Gemtuzumab Ozogamicin

2023年是抗体偶联药物（ADC）交易爆发的一年，其中最为引人注目的是辉瑞公司以430亿美元收购Seagen，刷新了ADC领域的交易规模纪录。 ADC领域，辉瑞布局已久。在收购Seagen之前已有2款商业化产品，分别是Mylotarg和Besponsa，来自2009年以680亿美元收购的惠氏（Wyeth）。 收购Seagen后，辉瑞又获得4个已获批ADC产品，包括Adcetris、Padcev、Tivdak、以及合作伙伴荣昌生物开发上市的Disitamab vedotin。同时，Seagen还带来众多临床阶段的ADC管线。另外，辉瑞还从和铂医药引进了一款MSLN靶向ADC。 通过多次交易，辉瑞已成为拥有最多ADC产品的企业。首个ADC艰难的探索之路 追溯辉瑞研发ADC历史，可以发现FDA批准的首个ADC药物Mylotarg（吉妥单抗）就来自辉瑞，于2000年获FDA加速批准上市，用于CD33阳性AML患者。 不过，后来在临床试验未能继续证实这款药物的临床获益，并且显示其与化疗相比具有更高的毒性后，辉瑞公司主动将该药物撤出美国市场。 2017年，鉴于AML患者的迫切需求，Mylotarg重新获得美国FDA批准，用于AML的成人和2岁及以上儿童患者。 同年，辉瑞的第二款ADC药物Besponsa（inotuzumab ozogamicin，奥加伊妥珠单抗）在欧盟和美国获批上市，用于前体B细胞急性淋巴细胞性白血病。 Besponsa是一种靶向CD22的抗体药物偶联物，由Inotuzumab（伊珠单抗），通过可切割连接子，与ozogamicin偶联而成，属于第三代ADC产品。 但是Besponsa市场表现并不突出，2023年收入2.36亿美元，同比增长7.8%。 此外辉瑞还有不少临床前期的ADC管线，但是亮眼管线不多。430亿美元成为ADC富翁 Seagen是ADC领域的先驱公司，有着深厚的ADC研发底蕴，以及众多的ADC管线。 迄今为止全球获批上市的ADC药物共16个，Seagen公司拥有3个自主研发的上市ADC，（Adcetris、Padcev、Tivdak），1个合作开发的上市ADC（与荣昌生物联合开发的Disitamab vedotin），还有2款使用了Seagen的ADC技术（Polivy和Blenrep）。 完成收购Seagen后，辉瑞旗下的已上市ADC药物队伍增至6个，成为拥有最多ADC药物的公司。 图1 辉瑞已上市ADC产品（蓝色）图片来源：辉瑞肿瘤创新日活动PPT表1. 辉瑞已上市的ADC药物来源产品名称/活性成分靶点适应症上市日期2023年销售额（亿美元）2009年收购惠氏(Wyeth)Mylotarg吉妥珠单抗CD33急性髓系白血病上市：美国   2000.05（2010年撤市，2017.09重获FDA批准）——Besponsa奥加伊妥珠单抗CD22前体B细胞淋巴细胞白血病上市：欧洲  2017.07美国 2017.082.362023年收购Seagen（其中，维迪西妥单抗为Seagen从荣昌生物引进）Adcetris维布妥昔单抗TNFRSF8(CD30)淋巴瘤上市：美国  2011.0816.5Padcev Enfortumab vediotinNectin-4尿路上皮癌上市：美国  2019.1210.3Tivdak Tisotumab vedotin-tftvTF宫颈癌上市：美国  2021.090.64爱地希维迪西妥单抗HER2胃癌、尿路上皮癌上市：中国  2021.06未披露资料来源：辉瑞、博药整理Adcetris Adcetris（brentuximab vedotin）是Seagen的首发管线，于2011年首次获FDA批准，用于系统性间变性大细胞淋巴瘤（sALCL）和霍奇金淋巴瘤（HL）；于2020年5月，获得我国国家药品监督管理局（NMPA）批准，进入中国市场。 Adcetris是全球第一款获批上市的第二代 ADC 药物，在临床疗效和安全性上都优于第一代。该药由抗CD30单克隆抗体brentuximab和微管破坏剂MMAE(monomethyl auristatin E)，通过蛋白酶可裂解连接子(linker)连接。这一连接子在血液循环中保持稳定，被表达CD30的细胞摄入后释放MMAE。 Adcetris上市后商业化表现优秀，销售额逐年增长。2023年Adcetris销售额为16.5亿美元，同比增长12%。 2024年3月13日，辉瑞公布Adcetris联合疗法用于治疗复发/难治性弥漫性大B细胞淋巴瘤(R/R DLBCL)患者的3期试验积极数据。分析显示，与活性对照组相比，接受Adcetris联合疗法患者的总生存期(OS)获得显著改善。辉瑞将与FDA讨论相关的监管递交，如果成功获批，Adcetris 将从较小的市场拓展到DLBCL这一更大的应用市场。Padcev Padcev（enfortumab vediotin）是Seagen上市的第二款ADC药物，与安斯泰来联合开发，由靶向nectin-4的全人源性IgG1单抗与MMAE通过可裂解二肽连接子连接。 2019年12月，FDA加速审批Padcev上市，用于接受过PD-1/PD-L1抑制剂和铂类化疗药物的局部晚期或转移性尿路上皮癌治疗，EV-201试验结果显示，相较前期治疗方案Padcev的客观缓解率达44%（55/125）。2021年7月，Padcev获得了FDA完全批准，且将适应症扩展为接受过PD-1/PD-L1抑制剂治疗且不符合顺铂治疗的局部晚期或转移性尿路上皮癌患者。 2023年12月，FDA又提前批准PADCEV联合PD-1单抗K药（帕博利珠单抗）一线治疗局部晚期或转移性尿路上皮癌，成为全球首个获批的“PD-1+ADC”组合疗法。数据显示，联合疗法患者的OS是化疗组患者的近2倍，降低患者死亡风险达53%。图片来源：辉瑞肿瘤创新日活动PPT接下来，Padcev将继续向肌层浸润性膀胱癌（MIBC）进军，包括顺铂耐受和顺铂不耐受人群，Ⅲ期研究EV-304和EV-303的数据将在2026年和2027年读出。图片来源：辉瑞肿瘤创新日活动PPT自Padcev获批上市以来，销售额快速增长，2023年销售额迈过10亿美元门槛，达到10.3亿美元。辉瑞高管曾表示，Padcev具有形成“杰出拳头产品”的潜力，认为其年销售额或能超过30亿美元。后劲十足开发“下一代”ADC平台 在2月底举办的肿瘤创新日活动上，辉瑞宣布，完成Seagen后重组肿瘤部门，将肿瘤药物的开发和商业化纳入一个独立的部门，由公司前研发主管Chris Boshoff领导。 