Preclinical data continue to support NVL-330's broad activity against HER2 oncogenic alterations, selectivity over wild-type EGFR, and differentiated brain-penetrant profile

临床前数据继续支持NVL-330对HER2致癌改变的广泛活性，对野生型EGFR的选择性以及分化的脑渗透特征

Zidesamtinib shown to be effective at suppressing on-target ROS1 resistance mutations in preclinical mutagenesis screens

齐地沙替尼在临床前诱变筛选中显示出有效抑制靶向ROS1抗性突变

CAMBRIDGE, Mass., April 8, 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 announced the presentation of new preclinical data for its novel HER2-selective inhibitor, NVL-330, and novel ROS1-selective inhibitor, zidesamtinib (NVL-520).

马萨诸塞州剑桥市，2024年4月8日/PRNewswire/--Nuvalent，Inc.（纳斯达克：NUVL），一家临床阶段生物制药公司，专注于为临床证实的癌症激酶靶标创建精确靶向治疗，今天宣布为其新型HER2选择性抑制剂NVL-330和新型ROS1选择性抑制剂齐地沙米替尼（NVL-520）提供新的临床前数据。

The two posters will be presented at the American Association for Cancer Research (AACR) Annual Meeting taking place from April 5 – 10 in San Diego. The posters will also be available on the Nuvalent website at www.nuvalent.com following the presentations..

这两张海报将于4月5日至10日在圣地亚哥举行的美国癌症研究协会（AACR）年会上发布。演示后，海报也将在Nuvalent网站www.Nuvalent.com上发布。。

'Today's presentations continue to reinforce the differentiated profiles of our drug candidates,' said Henry Pelish, Ph.D., Senior Vice President of Drug Discovery at Nuvalent. 'In comparative in vitro and in vivo analyses of NVL-330 with currently approved and investigational HER2-targeting agents, NVL-330 demonstrated a differentiated preclinical profile by achieving higher CNS penetration and deeper intracranial response.

Nuvalent负责药物发现的高级副总裁亨利·佩利什（HenryPelish）博士说，今天的演讲继续强化了我们候选药物的差异化特征在NVL-330与目前批准和研究的HER2靶向药物的体外和体内比较分析中，NVL-330通过实现更高的中枢神经系统渗透和更深的颅内反应表现出不同的临床前特征。

Importantly, in these preclinical studies, NVL-330 also demonstrated potency against a broad range of HER2 oncogenic alterations and selectivity over wild-type EGFR, in line with our goal of designing molecules that can thread the needle between multiple competing challenges.'.

重要的是，在这些临床前研究中，NVL-330还显示出对广泛的HER2致癌改变和对野生型EGFR的选择性的效力，这与我们设计可以在多种竞争挑战之间穿针引线的分子的目标一致。

Dr. Pelish continued, 'In our ongoing ARROS-1 clinical trial of zidesamtinib, preliminary Phase 1 data has demonstrated a differentiated profile combining activity against ROS1 resistance mutations, CNS penetrance, and TRK avoidance which we believe has the potential to translate to deep, durable responses for patients with ROS1-driven cancers.

佩利什博士继续说，“在我们正在进行的齐地沙米替尼ARROS-1临床试验中，初步的第一阶段数据表明，针对ROS1耐药突变，中枢神经系统外显率和TRK避免的活性相结合，我们认为这有可能转化为ROS1驱动的癌症患者的深度，持久的反应。

A new preclinical mutagenesis screen reinforces this potential, showing that on-target resistance is unlikely following treatment with zidesamtinib at its average observed clinical concentration.'.

一项新的临床前诱变筛选增强了这一潜力，表明在平均观察到的临床浓度下用齐地沙替尼治疗后不太可能产生靶向耐药性。”。

In 2024, the company expects to initiate a Phase 1 trial for its HER2 program and to share updated data from the ARROS-1 trial at a medical meeting.

