免双重TRK/ALK抑制剂与CNS相关的不良事件，并为患者在所有治疗线中提供深入持久的应答。NVL-655已获得孤儿药资格用以治疗ALK阳性的NSCLC患者。▲NVL-655展现良好安全性（图片来源：参考资料[2]）除了开发针对ALK阳性肿瘤的小分子药物，Nuvalent旗下管线还包含ROS1靶向抑制剂zidesamtinib（NVL-520）。NVL-520是一种创新、选择性、具脑渗透性的ROS1抑制剂，设计用以治疗那些对现有ROS1抑制剂具抗性的癌症，例如那些带有G2032R、S1986Y/F、L2026M或D2033N突变的肿瘤。由于NVL-520具脑渗透性，因此具潜力改善那些肿瘤转移至脑部患者的治疗。在2022年11月所公布的ARROS-1临床1/2期试验入组了那些带有ROS1阳性的NSCLC与其他实体瘤患者入组，这些患者之前曾接受过前期治疗。分析显示，该疗法展现出良好的安全性，且在所有可评估的患者中，有48%（10/21）达成部分缓解（PR），有76%（16/21）仍于试验中持续接受治疗。100%（3/3）具有可测量（>10mm）中枢神经系统转移的病患达成颅内部分缓解。目前NVL-520已进入该试验2期部分的病患招募阶段。▲Nuvalent管线图（图片来源：参考资料[2]）Nuvalent的另一款极具前景的在研脑渗透性小分子是人类表皮生长因子受体2（HER2）选择性TKI疗法NVL-330。该疗法被设计靶向带有HER2外显子20框内缺失（ in-frame deletions）、插入或重复的肿瘤。目前该疗法处IND-enabling阶段，预计在2024年启动1期临床试验。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Nuvalent Receives U.S. FDA Breakthrough Therapy Designation for NVL-655. Retrieved May 17, 2024 from https://www.prnewswire.com/news-releases/nuvalent-receives-us-fda-breakthrough-therapy-designation-for-nvl-655-302148228.html[2] Nuvalent Overview. Retrieved May 17, 2024 from https://filecache.investorroom.com/mr5ir_nuvalent/332/Nuvalent%20Overview_April%208%2C%202024_vFINAL.pdf免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

Updates from the ongoing Phase 1/2 ARROS-1 and ALKOVE-1 clinical trials expected at a medical meeting in the second half of 2024 Strong financial position with operating runway anticipated into 2027 CAMBRIDGE, Mass., May 9, 2024 /PRNewswire/ -- Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, today highlighted pipeline progress, reiterated key anticipated milestones, and reported first quarter 2024 financial results. "Guided by our OnTarget 2026 operating plan, 2024 is a year of focused execution on our path towards a potential first approval in 2026 from our pipeline of novel kinase inhibitors," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "We expect to share clinical updates from our parallel lead programs for ROS1-positive and ALK-positive NSCLC at a medical meeting in the second half of the year and are on-track to dose the first patient in our HER2 program this year. This is an important time for Nuvalent, and we are excited to carry this momentum forward in hopes of bringing our therapies to patients as efficiently as possible." Recent Pipeline Progress and Anticipated Milestones ROS1 Program Nuvalent presented new preclinical data at the American Association for Cancer Research (AACR) Annual Meeting demonstrating that zidesamtinib, its novel ROS1-selective inhibitor, was effective at suppressing on-target ROS1 resistance mutations in preclinical mutagenesis screens. The company expects to share updated data from the ARROS-1 Phase 1/2 trial at a medical meeting in the second half of 2024. Enrollment is ongoing in the global Phase 2 portion of the study. ALK Program Enrollment is ongoing in the global Phase 2 portion of the ALKOVE-1 trial of NVL-655 for patients with advanced ALK-positive NSCLC and other solid tumors. The Phase 2 cohorts are designed with registrational intent for TKI pre-treated patients with ALK-positive NSCLC and to enable preliminary evaluation in patients with ALK-positive NSCLC who are TKI naïve. The company expects to share updated data from the ALKOVE-1 trial at a medical meeting in the second half of 2024. Additionally, Nuvalent plans to outline its broader front-line development strategy for its ALK program in 2024. HER2 Program Nuvalent presented new preclinical data at AACR supporting the broad activity against HER2 oncogenic alterations, selectivity over wild-type EGFR, and differentiated brain-penetrant profile of its novel HER2-selective inhibitor, NVL-330. The company expects to initiate the Phase 1 trial for its HER2 program in 2024. Upcoming Events TD Cowen 5th Annual Oncology Innovation Summit: Management will be participating in a virtual fireside chat on May 29, 2024 at 9:30 am ET. A live webcast will be available in the Investors section of Nuvalent's website at , and will be archived for 30 days following the conference. First Quarter 2024 Financial Results Cash Position: Cash, cash equivalents and marketable securities were $691.8 million as of March 31, 2024. Nuvalent believes these existing cash, cash equivalents and marketable securities to be sufficient to fund its current operating plan into 2027. R&D Expenses: Research and development (R&D) expenses were $38.6 million for the first quarter of 2024. G&A Expenses: General and administrative (G&A) expenses were $14.0 million for the first quarter of 2024. Net Loss: Net loss was $44.5 million for the first quarter of 2024. About OnTarget 2026 OnTarget 2026 delineates Nuvalent's 3-year operating plan towards bringing new, potential best-in-class medicines to patients with cancer. As part of this