Bortezomib

对于冻干制品的性状本人经历了三重阶段，每重阶段都有着不一样的体会。 第一重阶段：追求自制制剂与参比制剂性状的绝对一致，如参比制剂为白色疏松块状物，自制制剂同样为白色疏松块状物，这一阶段只注重于形似而忽略了神，导致有些产品形似而神不似； 第二重阶段：不再追求自制制剂与参比制剂性状的绝对一致，转而保证自制制剂符合质量标准，却忽略了如有些产品萎缩、塌陷，但是并不影响其符合质量标准，但是产品萎缩、塌陷又属于不可控的处方工艺因素，可能设备性能的降低、设备变更、场地转移、批量扩大等变化都会导致产品不再符合质量标准； 第三重阶段：更加注重神似，让质量源于设计的理念深入处方工艺的每一处，把握好产品冻干工艺的设计空间，执行好产品冻干工艺的内控空间。 药饼萎缩、塌陷 药饼萎缩、塌陷是指冻干后的药饼出现了较明显的收缩，产品失去了原有的支撑结构，同样也会失去良好的外观，药饼萎缩可能会导致产品的复溶时间增加、水分增大、稳定性变差，药饼萎缩、塌陷有时侯可能并不会导致产品的理化性质发生显著改变，但是药饼萎缩、塌陷表明了产品处方工艺的不可控性，在产品开发过程中需要尽可能避免药饼萎缩、塌陷的出现。 1、药饼萎缩、塌陷发生的阶段？ 药饼萎缩多发生在一次干燥阶段和二次干燥阶段，较少发生在产品贮存阶段。一次干燥阶段，当产品的温度高于塌陷温度，升华通道被融化封闭，热量在固-冰交界面大量聚集，这时的药饼可能会发生萎缩。二次干燥阶段当产品的温度高于其玻璃态转化温度，这时的药饼也可能会发生萎缩。产品贮存阶段，贮存温度高于产品的玻璃态转化温度也可能会发生萎缩。 2、如何避免药饼萎缩、塌陷的发生？ 冻干产品的水分其实是个神奇的物质，产品的玻璃态转变温度与产品的水分密不可分，当产品水分高时，产品的玻璃态转变温度会变低，产品水分低时，产品的玻璃态转变温度会变高。 一次干燥阶段的前中期，由于产品的水分含量高，需要大量热能用于水汽升华，这时板层给予的热能不会聚集。一次干燥阶段的后期，随着水汽的不断升华，这时产品上部的干燥层逐渐变厚、产品的水分含量变低，水汽升华速度变慢，如果这时板层给予的热能来不及被水汽升华所完全吸收，热量会在固-冰交界面大量聚集，使固-冰交界面产品的温度高于塌陷温度，升华通道被融化封闭，热量进一步大量聚集，药饼可能会发生萎缩。 二次干燥阶段前中期，由于产品的水分含量高，产品的玻璃态转变温度低，这时如果给与产品大量热能，热能来不及被水汽升华所完全吸收，热量蓄积导致产品的温度高于玻璃态转变温度，药饼可能会发生萎缩。 贮存阶段出现产品萎缩极为少见，可能是由于产品初始水分过高、胶塞含水量同样过高，拉低了产品的玻璃态转化温度，导致了贮存温度高于产品的玻璃态转化温度。 3、实例解析 产品：药物类型：小分子化药，西林瓶：15ml，药液：5ml； 冻干工艺1： 产品普遍都发生了明显的萎缩，外观成型性较差，萎缩、塌陷严重的药物不易溶解，怀疑药饼萎缩可能发生在一次干燥阶段，决定优化冻干工艺。 冻干工艺2： 产品未再发生萎缩，外观成型性良好。 理化性质检测： 碎瓶 之前做过一个项目，小试阶段冻干出箱后发现部分制品出现了碎瓶现象，冻了大概有四五十瓶，碎瓶的有七八瓶，刚开始怀疑可能是瓶子在生产、运输途中受了内伤，随即更换了不同厂家相同规格的瓶子重新试验，结果碎瓶情况并未有所改善，又怀疑可能是清洗过程中冷热交替使瓶子受到了损伤。 为了验证这一猜想，将瓶子放入100℃烘箱2个小时，随即放入室温水中，也未出现碎瓶现象。最终猜测碎瓶现象的出现最大可能还是在冻干工艺，预冻阶段由于应力的增大导致了瓶子破碎。 1、碎瓶发生的阶段？ 冻干工艺的预冻阶段由于应力的增大可能导致瓶子破碎。 2、如何避免碎瓶的发生？ ①：通过降低结晶性辅料的浓度从而降低预冻阶段应力的变化对瓶子的影响。 ②：通过降低瓶装药液的高度从而降低预冻阶段应力的变化对瓶子的影响。 3、实例解析 产品：药物类型：小分子化药，西林瓶：20ml，瓶身直径28mm：药液：10ml； 冻干工艺1： 由于药液体积多、药液高度高，冻干工艺1为了提高冻干效率、缩短冻干周期，在预冻阶段采用了退火工艺，冻干结束出箱时约有五分之一的制品出现了碎瓶，怀疑可能是药液中结晶性辅料的浓度较高，加之药液的高度同样较高，预冻阶段退火过程中结晶性辅料得以充分的结晶，对瓶子产生了较大的应力，导致出现了碎瓶。 产品：药物类型：小分子化药，西林瓶：20ml，瓶身直径28mm：药液：10ml；　　　 冻干工艺2： 冻干工艺2采用了常规冻干工艺，冻干结束出箱时还是偶尔可以见到碎瓶，即使放弃采用退火工艺，碎瓶现象仍然无法杜绝，由瓶子破碎的位置可以看出应力对瓶底、瓶身有较大影响，怀疑可能是由于药液的高度较高，预冻时应力对瓶底、瓶身集中释放，造成一些位置的小瓶出现了破损。 产品：药物类型：小分子化药，西林瓶：30ml，瓶身直径32mm：药液：10ml； 冻干工艺3： 冻干工艺3虽然同样采用了常规冻干工艺，但是将西林瓶：20ml，瓶身直径28mm更换成了西林瓶：30ml，瓶身直径32mm，有效的降低了药液的高度，冻干出箱时未出现碎瓶，通过降低药液的高度有效的降低了预冻时应力对瓶底、瓶身的影响，解决了碎瓶这一问题。 理化性质检测： 产品出现萎缩、塌陷显示出了处方工艺的不可控性，除非是一些成型性不好的物料，否则产品一旦出现萎缩、塌陷等问题要引起我们的重视，可能检测时即使萎缩、塌陷的产品仍然符合质量标准，但是随着设备性能的下降、设备变更、场地转移、批量扩大等变化可能会导致产品不再符合质量标准。产品出现碎瓶更显示出了处方工艺的不可控性，碎瓶的出现可能会导致玻屑飞溅入周围产品中，影响输注使用的安全性。 我们应该在设计处方工艺之初就遵循质量源于设计的理念，把握好产品的设计空间，执行好产品的内控空间，保证产品的质量标准＞设计空间＞工艺空间＞内控空间，让质量源于设计的理念深入处方工艺的每一处。 来源：药事纵横 参考文献： 1.李娜, 桂江洋, 史宣宇. 一种注射用硼替佐米冻干粉针的冻干工艺:, CN109453125A[P]. 2019. 2.真空冷冻干燥-预冻方式的选择，大3B教主. 3.真空冷冻干燥-预冻番外篇2-应力的影响，，大3B教主. 4.周新丽,翁宇,陈光明.药品冷冻干燥过程的退火机理分析[J].化学工程,2005(06):4-7. ↓关注药通社，洞见行业趋势↓ 投稿/企业合作/内容沟通：华籍美人（Ww_150525） *添加请注明备注及来意

