Tarlatamab

2024一季度FDA准上市了10款新药，包括10款新分子实体（NME）和新生物实体（NBE），同比落后于2023年Q1的13个。下面着重分析几款比较重要的新药。 2024年FDA批准的新药一览Tevimbra（tislelizumab-jsgr）注射液公司：百济神州批准日期：2024年3月13日 治疗：食管癌PD-1抑制剂替雷利珠单抗Tevimbra （tislelizumab-jsgr） 是一种人源化免疫球蛋白 G4 （IgG4） 抗程序性细胞死亡蛋白 1 （PD-1） 单克隆抗体，用于治疗既往经系统化疗后不可切除、局部晚期或转移性食管鳞状细胞癌（ESCC）成年患者。此次批准基于一项全球 3 期 RATIONALE 302 试验结果。试验数据显示，与化疗相比，TEVIMBRA 延长了接受过系统治疗的患者的生存期。该研究对来自欧洲、亚洲和北美 11 个国家 132 个研究机构的 512 名患者进行了随机分组。在ITT人群中，TEVIMBRA治疗组的中位总生存期（OS）为8.6个月（95% CI：7.5，10.4），而化疗组为6.3个月（95% CI：5.3，7.0）（P=0.0001；危险比[HR]=0.70 [95% CI：0.57，0.85]）。Tevimbra也展现优于化疗的安全性。Tevimbra最常见（≥20%）的不良反应，包括实验室异常、血糖升高、血红蛋白降低、淋巴细胞减少、钠减少、白蛋白减少、碱性磷酸酶增加、贫血、疲劳、肝受损生物标志ALT与AST升高、肌肉骨骼疼痛、体重减轻和咳嗽。Tislelizumab 于 2023 年获得欧盟委员会批准用于治疗先化疗后的晚期或转移性 ESCC，并于2024 年2 月获得欧洲药品管理局 (EMA) 人用医药产品委员会 的积极意见，可用于治疗非小细胞肺癌的三个适应症。值得一提的是，百济神州已启动Tevimbra相关超过17项潜在的注册试验，其中11项3期随机试验和4项2期试验已获得积极结果。目前有40多项内部和外部组合研究正在进行中。据新闻稿，这次批准是替雷利珠单抗首次在美国获批。此外，除二线治疗ESCC外，目前替雷利珠单抗还有两项适应症的上市申请已经获得FDA受理，分别是联合化疗一线治疗ESCC和联合化疗一线治疗胃癌，预计完成审评时间分别为2024年7月和12月。首款NASH（非酒精性脂肪肝）治疗药物Rezdiffra公司：Madrigal Pharmaceuticals， Inc.批准日期：2024年 3 月 14 日 治疗：非酒精性脂肪性肝炎Resmetirom是一款“first-in-class”的每日一次、口服甲状腺激素受体（THR）-β选择性激动剂，与饮食和运动联合用于治疗伴有中至晚期肝纤维化（与 F2 至 F3 期纤维化一致）的非肝硬化非酒精性脂肪性肝炎 （NASH） 成人患者。这是获得FDA批准的首款NASH疗法，标志着该领域的一项重要里程碑。Madrigal针对Resmetiro开展的III期临床试验MAESTRO-NASH是首个在NASH患者中达到FDA提出的两个主要终点的3期临床试验。这项研究共纳入966名NASH患者，且纤维化阶段为F1B、F2或F3，按照1：1：1的比例随机分配接受每日一次80 mg或100 mg Rezdiffra或安慰剂治疗。在第52周时发现，分别有25.9%与29.9%的80 mg、100 mg Rezdiffra组患者实现NASH症状消除且纤维化未恶化，而安慰剂组中这一比例为9.7%。此外，80 mg与100 mg Rezdiffra组患者分别有24.2%与25.9%实现了纤维化至少一个阶段的改善，且NAFLD评分没有恶化。相比之下，安慰剂组仅有14.2%。这两项主要终点被认为很可能预测患者的临床益处。MAESTRO-NASH关键试验疗效结果安全性方面，各试验组的严重不良事件发生率相似：80 mg resmetirom组为11.8%，100 mg resmetirom组为12.7%，安慰剂组为12.1%。NASH是肝脏相关死亡的主要原因，并给全球医疗系统带来日益沉重的负担。据估计，到2026年，NASH市场将达到183亿美元。“first-in-class”口服小分子Voydeya片剂公司：阿斯利康批准日期：2024年 3 月 29 日 治疗：阵发性睡眠性血红蛋白尿症Voydeya （danicopan）是一种补体因子D抑制剂，用于治疗阵发性睡眠性血红蛋白尿症（PNH）成人患者的血管外溶血（EVH）状况。此次批准主要基于随机双盲ALPHA关键3期试验的积极结果。试验评估了Voydeya作为Ultomiris或Soliris附加疗法，对经历临床显著EVH（定义为血红蛋白≤9.5g/dL且绝对网织红细胞计数水平≥120x109/L）的PNH患者的疗效和安全性。结果显示，Voydeya达到了从基线到第12周血红蛋白变化的主要终点以及所有关键的次要终点，包括避免输血和慢性病治疗功能评估–疲劳（FACIT-Fatigue）评分的变化。ALPHA临床3期试验的结果显示，Voydeya总体耐受性良好，没有发现新的安全问题。Voydeya临床试验目前，Voydeya 已被FDA授予突破性疗法认定，并被欧洲药品管理局授予PRIME资格。不久前，Voydeya 已在日本获得批准 ，并被推荐在欧盟获得批准。其他国家的监管审评正在进行中。FDA Q2待批预览据统计，CDER在2024年第二季度即将审批的NME/NBE新药数量环比第一季度显著增加，达到了15种。2024年第二季度审批的NME/NBE | 数据来源：FDA官网、药智网2024年第二季度，有哪些关键的审批值得关注呢？结合BioPharma Dive等媒体报道，有2项关键的审批值得重点关注：包括Verona的用于治疗慢性阻塞性肺病的小分子药物ensifentrine(RPL554)和用于治疗晚期小细胞肺癌的双特异性抗体tarlatamab。Verona ：治疗COPD的EnsifentrineEnsifentrine是Verona Pharma开发的一款潜在“first-in-class”磷酸二酯酶3/4（PDE3/4）抑制剂，双重抑制机理使其能够凭借单个化合物同时实现支气管扩张和抗炎效果。去年6月28日，Verona 递交Ensifentrine的NDA申请。在两项3期临床试验ENHANCE-1和ENHANCE-2中，Verona评估了雾化ensifentrine作为维持疗法治疗COPD的效果。Ensifentrine在两项试验中均达到主要终点，患者肺功能获得统计显著和具有临床意义的改善。对ENHANCE-1和ENHANCE-2试验的合并数据分析显示，ensifentrine大幅度降低COPD恶化的风险。该药物PDUFA日期为2024年6月26日，如果获批，它可能成为10多年来治疗COPD的首款新机制疗法。安进：小细胞肺癌新药TarlatamabTarlatamab（AMG 757，塔拉妥单抗）是美国安进（Amgen）公司研发的一种双特异性T 细胞接合剂（BiTE）抗体，靶向DLL3和CD3。DLL3是SCLC提供的有前景的治疗靶点，大约85%至94%的患者在SCLC细胞的细胞表面表达DLL3，但在正常细胞中表达很少。Tarlatamab可结合癌细胞上的DLL3和T细胞上的CD3，将T细胞募集到小细胞肺癌细胞附近，激活T细胞杀伤肿瘤细胞。双特异性T细胞接合剂Tarlatamb作用机制示意图|来源：AmgenFDA于2023年12月授予tarlatamab BLA优先审评资格，用于治疗铂类化疗期间或之后疾病进展的晚期SCLC成人患者的三线或以上治疗。BLA是基于一项全球性2期临床试验DeLLphi-301的结果。结果显示, tarlatamab在铂类化疗期间或之后疾病进展的晚期SCLC患者中具有持久的抗肿瘤活性。安全性方面，与1期临床试验相比，未观察到新的安全性信号。Tarlatamab的PDUFA日期为2024年6月12日。如果获得批准，tarlatamab将成为首款用于治疗实体肿瘤的BiTE疗法。以上受到重点关注的FDA审批也足以反映当前的行业最新动向。细胞系产品查询投稿丨商务合作转载丨加交流群往期推荐视角 | 纸面之外的药明康德2023年报Claudin18.2ADC赛道群雄逐鹿：3家率先进入III期临床下一个10亿美元重磅炸弹选手"裁员潮”仍在加剧：2月多家药企裁员点击下方“药研网”，关注更多精彩内容