plan announced in January 2024, Nuvalent outlined the following anticipated milestones throughout 2024, leading to the company's first potential pivotal data in 2025 and first potential approved product in 2026: 2024: Execute on Global Registrational Strategies Progress the Phase 2 portion of its ARROS-1 trial of zidesamtinib in patients with advanced ROS1-positive NSCLC with registrational intent; Initiate the Phase 2 portion of its ALKOVE-1 trial of NVL-655 in patients with advanced ALK-positive NSCLC with registrational intent; Launch the front-line development strategy for its ALK program; Present interim data from its ongoing ARROS-1 and ALKOVE-1 clinical trials at medical meetings; and, Initiate the Phase 1 trial for its HER2 program. 2025: First Pivotal Data 2026: First Approved Product About Nuvalent Nuvalent, Inc. (Nasdaq: NUVL) is a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for patients with cancer, designed to overcome the limitations of existing therapies for clinically proven kinase targets. Leveraging deep expertise in chemistry and structure-based drug design, we develop innovative small molecules that have the potential to overcome resistance, minimize adverse events, address brain metastases, and drive more durable responses. Nuvalent is advancing a robust pipeline with investigational candidates for ROS1-positive, ALK-positive, and HER2-altered non-small cell lung cancer, and multiple discovery-stage research programs. 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 Nuvalent's strategy, business plans, and focus; the period over which Nuvalent estimates its cash, cash equivalents and marketable securities will be sufficient to fund its future operating expenses and capital expenditure requirements; the expected timing of data announcements, clinical trial initiations and FDA product approvals, including the projections in our OnTarget 2026 operating plan; the preclinical and clinical development programs for zidesamtinib, NVL-655 and NVL-330; the potential benefits and effects of Nuvalent's product development candidates; the design and enrollment of the ARROS-1 and ALKOVE-1 trials, including their intended pivotal registration-directed design; the potential of Nuvalent's pipeline programs, including zidesamtinib, NVL-655 and NVL-330; the implications of data readouts and presentations; Nuvalent's research and development programs for the treatment of cancer; and risks and uncertainties associated with drug development. The words "may," "might," "will," "could," "would," "should," "expect," "plan," "anticipate," "aim," "goal," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" or the negative of these terms and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. You should not place undue reliance on these statements or the scientific data presented. 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 that Nuvalent may not fully enroll the ARROS-1 or ALKOVE-1 trials or that enrollment will take longer than expected; unexpected concerns that may arise from additional data, analysis, or results obtained during preclinical studies or clinical trials; the risk that results of earlier clinical trials may not be predictive of the results of later-stage clinical trials; the risk that data from our clinical trials may not be sufficient to support registration and that Nuvalent may be required to conduct one or more additional studies or trials prior to seeking registration of our product candidates; risks that Nuvalent may not achieve the goals and milestones set forth in its OnTarget 2026 operating plan; the occurrence of adverse safety events; risks that the FDA may not approve our potential products on the timelines we expect, or at all; risks of unexpected costs, delays, or other unexpected hurdles; risks that Nuvalent may not be able to nominate drug candidates from its discovery programs; the direct or indirect impact of public health emergencies or global geopolitical circumstances on the timing and anticipated timing and results of Nuvalent's clinical trials, strategy, and future operations, including the ARROS-1 and ALKOVE-1 trials; the timing and outcome of Nuvalent's planned interactions with regulatory authorities; and risks related to obtaining, maintaining, and protecting Nuvalent's intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in Nuvalent's Annual Report on Form 10-K for the fiscal year ended December 31, 2023, as well as any prior and subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Nuvalent's views only as of today and should not be relied upon as representing its views as of any subsequent date. Nuvalent explicitly disclaims any obligation to update any forward-looking statements. SOURCE Nuvalent, Inc.