Initiated rolling NDA submission for zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC, with target completion in the third quarter of 2025 Initiated ALKAZAR Phase 3 randomized, controlled trial of neladalkib for front-line ALK-positive NSCLC Topline pivotal data for neladalkib for TKI pre-treated patients with advanced ALK-positive NSCLC expected by year-end 2025 Preliminary data for neladalkib in patients with ALK-positive solid tumors beyond NSCLC to be presented at the ESMO Congress 2025 Jason Waters, MBA, promoted to Senior Vice President, Commercial CAMBRIDGE, Mass., Aug. 7, 2025 /PRNewswire/ -- Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, today outlined pipeline and business achievements, reiterated key anticipated milestones, and reported second quarter 2025 financial results. "With the initiation of our rolling NDA submission for zidesamtinib in TKI pre-treated advanced ROS1-positive NSCLC and the dosing of the first patient in our ALKAZAR Phase 3 trial of neladalkib in TKI-naïve advanced ALK-positive NSCLC, 2025 has been marked by transformative milestones towards our mission to discover, develop, and deliver precisely targeted therapies for patients with cancer," said Alexandra Balcom, Chief Financial Officer of Nuvalent. "We remain focused on continuing to deliver value that is grounded in prioritizing patient impact with topline pivotal data from our ALKOVE-1 trial of neladalkib in TKI pre-treated advanced ALK-positive NSCLC expected by year-end and the first report of preliminary data for other ALK-positive solid tumors at ESMO, continued momentum in our HEROEX-1 trial of NVL-330 for HER2-altered NSCLC, and a robust discovery pipeline." "In parallel to our continued execution against development and regulatory milestones, we are actively building the strong commercial infrastructure needed to achieve our vision of becoming a fully integrated, commercial-stage biopharmaceutical company," said James Porter, Ph.D., Chief Executive Officer of Nuvalent. "Today we are proud to announce the promotion of Jason Waters to Senior Vice President, Commercial, in recognition of his leadership in establishing our commercial strategy and shaping a launch-ready organization that extends from our founding values of Patient Impact, Empowerment, and Collaboration. Supported by a growing team and strong cash runway into 2028, we believe we are well-positioned to achieve our goals." Recent Pipeline Achievements and Anticipated Milestones ROS1 Program The company has initiated its rolling NDA submission for zidesamtinib, a novel ROS1-selective inhibitor, in tyrosine kinase inhibitor (TKI) pre-treated patients with advanced ROS1-positive non-small cell lung cancer (NSCLC). The FDA agreed to accept the NDA for participation in the Real-Time Oncology Review (RTOR) pilot program, which facilitates earlier submission of topline efficacy and safety results prior to the submission of the complete