VANCOUVER, British Columbia, April 08, 2024 (GLOBE NEWSWIRE) -- Zymeworks Inc. (Nasdaq: ZYME), a clinical-stage biotechnology company developing a diverse pipeline of novel, multifunctional biotherapeutics to improve the standard of care for difficult-to-treat diseases, today announced five presentations including new data from its preclinical development-stage programs at the 2024 American Association for Cancer Research (AACR) Annual Meeting being held in San Diego, California April 5-10, 2024. “Our team is looking forward to share new data from our strong portfolio of multispecific antibody therapeutics and antibody-drug conjugates including ZW191, an anticipated 2024 IND candidate,” said Paul Moore, Ph.D., Chief Scientific Officer at Zymeworks. “These data provide important new insights highlighting the potential of our candidates to represent major advances in the treatment of cancer while also demonstrating the potential to develop a new generation of novel antibody-drug conjugates and multispecific antibody therapeutics.” Presentation Highlights ZW191 - a FRα-targeting antibody-drug conjugate with strong preclinical activity across multiple FRα-expressing indications Abstract: 1862 Session Category: Experimental and Molecular Therapeutics Session Title: Antibody-Based Technologies and New Inhibitors ZW191 is a FRα-targeting antibody-drug conjugate (ADC) differentiated by its novel antibody and novel topoisomerase I inhibitor payload. The compelling preclinical activity pro ZW191 development across multiple tumor types, including FRα-high/mid/low ovarian cancers and other FRα-expressing indications, including non-small cell lung cancer, endometrial cancer, and triple-negative breast cancer. An investigational new drug (IND) submission or foreign equivalent is planned for 2024. Key Results: Superior internalization, payload delivery, and spheroid penetration to other FRα-targeted multi-specific antibodies. Bystander active payload drives activity in settings with heterogeneous FRα expression. Well-tolerated, with a highest non-severely toxic dose of 60 mg/kg in non-human primates. Screening novel format antibodies to design bispecific ADCs that address target heterogeneity Abstract: 2052 Session Category: Experimental and Molecular Therapeutics Session Title: New Technologies Inter-patient and intra-tumoral target expression heterogeneity is an obstacle in the design of ADCs that target a single tumor associated antigen (TAA). While bystander active payloads mitigate intra-tumoral target heterogeneity, bispecific ADCs that target two different TAAs independently provide an additional approach to overcome limitations associated with the expression pro any single target antigen. Critical to this bispecific ADC approach however is identification of the optimal bispecific antibody format suited for payload delivery to two independent tumor antigens. To address this challenge a novel design and screening approach of bispecific ADCs was employed, using FRα and NaPi2b as an exemplary target pair, independently expressed across various cancer types. Key Results: Leveraging Azymetric™, bioconjugation, analytical mass spectrometry, and high throughput functional screening, a workflow for the rapid generation and characterization of bispecific ADCs was established to identify optimal format, paratope, and valency. A library of 48 bispecific ADC molecules co-targeting FRα and NaPi2b was rapidly generated covering multiple paratopes, antibody formats, and valency bins (1+1, 2+1, 2+2). Functional screening of the library across multiple cancer cell lines expressing FRα and/or NaPi2b revealed ranges in binding, internalization, and cytotoxicity that were dependent on epitope, valency, and format geometry. Development of three-dimensional cancer cell line spheroid models for the in vitro functional characterization of cytotoxic antibody-drug conjugates