2024年，该公司预计将启动HER2计划的第一阶段试验，并在医疗会议上分享ARROS-1试验的最新数据。

AACR Presentation Overviews:

AACR演示概述：

Title: Preclinical characterization of NVL-330, a selective and brain penetrant HER2 tyrosine kinase inhibitor with broad activity on HER2 oncogenic alterations

标题：NVL-330的临床前表征，NVL-330是一种选择性和脑渗透性HER2酪氨酸激酶抑制剂，对HER2致癌改变具有广泛活性

Authors: Yuting Sun*1, Kristin L. Andrews1, Anupong Tangpeerachaikul1, Tuan M. Nguyen1, Baudouin Gerard1, Nancy E. Kohl2, Joshua C. Horan1, Henry E. Pelish1

作者：孙玉婷*1，克里斯汀·L·安德鲁斯1，阿努蓬·唐佩拉·查库1，图安·M·恩古耶恩1，博杜因·杰拉德1，南希·E·科尔2，约书亚·C·霍兰1，亨利·E·佩利什1

Abstract Number: 1979

摘要编号：1979

Session Category: Experimental and Molecular Therapeutics

课程类别：实验和分子疗法

Session Title: Kinase and Phosphatase Inhibitors 2

课程名称：激酶和磷酸酶抑制剂2

Session Date and Time: Monday April 8, 2024, from 9:00 – 12:30 p.m. PT

会议日期和时间：2024年4月8日星期一，下午9:00–12:30

Location: Poster Section 25

位置：海报第25节

Presentation summary:

演示文稿摘要：

NVL-330 had broad preclinical activity on HER2 oncogenic alterations, including HER2 exon20ins, HER2 activating point mutations, and amplified wild-type HER2.

NVL-330对HER2致癌改变具有广泛的临床前活性，包括HER2外显子20ins，HER2激活点突变和扩增的野生型HER2。

In a preclinical comparison with the selective tyrosine kinase inhibitor, zongertinib, NVL-330 demonstrated:

在与选择性酪氨酸激酶抑制剂zongertinib的临床前比较中，NVL-330证明：

Similar potency and selectivity over wild-type EGFR; and,

与野生型EGFR相似的效力和选择性；而且，

Higher CNS penetrance.

中枢神经系统渗透率更高。

In a preclinical comparison with antibody drug conjugate, T-DXd (Enhertu), NVL-330 demonstrated:

在与抗体-药物偶联物T-DXd（Enhertu）的临床前比较中，NVL-330证明：

Deeper response and higher CNS penetrance in an intracranial tumor model; and,

颅内肿瘤模型中更深的反应和更高的中枢神经系统渗透率；而且，

Activity in cells with acquired resistance to T-DXd.

对T-DXd具有获得性抗性的细胞中的活性。

Title: Mutagenesis screens support potential best-in-class profile for selective, brain-penetrant, and TRK-sparing ROS1 inhibitor zidesamtinib (NVL-520)

标题：诱变筛选支持选择性，脑渗透性和TRK保留的ROS1抑制剂齐地沙替尼（NVL-520）的潜在最佳概况

Authors: Anupong Tangpeerachaikul*1, Franklin Gu1, Henry E. Pelish1

作者：Anupong Tangpeerachaikul*1，Franklin Gu1，Henry E.Pelish1

Abstract Number: LB182

摘要编号：LB182

Session Title: Late-Breaking Research: Experimental and Molecular Therapies 2

课程名称：晚期突破性研究：实验和分子疗法2

Session Date and Time: Monday April 8, 2024, from 1:30 – 5:00 p.m. PT

会议日期和时间：2024年4月8日星期一，下午1:30–5:00

Location: Poster Section 52

位置：海报第52节

Presentation summary:

演示文稿摘要：

Comparison of the clinical concentration of zidesamtinib to its efficacious in vitro concentration suggests a potential for a deep and sustained inhibition of ROS1 and ROS1 G2032R fusions in humans, including in the CNS.