application, to support an earlier start to the FDA's evaluation of the application. Completion of the NDA submission is targeted for the third quarter of 2025. The NDA submission is based on positive pivotal data for TKI pre-treated patients with advanced ROS1-positive NSCLC enrolled in the global ARROS-1 Phase 1/2 clinical trial. These data were recently reported along with preliminary data from the ongoing Phase 2 TKI-naïve cohort of ARROS-1, in which a total of 104 patients had been enrolled as of June 16, 2025. The company continues to engage with the FDA on potential opportunities for line-agnostic expansion. ALK Program Nuvalent recently announced the dosing of the first patient in ALKAZAR, the company's global Phase 3 randomized, controlled trial designed to evaluate neladalkib for the treatment of patients with TKI-naïve ALK-positive NSCLC. Patients will be randomized 1:1 to receive neladalkib monotherapy or alectinib monotherapy, a front-line standard of care, reflecting input from collaborating physician-scientists and alignment with global regulatory agencies. Evaluation of neladalkib is ongoing in the ALKOVE-1 Phase 1/2 trial for patients with advanced ALK-positive NSCLC and other solid tumors: The company expects to report pivotal data for TKI pre-treated patients with advanced ALK-positive NSCLC by year-end 2025. The company will present preliminary data from the Phase 2 exploratory cohort for patients with ALK-positive solid tumors beyond NSCLC during a poster presentation at the European Society for Medical Oncology (ESMO) Congress 2025, taking place October 17-21, 2025, in Berlin, Germany. Details of the presentation are as follows: Title: Neladalkib (NVL-655) efficacy and safety in patients with ALK-positive solid tumors in the ALKOVE-1 study Presentation Number: 972P Session Category: Poster Session Session Title: Developmental Therapeutics Presentation Date and Time: Sunday, October 19, 2025, 12:00 – 12:45 CEST Location: Hall 25 Presenter: Benjamin J. Solomon, MBBS, Ph.D. (Peter MacCallum Cancer Centre, Melbourne, Australia) HER2 Program Enrollment is ongoing in the HEROEX-1 Phase 1a/1b clinical trial evaluating the overall safety and tolerability of NVL-330 for pre-treated patients with HER2-altered NSCLC. Additional objectives include determination of the recommended Phase 2 dose, characterization of NVL-330's pharmacokinetic profile, and preliminary evaluation of anti-tumor activity. The company expects to continue to progress the HEROEX-1 trial throughout 2025. Business Updates Jason Waters, MBA, Promoted to Senior Vice President, Commercial: Jason joined Nuvalent in 2024, bringing more than 20 years of experience in biopharma, and 15 years in commercial oncology focused on product launches and commercialization. Most recently, Jason served as the Head