公司将进一步加强ADC药物的开发，正在开发的“下一代”ADC平台，将结合辉瑞的蛋白质工程、抗体设计能力项目和Seagen的ADC技术，瞄准新靶点、改进差异化有效载荷，推出业内最广泛的ADC产品组合。 辉瑞披露的重点推进的临床阶段和临床前的ADC项目有8款。 表2. 辉瑞重点推进的ADC管线来源产品名称靶点适应症研发阶段Seagen（并购）Sigvotatug vedotinIB6非小细胞肺癌临床Ⅲ期Felmetatug vedotinB7H4乳腺癌临床Ⅰ期PDL1V (PF-08046054)PD-L1实体瘤临床Ⅰ期CEACAM5C (PF-08046050)CEACAM5实体瘤临床Ⅰ期35C (PF-08046044)CD30淋巴瘤临床Ⅰ期35T (PF-08046045)CD30血液癌临床Ⅰ期PDL1iT (PF-08046037)PD-L1肺癌、头颈鳞癌、黑色素瘤临床前和铂医药（license in）MesoC2 (PF-08052666)MSLN实体瘤临床Ⅰ期资料来源：辉瑞、博药整理辉瑞在研ADC中多数来自Seagen的ADC平台，其中进展较快的几款使用与Seagen已上市ADC同样的蛋白酶可切割mc-vc-PABC连接子与MMAE组合，例如：Sigvotatug vedotin、Felmetatug vedotin、PDL1V (PF-08046054)。Sigvotatug vedotin Sigvotatug vedotin是一款潜在“first-in-class”整合素β6靶向ADC药物。该药通过对抗体的工程化改造让它对整合素β6（IB6）具有特异性，从而不与其他整合素结合，提高了该ADC的肿瘤选择性。目前正在进行2-3线未经紫杉醇治疗的非鳞状非小细胞肺癌人群的Ⅲ期临床试验，结果预计将在2026或2027年公布。 Felmetatug vedotin Felmetatug vedotin是一款B7-H4定向vedotin ADC，目前处于Ⅰ期临床阶段，初步结果（SGNB7H4V-001）显示Felmetatug vedotin在乳腺癌和其他实体瘤患者中显示出良好的抗肿瘤活性和可控的安全性。 PDL1V (PF-08046054) PDL1V是一款潜在“first-in-class”PD-L1靶向ADC。在临床前研究中，该药在PD-L1低表达或表达异质性高的动物模型中也展现出抗癌活性。在PD-L1阳性头颈鳞状细胞癌（HNSCC）患者中进行的Ⅰ期临床试验中，PF-08046054表现出有利的初步疗效。 在下一代ADC中，辉瑞对payload、linker都进行了改进，例如使用新型TOPO1为payload：CEACAM5C (PF-08046050)、35C (PF-08046044)、MesoC2 (PF-08052666)；新型Auristatin为payload：35T (PF-08046045)；新机制payload：PDL1iT (PF-08046037)。图片来源：辉瑞肿瘤创新日活动PPTCEACAM5C (PF-08046050) CEACAM5C是一款CEACAM5靶向ADC，由Seagen和赛诺菲联合开发，使用具有潜在“Best-in-Class”的TOPO1抑制剂，药物抗体比（DAR）为8。PF-08046050在CRC和肺癌PDX模型中展现出了显著的抗肿瘤效果。目前正在进行Ⅰ期剂量递增研究。图片来源：辉瑞肿瘤创新日活动PPT35C (PF-08046044) 35C 是一款CD30靶向ADC，采用了新的TOPO1抑制剂作为payload，临床前展现出更好的耐受性和质量窗口。 MesoC2 (PF-08052666) MesoC2是一款靶向人间皮素（MSLN）的ADC，来自和铂医药HarbourMice平台产生。2023年12月，辉瑞与和铂医药子公司诺纳生物达成全球权益合作，以5300万美元预付款和近期付款，引进该药。根据协议，诺纳生物获得5300万美元预付款，及最高10.5亿美元里程碑付款和特许权使用费。 35T (PF-08046045) 35T是一款新一代CD30靶向ADC，采用新一代Auristatin为payload，耐受性更好，目前已进入I期临床。 PDL1iT (PF-08046037) PDL1iT是一款新机制的ADC，旨在向肿瘤微环境递送免疫刺激TLR7激动剂，与PDL1抗体相比，PDL1iT表现出更好的疗效。辉瑞预计将在2024年提交IND申请，目标适应症包括NSCLC、HNSCC和黑色素瘤。图片来源：辉瑞肿瘤创新日活动PPT小结辉瑞在ADC领域拥有悠久的历史，曾在2000年推出全球首个ADC药物Mylotarg，但由于安全性和获益问题，2010年无奈撤市；2017年，辉瑞又推出Besponsa，同时带着改良版Mylotarg回归。但或许由于这两个ADC商业回报都不算出色，2023年辉瑞决定并购ADC领域的先驱公司Seagen。 Seagen的加入为辉瑞肿瘤板块注入了强大的活力，带来了三个已上市的ADC产品，其中两个的年销售额更是突破十亿美元大关。不仅如此，Seagen还为辉瑞带来了众多ADC在研管线，通过整合Seagen的研发资源和能力，辉瑞将进一步丰富其ADC产品组合。展望未来，ADC有望成为辉瑞的优势领域，和最重要的收入来源。 参考来源：1. 辉瑞肿瘤创新日活动PPT2. BiG生物创新社：Besponsa：辉瑞第二款ADC，这次“命运”会好点吗？3. Drugs and technology公众号：辉瑞(Pfizer)ADC管线4. 同写意：买下ADC巨头一年后：辉瑞与它的抗肿瘤王国来源 | 博药（药智网获取授权转载）撰稿 | 游游责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信） 阅读原文，是受欢迎的文章哦

