Repotrectinib

Achievement of all anticipated 2024 milestones and accelerated development timelines reinforce progress on OnTarget 2026 operating plan towards first approved product in 2026 Leading medical oncologist Alice Shaw, M.D., Ph.D. appointed to Scientific Advisory Board Strong cash position of $1.2 billion, including proceeds from upsized $575 million public offering, expected to extend operating runway into 2028 CAMBRIDGE, Mass., Nov. 12, 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 third quarter 2024 financial results. "Throughout 2024, the Nuvalent team has made significant strides in advancing our pipeline of novel kinase inhibitors, exemplified by the achievement of all of the 2024 milestones originally laid out in our OnTarget 2026 operating plan. We believe our recent upsized public offering reflects the shared excitement around these achievements and the potential for multiple value-creating catalysts ahead," said Alexandra Balcom, Chief Financial Officer at Nuvalent. "We believe we are well-positioned to execute on our mid- and long-term goals and remain sharply focused on moving our programs forward as efficiently as possible for patients." "Our portfolio achievements and the acceleration of our development timelines have stemmed from a foundational tenet of our approach to drug discovery and development: collaboration with leading physician-scientists from the outset of each program," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "Today, we are thrilled to welcome Dr. Alice Shaw, Chief of Strategic Partnerships at Dana-Farber Cancer Institute, to our Scientific Advisory Board in recognition of her invaluable contributions to our ROS1 and ALK programs since our company's formation. A leading expert in targeted oncology, Dr. Shaw's research has deepened the scientific understanding of oncogene-driven lung cancers and their mechanisms of resistance, and contributed to numerous new therapeutic options for patients. We look forward to continuing to leverage her insights and expertise as we advance our clinical programs and discovery pipeline." "Targeted kinase inhibitors are important treatment options for cancer patients, but key challenges, including drug resistance and off-target side effects, can limit their therapeutic impact," said Dr. Shaw. "I am excited by Nuvalent's pursuit of new therapeutic approaches to overcome the limitations of existing therapies. The clinical proof-of-concept data from both the ROS1 and ALK programs are encouraging and support the approach of designing highly selective and brain-penetrant inhibitors that retain potency against known resistance mutations. I look forward to working with the team to advance the current pipeline of novel therapeutic candidates and identify additional areas of medical need where Nuvalent could potentially make a meaningful impact for patients." Recent Pipeline Progress and Anticipated Milestones ROS1 Program Nuvalent recently reported updated data from the fully enrolled Phase 1 portion of its ongoing ARROS-1 Phase 1/2 clinical trial in patients with advanced ROS1-positive NSCLC during an oral presentation at the European Society for Medical Oncology (ESMO) Congress 2024. Data presented showed that treatment with zidesamtinib resulted in durable clinical responses in heavily pre-treated patients with ROS1-positive NSCLC, including in subgroups of patients who had likely exhausted all available therapies including lorlatinib and/or repotrectinib, had a history of brain metastases, or had the G2032R resistance mutation. Additionally, zidesamtinib was well-tolerated with a preliminary safety profile that was favorable and consistent with its ROS1-selective, TRK-sparing