of Commercial at Mersana Therapeutics, where he led launch preparedness efforts and companion diagnostic strategy for the market entry of a novel antibody-drug conjugate. Prior to this, he held various commercial leadership roles at GSK, including Field Vice President and US Brand Lead for ZEJULA®, where he led the integration and multiple launches of the brand following the acquisition of TESARO in acquisition in 2019. At TESARO, Jason served as the Global Brand Lead for ZEJULA®, coordinating its EU launch. Earlier in his career, Jason was Senior Director, Sales Strategy at Takeda Oncology, where he contributed to the launches of subcutaneous VELCADE® and NINLARO®. He also held various sales, operational, and leadership roles at Sanofi, Aventis, and Abbott Laboratories. Christy Oliger Appointed to Board of Directors: Nuvalent announced the appointment of Christy Oliger to its board of directors. Ms. Oliger brings more than 30 years of commercial and business experience in the pharmaceutical and biotechnology industry to the Nuvalent board. Most recently, Ms. Oliger served as Senior Vice President of the Oncology Business Unit at Genentech, where she was responsible for all commercial activities in the U.S. During her 20-year tenure at Genentech, Ms. Oliger held a number of senior leadership roles in both commercial and research and development across a variety of therapeutic areas, including oncology, neurology, rare disease, respiratory, dermatology and immunology. Prior to Genentech, she held management positions at Schering-Plough. Second Quarter 2025 Financial Results Cash Position: Cash, cash equivalents and marketable securities were $1.0 billion as of June 30, 2025. Nuvalent continues to believe its existing cash, cash equivalents and marketable securities will be sufficient to fund its current operating plan into 2028. R&D Expenses: Research and development (R&D) expenses were $80.9 million for the second quarter of 2025. G&A Expenses: General and administrative (G&A) expenses were $23.7 million for the second quarter of 2025. Net Loss: Net loss was $99.7 million for the second quarter of 2025. 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, NDA submissions and FDA product approvals; the preclinical and clinical development programs for zidesamtinib, neladalkib and NVL-330; the potential benefits and effects of Nuvalent's product development candidates; the design and enrollment of the ARROS-1, ALKAZAR, ALKOVE-1, and HEROEX-1 trials; the potential of Nuvalent's pipeline programs, including zidesamtinib, neladalkib 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 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. 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 quarter ended March 31, 2025, 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