Trem-cel and VCAR33ALLO clinical trial data expected in the second half of 2024VCAR33ALLO granted Fast Track and Orphan Drug Designation by U.S. Food & Drug Administration Cash runway extends into second half of 2025 CAMBRIDGE, Mass., March 20, 2024 (GLOBE NEWSWIRE) -- Vor Bio (Nasdaq: VOR), a clinical-stage cell and genome engineering company, today reported financial results for the three-month period and full year ended December 31, 2023, and provided a business update. “We are very pleased with the foundational progress we made in 2023. Building on this, we expect 2024 to be an exciting year in which we demonstrate the Vor Bio approach to be instrumental in reducing the disease burden of AML, a devastating cancer where we desperately need effective treatment options,” said Dr. Robert Ang, Vor Bio’s President and Chief Executive Officer. Corporate Updates Multiple patients expected to be dosed with VCAR33ALLO in the first half of 2024; initial data anticipated in second half of 2024 VBP301, a Phase 1/2, multicenter, open-label, first-in-human study of VCAR33ALLO, is a transplant donor-derived anti-CD33 CAR-T cell therapy for patients with AML who have relapsed following a standard-of-care or trem-cel transplant. The first patient was dosed in January 2024, and multiple patients are expected to be dosed in the first half of 2024. We anticipate initial data in the second half of 2024.The U.S. Food & Drug Administration (FDA) has granted Fast Track Designation and Orphan Drug Designation to VCAR33ALLO. The FDA Fast Track process aims to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need. Orphan Drug Designation entitles companies to development incentives including tax credits for clinical testing, prescription drug user fee exemptions and seven-year marketing exclusivity in the event of regulatory approval. VCAR33ALLO is manufactured from lymphocytes collected from the patient’s original transplant donor, generating a CAR-T cell therapy that is exactly matched to the recipient’s engrafted blood system. By using healthy transplant donor cells as the starting material to produce VCAR33ALLO, the CAR-T cells have a more stem-like phenotype, leading to greater potential for expansion, persistence, and anti-leukemia activity compared to a product derived from a patient’s own lymphocytes. VBP101 clinical trial of trem-cel enrolling steadily, with the next data readout expected in the second half of 2024 Dose escalation of Mylotarg to 1.0 mg/m2 has commenced with multiple patients now treated.Patients receiving a trem-cel transplant who become measurable residual disease (MRD) positive or relapse have the option to receive induction-course Mylotarg or VCAR33ALLO.The Company expects to report further engraftment and protection data from the VBP101 clinical trial in the second half of 2024.The latest data update from VBP101, the Phase 1/2a clinical study of trem-cel, was presented at the ASH Annual Meeting on December 10, 2023, showing primary neutrophil engraftment in all eight patients and hematologic