design. Additionally, during a poster session at the ESMO Congress 2024, the company presented new preclinical data further characterizing the intracranial activity of zidesamtinib. Enrollment is ongoing in the Phase 2 portion of the ARROS-1 Phase 1/2 trial of zidesamtinib for patients with advanced ROS1-positive NSCLC and other solid tumors. Between September 2023 and September 1, 2024, 227 patients were enrolled in the ongoing single-arm, multi-cohort Phase 2 portion of the ARROS-1 trial, which is designed with registrational intent. The company expects to report pivotal data from this trial in 2025. ALK Program Nuvalent recently reported updated data from the fully enrolled Phase 1 portion of its ongoing ALKOVE-1 Phase 1/2 clinical trial in patients with advanced ALK-positive NSCLC during an oral presentation at the ESMO Congress 2024. Data presented showed that treatment with NVL-655 resulted in durable clinical responses in heavily pre-treated patients with ALK-positive NSCLC, including in subgroups of patients who had likely exhausted all available therapies including lorlatinib, had a history of brain metastases, or had single or compound ALK resistance mutations. Additionally, NVL-655 demonstrated a favorable preliminary safety profile consistent with its ALK-selective, TRK-sparing design. Enrollment is ongoing in the Phase 2 portion of the ALKOVE-1 Phase 1/2 trial of NVL-655 for patients with advanced ALK-positive NSCLC and other solid tumors. Between February 2024 and September 1, 2024, 229 patients were enrolled in the ongoing single-arm, multi-cohort Phase 2 portion of the ALKOVE-1 trial, which is designed with registrational intent for TKI pre-treated patients. The company expects to report pivotal data from this trial in 2025. Nuvalent recently announced the ALKAZAR Phase 3 trial, its front-line development strategy for the company's ALK program. The Phase 3 ALKAZAR trial will be a global, randomized, controlled trial designed to evaluate NVL-655 versus the current standard of care for the treatment of patients with TKI-naïve ALK-positive NSCLC. Patients will be randomized 1:1 to receive NVL-655 monotherapy or ALECENSA® (alectinib) monotherapy, reflecting input from collaborating physician-scientists and alignment with the U.S. Food and Drug Administration (FDA). The company plans to initiate the ALKAZAR study in the first half of 2025. A manuscript describing the design and characterization of NVL-655 and detailing Nuvalent's approach to rationally targeting ALK, was published in Cancer Discovery, a journal of the American Association for Cancer Research. The publication, Nuvalent's second in Cancer Discovery, provides a comprehensive assessment of NVL-655's preclinical activity and includes preliminary clinical case studies. HER2 Program Enrollment is ongoing in the HEROEX-1 Phase 1a/1b clinical trial evaluating NVL-330 for pre-treated patients with HER2-altered NSCLC. The trial will evaluate the overall safety and tolerability of NVL-330. Additional objectives include determination of the recommended Phase 2 dose (RP2D), characterization of the pharmacokinetic profile, and preliminary evaluation of anti-tumor activity. Corporate Highlight Nuvalent has appointed leading medical oncologist Alice T. Shaw, M.D., Ph.D., to its Scientific Advisory Board. Dr. Shaw is the Chief of Strategic Partnerships at Dana-Farber Cancer Institute and oversees the collaborative efforts between researchers and the life sciences industry to help accelerate the development of new and innovative therapies for patients with cancer. Dr. Shaw was previously Vice President and Global Head of Translational Clinical Oncology at Novartis Institutes for