Abstract: 3127 Session Category: Experimental and Molecular Therapeutics Session Title: Antibody-Drug Conjugates Antibody-drug conjugates are an effective class of cancer therapeutics comprised of a linker-payload conjugated to a monoclonal antibody targeting a TAA, to enable the delivery of the cytotoxic payload to cancer cells. Current standard in vitro monolayer models do not sufficiently reflect in vivo tumor tissue complexity, particularly in consideration of the interaction between protein-based therapeutics such as antibodies in a three-dimensional (3D) environment. To address this, methodology to yield in vitro 3D spheroid models from cancer cell lines in a rapid, robust, and uniform manner was developed. Subsequently methods were integrated to evaluate the tissue penetration capability and cytotoxic activity of structurally distinct antibodies or ADCs bearing various payload classes targeting multiple TAAs. Key Results: A readily implementable method for the rapid generation of cancer cell line spheroids was established and applied to over 50 distinct immortalized cancer cell lines derived from more than 10 tissue types, demonstrating varying morphological features with a success rate of >95%. In vitro assays were developed to evaluate the spheroid penetration capability and 3D cytotoxic activity of multispecific antibodies and ADCs, enabling the interrogation of various antibody formats and payload classes. These 3D models and assays serve as valuable functional tools that provide improved translation between in vitro and in vivo activity, supporting the characterization of therapeutic ADC candidates and their pipeline advancement. TriTCE Co-Stim: A next generation trispecific T cell engager platform with integrated CD28 costimulation, engineered to improve responses in the treatment of solid tumors Abstract: 6719 Session Category: Immunology Session Title: Targeted ICEs Low T cell infiltration and T cell anergy are challenges associated with the treatment of solid tumors with conventional CD3-engaging bispecific T cell engagers (TCEs)1. By optimizing “Signal 1” (CD3) and “Signal 2” (CD28) within the context of a single molecule, co-stimulatory trispecific TCEs (TriTCE Co-Stim) have the potential to increase therapeutic responses beyond that achievable by conventional CD3-based TCEs by stimulating T cell proliferation in patients with poorly infiltrated tumors and providing more durable anti-tumor control by enhancing T cell activation. Key Results: Relative to comparator bispecific TCEs, the lead CLDN18.2 TriTCE Co-Stim molecule mediates enhanced T cell-mediated killing of tumor cells at low E:T ratios, exhibits sustained T cell mediated activity in serial challenge assays and supports superior antitumor activity in humanized models of gastric cancer. TriTCE Co-stim design facilitates obligate cis T cell binding and activation of CD28 that requires co-engagement of CD3 with no detectable cytokine levels observed upon incubation with human peripheral blood mononuclear cells in the absence of tumor target engagement. CLDN18.2 TriTCE Co-stim was well tolerated in non-human primates upon repeat dosing, with minimal peripheral cytokine elevations and no on-target histopathological changes observed. DLL3 TriTCE Co-Stim: A next generation trispecific T cell engager with integrated CD28 costimulation for the treatment of DLL3-expressing cancers Abstract: 6716 Session Category: Immunology Session Title: Targeted ICEs Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with a poor prognosis and high unmet medical need2. DLL3 is a therapeutic target that is selectively expressed in SCLC and other neuroendocrine tumors. Bispecific TCEs targeting DLL3 have entered