齐地沙替尼的临床浓度与其有效的体外浓度的比较表明，在包括中枢神经系统在内的人类中，ROS1和ROS1 G2032R融合可能会受到深度和持续的抑制。

Zidesamtinib effectively suppressed on-target resistance in ENU mutagenesis screens with both ROS1 and ROS1 G2032R fusions, predicting that on-target resistance is unlikely when used as either a first-line or a later-line therapy.

齐地沙替尼在具有ROS1和ROS1 G2032R融合的ENU诱变筛选中有效抑制了靶向耐药性，预测当用作一线或后一线治疗时不太可能产生靶向耐药性。

On-target resistance is predicted to be more likely for earlier-generation ROS1 inhibitors crizotinib, entrectinib, and potentially repotrectinib as a first-line therapy.

预计早期ROS1抑制剂克唑替尼，entrectinib和潜在的repotrectinib作为一线治疗更有可能产生靶向耐药性。

These mutagenesis screens provide additional preclinical support for zidesamtinib's potential to drive deep and durable responses for patients with ROS1-driven cancers.

这些诱变筛选为齐地沙替尼驱动ROS1驱动的癌症患者产生深度和持久反应的潜力提供了额外的临床前支持。

*Presenter, corresponding author; 1Nuvalent, Inc., Cambridge, MA, USA; 2Kohl Consulting, Wellesley, MA, USA

*主持人，通讯作者；1Nuvalent，Inc.，美国马萨诸塞州剑桥；2Kohl Consulting，美国马萨诸塞州韦尔斯利

About NVL-330

关于NVL-330

NVL-330 is a novel brain-penetrant HER2-selective tyrosine kinase inhibitor designed to address the combined medical need of treating HER2-mutant tumors, including those with HER2 exon 20 insertion mutations, avoiding treatment related adverse events due to off-target inhibition of wild-type EGFR, and treating brain metastases..

NVL-330是一种新型的脑渗透性HER2选择性酪氨酸激酶抑制剂，旨在解决治疗HER2突变肿瘤（包括HER2外显子20插入突变肿瘤）的综合医疗需求，避免由于野生型EGFR的脱靶抑制引起的治疗相关不良事件，并治疗脑转移。。

About zidesamtinib (NVL-520)

关于齐德沙替尼（NVL-520）

Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R.

齐地沙替尼是一种新型脑渗透ROS1选择性抑制剂，旨在克服目前可用的ROS1抑制剂所观察到的局限性。齐地沙替尼被设计用于在对目前可用的ROS1抑制剂产生耐药性的肿瘤中保持活性，包括具有治疗紧急ROS1突变的肿瘤，例如G2032R。

In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy.

此外，齐地沙米替尼旨在改善中枢神经系统（CNS）的外显率，以改善脑转移患者的治疗选择，并避免抑制结构相关的原肌球蛋白受体激酶（TRK）家族。总之，这些特征有可能避免双重TRK/ROS1抑制剂所见的TRK相关中枢神经系统不良事件，并在所有治疗方案中为患者带来深度，持久的反应。

Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC. Zidesamtinib is currently being investigated in the ARROS-1 trial (NCT05118789), a first-in-human Phase 1/2 clinical trial for patients with advanced ROS1-positive NSCLC and other solid tumors..

齐地沙替尼已获得突破性治疗指定，用于治疗ROS1阳性转移性非小细胞肺癌（NSCLC）患者，这些患者先前曾接受过2种或更多ROS1酪氨酸激酶抑制剂的治疗，并被指定为ROS1阳性NSCLC的孤儿药。齐达姆替尼目前正在ARROS-1试验（NCT05118789）中进行研究，这是针对晚期ROS1阳性NSCLC和其他实体瘤患者的首次人体1/2期临床试验。。

About Nuvalent

关于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，Inc.（纳斯达克股票代码：NUVL）是一家临床阶段的生物制药公司，专注于为癌症患者创建精确的靶向治疗，旨在克服现有治疗方法对临床证实的激酶靶标的局限性。利用化学和基于结构的药物设计方面的丰富专业知识，我们开发了创新的小分子，这些小分子有可能克服耐药性，最大程度地减少不良事件，解决脑转移，并推动更持久的反应。

Nuvalent is advancing a robust pipeline with investigational candidates for ROS1-positive, ALK-positive, and HER2-positive non-small cell lung cancer, and multiple discovery-stage research programs..