BioMedical Research (NIBR) where she led early drug development in oncology for almost five years. Prior to Novartis, Dr. Shaw was the Director of the Center for Thoracic Cancers at Massachusetts General Hospital (MGH), the Paula O'Keeffe Endowed Chair of Thoracic Oncology at MGH, Co-Leader of the Dana-Farber/Harvard Cancer Center Thoracic Oncology Program, and Professor of Medicine at Harvard Medical School. During her time at MGH, Dr. Shaw studied resistance to targeted therapies in the lab and the clinic, and helped develop numerous targeted therapies for patients with oncogene-driven lung cancer. She was the overall principal investigator of multiple Phase 1, 2 and 3 studies, including registrational trials leading to FDA approval of crizotinib for ALK and ROS1-positive NSCLC, ceritinib, alectinib, and lorlatinib. Dr. Shaw was recently elected to the American Association for Cancer Research (AACR) Board of Directors. She was previously Co-Leader of the SU2C Lung Cancer Dream Team and a standing member of the US FDA Oncologic Drug Advisory Committee (ODAC). Financing Highlight On September 18, 2024, Nuvalent closed an upsized underwritten public offering of 5,750,000 shares of Class A common stock, which included 750,000 shares of Class A common stock sold pursuant to the exercise in full by the underwriters of their option to purchase additional shares, at a price to the public of $100.00 per share. The gross proceeds of the offering were approximately $575.0 million, before deducting underwriting discounts and commissions and other offering expenses. Upcoming Events Guggenheim's Inaugural Healthcare Innovation Conference: Management will be participating in a fireside chat on Wednesday, November 13, 2024, at 9:00 a.m. ET in Boston. Stifel 2024 Healthcare Conference: Management will be participating in a fireside chat on Tuesday, November 19, 2024, at 3:35 p.m. ET in NYC. A live webcast of each fireside chat will be available in the Investors section of Nuvalent's website at , and will be archived for 30 days following the conference. Third Quarter 2024 Financial Results Cash Position: Cash, cash equivalents and marketable securities were $1.2 billion as of September 30, 2024. The company's cash, cash equivalents and marketable securities as of September 30, 2024, inclusive of the proceeds from the $575 million public offering, are expected to extend the company's operating runway into 2028. R&D Expenses: Research and development (R&D) expenses were $60.6 million for the third quarter of 2024. G&A Expenses: General and administrative (G&A) expenses were $15.8 million for the third quarter of 2024. Net Loss: Net loss was $84.3 million for the third 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 clinical development programs for zidesamtinib, NVL-655 and NVL-330; the design and timing of the ALKAZAR trial, including alignment with the FDA regarding the design of the trial; the potential clinical effects of Nuvalent's product development candidates; the design and enrollment of Nuvalent's clinical trials, including for ARROS-1 and ALKOVE-1 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 its clinical trials or that enrollment will take longer than expected; unexpected concerns that may arise from additional data, analysis, or results obtained during 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 zidesamtinib or NVL-655 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, ALKOVE-1, ALKAZAR and HEROEX-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 Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2024, 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. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