the clinic and demonstrated encouraging anti-tumor activity in SCLC patients3,4; however, SCLC is frequently characterized by an immunosuppressive microenvironment and poor T cell infiltration, which may limit clinical activity of CD3 engagers5. DLL3 TriTCE Co-Stim is a TriTCE designed to optimally engage CD3 and CD28 to redirect and enhance cytotoxic T cell responses to DLL3-expressing tumor cells while maintaining a desired safety profile. This approach has the potential to improve outcomes for patients, especially those with poorly infiltrated tumors, by increasing the depth and durability of response. Using Zymeworks’ TriTCE Co-stim platform in combination with our Azymetric™️ and EFECT™️ technologies, we generated a panel of DLL3 TriTCE Co-Stim antibody formats and evaluated multiple formats, geometries, and paratope affinities, which allowed for optimization of selectivity and activity to promote a widened therapeutic index with enhanced anti-tumor activity. Key Results: Induces greater in vitro cytotoxicity and improves T cell proliferation and survival compared to bispecific TCEs. Displays no cross-linking of T cells and exhibits obligate cis T cell binding of CD28, requiring co-engagement of CD3. Mediates improved in vivo tumor regression in an established SCLC humanized xenograft model relative to a clinical benchmark TCE. Posters will be available at the time of presentation at the conference on the Company's website located at . About Zymeworks Inc. Zymeworks is a global biotechnology company committed to the discovery, development, and commercialization of novel, multifunctional biotherapeutics. Zymeworks’ mission is to make a meaningful difference in the lives of people impacted by difficult-to-treat cancers and other diseases. The Company’s complementary therapeutic platforms and fully integrated drug development engine provide the flexibility and compatibility to precisely engineer and develop highly differentiated antibody-based therapeutic candidates. Zymeworks engineered and developed zanidatamab, a HER2-targeted bispecific antibody using the Company’s proprietary Azymetric™ technology. Zymeworks has entered into separate agreements with BeiGene, Ltd. (BeiGene) and Jazz Pharmaceuticals Ireland Limited (Jazz), granting each exclusive rights to develop and commercialize zanidatamab in different territories. Zanidatamab is currently being evaluated in multiple global clinical trials as a potential best-in-class treatment for patients with HER2-expressing cancers. A Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) seeking accelerated approval for the HER2-targeted bispecific antibody zanidatamab as a treatment for previously treated, unresectable, locally advanced, or metastatic HER2-positive biliary tract cancer (BTC) has been submitted. If approved, zanidatamab would be the first HER2-targeted treatment specifically approved for BTC in the U.S. Zymeworks is rapidly advancing a deep pipeline of product candidates based on its experience and capabilities in both antibody-drug conjugates and multispecific antibody therapeutics across multiple novel targets in indications that represent areas of significant unmet medical need. In addition to Zymeworks’ wholly owned pipeline, its therapeutic platforms have been further leveraged through strategic partnerships with global biopharmaceutical companies. For information about Zymeworks, visit and follow @ZymeworksInc on X. Cautionary Note Regarding Forward-Looking Statements This press release includes “forward-looking statements” or information within the meaning of the applicable securities legislation, including Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements in this press release