Nuvalent正在推进一个强大的管道，其中包括ROS1阳性，ALK阳性和HER2阳性非小细胞肺癌的研究候选人，以及多个发现阶段的研究计划。。

Forward-Looking Statements

前瞻性声明

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 expected timing of data announcements; the development programs for zidesamtinib (NVL-520) and NVL-330; the potential benefits of zidesamtinib and NVL-330; the potential of Nuvalent's pipeline programs, including zidesamtinib and NVL-330; Nuvalent's research and development programs for the treatment of cancer; and risks and uncertainties associated with drug development.

本新闻稿包含1995年《私人证券诉讼改革法案》修订版所指的前瞻性声明，包括但不限于有关Nuvalent战略、业务计划和重点的暗示和明示声明；数据公布的预期时间；齐地沙替尼（NVL-520）和NVL-330的开发计划；齐地沙替尼和NVL-330的潜在益处；Nuvalent的管道项目的潜力，包括齐达姆替尼和NVL-330；Nuvalent的癌症治疗研究与开发计划；以及与药物开发相关的风险和不确定性。

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.

“可能”、“可能”、“将”、“可能”、“将”、“应该”、“期望”、“计划”、“预期”、“目标”、“打算”、“相信”、“期望”、“估计”、“寻求”、“预测”、“未来”、“项目”、“潜力”、“继续”、“目标”或这些术语的否定词以及类似的词语或表达都旨在识别前瞻性陈述，尽管并非所有前瞻性陈述都包含这些识别词。

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..

药物开发和商业化涉及高度风险，只有少数研究和开发计划会导致产品商业化。您不应过度依赖这些陈述或提供的科学数据。。

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: 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; 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; the timing and outcome of Nuvalent's planned interactions with regulatory authorities; and risks related to obtaining, maintaining, and protecting Nuvalent's intellectual property.

本新闻稿中的任何前瞻性声明均基于管理层当前的期望和信念，并受到许多风险、不确定性和重要因素的影响，这些风险、不确定性和重要因素可能导致实际事件或结果与本新闻稿中任何前瞻性声明所表达或暗示的事件或结果产生重大差异，包括但不限于：临床前研究或临床试验期间获得的额外数据、分析或结果可能引起的意外担忧；早期临床试验结果可能无法预测后期临床试验结果的风险；我们的临床试验数据可能不足以支持注册，并且Nuvalent可能需要在寻求注册我们的候选产品之前进行一项或多项额外的研究或试验；不良安全事件的发生；FDA可能无法在我们预期的时间内批准我们的潜在产品，或者根本无法批准；意外成本、延误或其他意外障碍的风险；Nuvalent可能无法从其发现计划中提名候选药物的风险；突发公共卫生事件或全球地缘政治环境对Nuvalent临床试验、战略和未来运营的时间安排、预期时间安排和结果的直接或间接影响；Nuvalent计划与监管机构互动的时间和结果；以及与获取、维护和保护Nuvalent知识产权有关的风险。

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 Se.

这些以及其他风险和不确定性在Nuvalent截至2023年12月31日的10-K表年度报告中题为“风险因素”的部分以及之前和之后向Se提交的任何文件中有更详细的描述。

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SOURCE Nuvalent, Inc.

SOURCE Nuvalent公司。

Company Codes: NASDAQ-NMS:NUVL

公司代码：NASDAQ-NMS:NUVL