protection from acute Mylotarg toxicity through repeat doses. Trem-cel is a shielded transplant in development for patients with AML, in which healthy transplant donor cells are genetically engineered by removing CD33, with the potential to enable targeted therapies such as Mylotarg and CD33-targeted CAR-T therapy post-transplant, while avoiding on-target toxicities. Continued progress on dual-targeted CAR-T and multiplex engineering approach The Company continues to make progress with a dual-specific CAR-T targeting CD33 and CLL-1, two of the most promising antigens in AML. This is being paired with a hematopoietic stem cell (HSC) multiplex engineering approach, which could allow removal or modification of these two genes. The Company has demonstrated in vitro proof of concept for this approach. IND-enabling work is progressing for the Company’s dual-specific CAR-T with key in vivo proof-of-concept experiments underway. Upcoming Milestones Trem-cel clinical data update expected in the second half of 2024VCAR33ALLO clinical data update expected in the second half of 2024 Fourth Quarter and Full Year 2023 Financial Results Cash Position: Cash, cash equivalents and marketable securities were $137.2 million as of December 31, 2023, which is projected to fund operations into the second half of 2025. Research & Development (R&D) Expenses: R&D expenses for the fourth quarter of 2023 were $20.9 million, compared to $17.1 million for the fourth quarter of 2022, and for the year ended December 31, 2023, were $94.3 million, compared to $64.6 million for the year ended December 31, 2022. The increase in R&D expenses was attributable primarily to an increase in clinical trial, manufacturing and personnel expenses, and the execution of our non-exclusive license agreement with Editas Medicine.General & Administrative (G&A) Expenses: G&A expenses for the fourth quarter of 2023 were $7.2 million, compared to $7.7 million for the fourth quarter of 2022, and for the year ended December 31, 2023, were $31.7 million, compared to $28.9 million for the year ended December 31, 2022. The increase in G&A expenses was primarily attributable to an increase in personnel expenses, including an increase in share-based compensation expense.Net Loss: Net loss for the fourth quarter of 2023 was $26.3 million, compared to $23.9 million for the fourth quarter of 2022, and for the year ended December 31, 2023, was $117.9 million, compared to $92.1 million for the year ended December 31, 2022. About Vor BioVor Bio is a clinical-stage cell and genome engineering company that aims to change the standard of care for patients with blood cancers by engineering hematopoietic stem cells to enable targeted therapies post-transplant. For more information, visit: www.vorbio.com. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The words “aim,” “anticipate,” “can,” “continue,” “could,” “design,” “enable,” “expect,” “initiate,” “intend,” “may,” “on-track,” “ongoing,” “plan,” “potential,” “should,” “target,” “update,” “will,” “would,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Forward-looking statements in this press release include Vor Bio’s statements regarding the potential of its product candidates to positively impact quality of life and alter the course of disease in the patients it seeks to treat, the timing an pace of patient enrollment and dosing in clinical trials and the availability of data therefrom, the expected safety profile of its product candidates, its intentions to use VCAR33ALLO in combination with trem-cel as a Treatment System, its potential upcoming milestones, its cash runway and expected capital requirements. Vor Bio may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of Vor Bio’s product candidates; availability and timing of results from preclinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products; the success of Vor Bio’s in-house manufacturing capabilities and efforts; and availability of funding sufficient for its foreseeable and unforeseeable operating expenses and capital expenditure requirements. These and other risks are described in greater detail under the caption “Risk Factors” included in Vor Bio’s most recent annual or quarterly report and in other reports it has filed or may file with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Vor Bio expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise, except as may be required by law. Condensed Consolidated Balance Sheet Data(in thousands) December 31, December 31, 2023 2022 Cash, cash equivalents and marketable securities $137,175 $230,245 Total assets 198,126 299,366 Total liabilities 47,402 48,759 Total stockholders' equity 150,724 250,607 Consolidated Statement of Operations(in thousands, except share and per share data) Three Months Ended Twelve Months Ended December 31, December 31, 2023 2022 2023 2022 Operating expenses: Research and development $20,897 $17,062 $94,315 $64,550 General and administrative 7,227 7,663 31,721 28,868 Total operating expenses $28,124 $24,725 $126,036 $93,418 Loss from operations $(28,124) $(24,725) $(126,036) $(93,418)Other income: Interest income 1,863 814 8,173 1,324 Total other income 1,863 814 8,173 1,324 Net loss $(26,261) $(23,911) $(117,863) $(92,094)Net loss per share attributable to common stockholders, basic and diluted $(0.39) $(0.53) $(1.75) $(2.33)Weighted-average common shares outstanding, basic and diluted 67,839,463 45,394,089 67,191,973 39,551,420 Contact:Investors & MediaSarah Spencer +1 857-242-6076sspencer@vorbio.com