include, but are not limited to, statements that relate to the anticipated data presentations; Zymeworks’ preclinical pipeline; the potential therapeutic effects of zanidatamab and Zymeworks’ other product candidates; anticipated regulatory submissions and the timing thereof; Zymeworks’ clinical development of its product candidates and enrollment in its clinical trials; the ability to advance product candidates into later stages of development; and other information that is not historical information. When used herein, words such as “plan”, “believe”, “expect”, “may”, “anticipate”, “potential”, “will”, “continues”, and similar expressions are intended to identify forward-looking statements. In addition, any statements or information that refer to expectations, beliefs, plans, projections, objectives, performance or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking. All forward-looking statements are based upon Zymeworks’ current expectations and various assumptions. Zymeworks believes there is a reasonable basis for its expectations and beliefs, but they are inherently uncertain. Zymeworks may not realize its expectations, and its beliefs may not prove correct. Actual results could differ materially from those described or implied by such forward-looking statements as a result of various factors, including, without limitation: future clinical trials may not demonstrate safety and efficacy of any of Zymeworks’ or its collaborators’ product candidates; clinical trials may not demonstrate safety and efficacy of any of Zymeworks’ or its collaborators’ product candidates; any of Zymeworks’ or its partners’ product candidates may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; regulatory agencies may impose additional requirements or delay the initiation of clinical trials; the impact of new or changing laws and regulations; market conditions; inability to maintain or enter into new partnerships or strategic collaborations; and the factors described under “Risk Factors” in Zymeworks’ quarterly and annual reports filed with the Securities and Exchange Commission from time to time (copies of which may be obtained at and ). Although Zymeworks believes that such forward-looking statements are reasonable, there can be no assurance they will prove to be correct. Investors should not place undue reliance on forward-looking statements. The above assumptions, risks and uncertainties are not exhaustive. Forward-looking statements are made as of the date hereof and, except as may be required by law, Zymeworks undertakes no obligation to update, republish, or revise any forward-looking statements to reflect new information, future events or circumstances, or to reflect the occurrences of unanticipated events. Contacts: Investor Inquiries: Shrinal Inamdar Director, Investor Relations (604) 678-1388 ir@zymeworks.com Media Inquiries: Diana Papove Senior Director, Corporate Communications (604) 678-1388 media@zymeworks.com ___________________ 1 Arvedson T., et al. 2022. Targeting Solid Tumors with Bispecific T Cell Engager Immune Therapy (Vol. 6, pp.17-34). 2 Saltos, A. et al. 2020. Update in the biology, management, and treatment of Small Cell Lung Cancer (SCLC). Front. Oncol. 10, 1074 3 Eastland, J. DLL3 market opportunity and KOL discussion of HPN328. Harpoon Therapeutics. Corporate slide deck Sept 15 2023. 4 Paz-Ares. et al. 2023. Tarlatamab, a first-in-class DLL3-targeted bispecific T-cell engager, in recurrent small-cell lung cancer: an open-label, phase I study. J. Clin. Oncol. 41:2898-2903 5 Tian, Y. et al. 2019. Potential immune escape mechanisms underlying the distinct clinical outcome of immune checkpoint blockades in small cell lung cancer. J Hematol Oncol. 12:67