药物名/剂型 Capivasertib包衣片剂 规格 160和200mg 给药途径 口服 Rx/OTC分类 （原研）Rx 适应症 RADENAME是用于治疗激素受体（HR）阳性、人类表皮生长因子受体2（HER2）阴性（定义为IHC 0或1+，或IHC 2+/ISH-）的成人患者，在内分泌方案中复发或进展后局部晚期或转移性乳腺癌。 申请人 AstraZeneca Pharmaceuticals LP 提交日期 2023.3.28 收到日期 2023.3.28 PDUFA目标日期 2023.11.28 审评部门 肿瘤部 审评完成时间 2023.10.30 通常名 Capivasertinib 拟定商品名 Trugap(capivasertib) 药理分类 激酶抑制剂 Type  C会议： Q1：企业拟定capivasertib原料药的粒度为XX，基于模型数据和科学数据，请问FDA是否同意？ 答：目前FDA无法根据有限的信息给到建议。会议资料不包括有关生产工艺描述、开发和控制策略的足够详细信息。 FDA建议在NDA时提供以下信息： 提供更多批次数据用于支持拟定原料药粒度分布标准 选定的原料药生产工艺更多的信息 证明在生产过程中没有观察到原料药晶型的变化。 最终的生产控制策略的充分性判断将在NDA时给到最终结论。 FDA承认，企业根据PBPK建模和科学理由提出了原料药粒度标准。在达成一致意见前，请收集更多XX数据。由于会议资料中不包括模型信息和数据，我们无法评论模型的适当性。 为了支持拟定的PBPK模型，我们建议提供一份完整的PBPK报告以及建模摘要，该摘要在分步过程中提供了建模策略的概述和建模过程的细节。 为了清楚的信息，最好包含流程图、决策树、演示或其他类似表示。PBPK模型开发和验证报告可以作为补充申请提交给IND进行审评。 如果您选择将其作为IND补充申请提交，请在补充申请的说明信中附上一份声明，即企业反馈请求和通知FDA，以便在提交后3个月内及时审评和反馈。 「解读」在PNDA之前沟通质量标准项目问题，比如原料药的粒度，说明粒度可能会是原料药的关键质量属性。但于递交的研究数据有限，企业使用了PBPK模型来拟定原料药粒度限度。 PBPK模型，‌即生理药代动力学模型（‌Physiologically Based Pharmacokinetic Model）‌，‌是一种基于生理学、‌生物化学和解剖学知识的药物动力学模型，使用此模型可以加速药物开发的速度。FDA建议提供更全面的模型数据和信息。由于药物还处于研发阶段，企业可以通过补充申请的方式递交更多的数据来与FDA讨论原料药粒度范围。 Q2：如会议资料信息所述，capivasertib包衣片剂的溶出不会受到处方或生产工艺参数变化的显著影响，并且体内性能已被证明不会受到溶出的显著影响（参考胶囊数据）。企业已经开发出一种溶出方法（包括900毫升pH1.2介质，标准溶出60rpm的USP 2设备），目前该方法用于临床放行和稳定性研究。后面更多信息被省略。 请问是否同意企业拟定的溶出方法用于后商业化产品的放行和稳定性测试？ 请问是否同意会议资料数据是否可以支持该溶出方法作为商业化QC方法？ 答：根据会议资料提交的有限信息确定这两个问题还为时过早。建议企业提供在NDA的资料中提供以下信息： 原料药在生理pH范围内的溶解度概况（pH1.2至6.8）。 拟定制剂在pH值1.2、4.5和6.8时的溶出曲线情况。 显示XX两者之间关系的数据 溶出方法的完整开发和验证数据 NDA期间补充递交关键临床批次/拟商业化批次的溶出数据用于拟定的溶出方法。针对溶出方法的意见最终会在NDA审评时给到。此外，请注意，NDA时生物豁免和处方/生产变更的体外桥接研究应通过溶出曲线比较和相似性测试来支持。 「解读」企业直接提出当前的溶出方法用于将来的商业QC方法，虽然没有充分的数据，这也许是一个策略性问题。 FDA给到了5点建议，包括原料药的溶解度，三种常用pH值的溶出曲线情况，溶出方法开发的全部数据及验证数据，关键临床批次和拟商业化批次之间的溶出相似情况。并且提到当发生处方工艺或产地变更时，需要有溶出曲线之间的对比情况。 企业提的这种问题非常好，当自身不能完全确定当下的溶出方法开发所需要的关键数据，何不向FDA学习一下，把自身不足的地方暴露出来，让FDA给你提建议。 Q3：基于Capivasertib制剂产品的良好稳定性和耐用性能，企业计划实施符合XX的控制策略，该建议包括产品放行测试使用NIR光谱进行含量和鉴定测试。 请问FDA是否同意以上提议？ 答：根据企业提供的会议资料，FDA不同意企业提出的质量控制策略。企业关于使用NIR光谱进行检测和鉴定测试的建议似乎是合理的。在我们审评NDA中提交的完整CMC数据后，将做出最终决定，其中应包括NIR方法开发、验证和其他支持数据。 根据会议中的有限信息，在放行/稳定性质量标准中删除微生物测试的提议还为时过早。以下是建议企业在NDA补充递交的信息，以证明可以免除对产品放行和稳定性的微生物测试理由： 确定并证明生产过程中可能影响原料药微生物负荷的关键控制点。定义包衣溶液的最大存放时间。 描述您确定的关键控制点的微生物监测和接受标准。应根据21 CFR 211.188在批次记录中记录是否符合为每个关键控制点确定的接受标准。 描述在关键控制点不符合微生物接受标准时采取的活动。 同时还需要提供如下信息： 对制剂代表性批次或稳定性批次进行的微生物极限测试结果。应验证测试方法的适用性（如果使用附录方法）或验证。 根据ICH Q1A第2.2.6节提供的时间表，稳定性批次的微生物极限测试结果。  「解读」企业非常大胆地提出使近红处（NIR）对药品进行含量和鉴别的测试。使用先进技术用于新药的质量控制需要小心，常常先进技术还没有得到广泛的使用，尤其是用于关键质量属性的检测。但用于鉴别是比较容易得到认可的。   制剂微生物检测是常见的，要想免除这个检项，需要有比较多的理由来证明其风险得到控制，比如微生物负荷的关键控制点的评估，如果出现超标情况下的活动，多批次和稳定性批次的检测结果。通常在NDA时很难得到同意微生物检项免除，可以采用商业化批次积累到一定程度后，再与监管机构沟通跳检的控制策略。 PNDA会议： Q1: 在NDA中，企业将递交出示XX一个HDPE瓶对于初始产品上市，申请人打算使用HDPE瓶XX。 因此，包括ICH稳定性在内的必要支持数据将在NDA中提供，以支持拟定的效期。PIL/包装设计也会在NDA时递时用于支持包装。 请问FDA是否同意？ 答：是的，在计划的NDA中提交稳定性数据以支持上市后批次的制剂包装系统批准后似乎是合理的。稳定性数据应包括长期12个月数据，加速6个月数据，包括两个规格制剂在HDPE瓶包装中。 「解读」由于在前面的Type- C会议中，企业基本将CMC的技术问题与FDA沟通完成，因此在PNDA时，CMC仅问了一个问题，关于商业化产品的包装。使用稳定性数据支持即可上市包装即可，没有特别的地方。 作者精彩原创集锦 1、创新药研发中原料药工艺与沟通交流常见难点 2、创新药研发中「制剂工」常见难点 3、创新药研发中「变更」相关难点 4、创新药研发中「质量分析控制」相关难点（1） 5、创新药研发中「质量分析控制」相关难点（2） 6、创新药研发难点分析与CMC研究策略探讨 7、《已上市化学药品药学变更研究技术指导原则（试行）原料药变更的问答》浅析 8、FDA：原料药中亚硝胺风险评估的最新观点 9、亚硝胺「传奇」：5年来监管和制药界的反思 10、【学习笔记】2023年度CDE审评报告 11、FDA审评：吡托布鲁替尼的药学变更桥接(完) 12、CDE：ICH指南在国内的实施概况 13、「解读」FDA审评：repotrectinib胶囊5次CMC会议内容 14、FDA：IND阶段CMC关注点 15、药品注册检验难点与建议 16、最新 FDA 人用药物亚硝胺杂质指南更新的「底层」参考 17、不同国家地区注册检验差异对比 曾文亮 博士   近20年药物研发经验，擅长新药研发与注册申报，近5年积累了近十个小分子新药中美IND申报成功和两个1类抗肿瘤新药上市申报成功经验。先后任职于某大型CRO医药研发公司、USP大中华区研发中心和港资原料药厂等，主导过MNC质量研究项目、USP各论更新和药厂QC实验室通过国家GMP检查和WHO审计。   受中国医药保健品进出口商会邀请在二十二届世界制药原料药中国展（CPHI）主导策划了“小分子创新药质量研究和注册策略”沙龙并发表主题演讲；同时受专业药学论坛邀请发表了《创新药质量研究要点和案例分析》、《中美新药申报沟通交流常见问题和案例分析》、《亚硝胺杂质的FDA和EMA控制策略》、《分析方法开发，验证和转移的统计学评价》和《FDA483中清洁验证的典型案例分析》等十余次主题演讲。   更多精彩内容可关注： ▲ 关注文亮频道，探索未知世界