Iconic Therapeutics, Inc.

Exelixis said its tissue factor (TF)-targeting antibody-drug conjugate “is unlikely to improve upon” tisotumab vedotin—an approved TF-focused ADC marketed for cervical cancer as Tivdak. Exelixis is giving up on its tissue factor (TF)-targeting antibody-drug conjugate after concluding the candidate was unlikely to best Pfizer and Genmab’s Tivdak.The biotech had been evaluating the ADC, dubbed XB002, in the phase 1 JEWEL-101 trial in advanced solid tumors and said that it would unveil the data “at a later date.” But, based on what the company has seen so far, Exelixis said the compound “is unlikely to improve upon” tisotumab vedotin—an approved TF-focused ADC marketed for cervical cancer as Tivdak—“or other competitor TF-targeting ADCs currently in development.”Resources from the XB002 program will be reallocated to the late-stage tyrosine kinase inhibitor zanzalintinib, as well as the phase 1 USP1 inhibitor XL309 and the biotech’s “growing pipeline,” Exelixis said in its second-quarter earnings release.Exelixis isn’t ready to give up on ADCs quite yet. The company pointed out that XB371, its ADC consisting of a topoisomerase payload conjugated to a TF-targeting monoclonal antibody, remains in preclinical development.In his statement to accompany the release, Exelixis CEO Michael Morrissey, Ph.D., focused the spotlight on Cabometyx, which is already approved for renal cell carcinoma, hepatocellular carcinoma and thyroid cancer. The Ipsen-partnered tyrosine kinase inhibitor brought in $433.3 million in net U.S. revenues in the second quarter and the FDA is mulling an application to approve the drug in advanced neuroendocrine tumors (NETs). “We’re actively preparing for launch and excited at the prospect of bringing this new treatment option to previously treated advanced NET patients with high unmet medical need,” Morrissey said.“At the same time, we are prioritizing our clinical pipeline with plans to initiate a new phase 3 pivotal trial for zanzalintinib in NET, advance phase 1 efforts for XL309 and XB010, and discontinue development of XB002,” the CEO added.“In our view, Exelixis enters 2024 at an inflection point, in which the growth of its flagship Cabometyx franchise is stabilizing while pipeline programs, especially zanzalintinib, are holding increasing responsibility to offset Cabometyx’s market exclusivity expiry in 2031,” William Blair analysts said in an Aug. 7 note.“In the midterm, NETs and [metastatic castration-resistant prostate cancer] could emerge as material growth opportunities for the franchise,” the analysts added.It’s been a year of change at Exelixis, which laid off 175 employees—equivalent to around 13% of its workforce—in January as part of a broader restructuring aimed at “concentrate[ing] R&D resources to advance our emerging pipeline.”At the time, that strategy included progressing XB002 through a phase 1 trial. Exelixis had licensed the ADC from Iconic Therapeutics back in 2020, citing preclinical data that supported the asset’s “best-in-class potential in treatment of solid tumors.”

作者｜大道至简 前言 宫颈癌，是最常见的女性生殖道恶性肿瘤。 2023年ICO/IARC中国HPV（人乳头瘤病毒）和相关疾病报告显示，中国女性约98%的宫颈癌由高危型HPV导致。2020年在中国15~44岁女性中，宫颈癌发病率和死亡率均居女性肿瘤第三位，2020年我国宫颈癌新发病例数约11万例，死亡病例约6万例。 宫颈癌变成浸润癌以后，发展很快，如果不经治疗，患者可在2-5年内死亡。对于难治性、复发性或转移性宫颈癌，临床推荐的一线标准治疗预后较差，客观缓解率通常不足15%，亟需更优的治疗方案。 鉴于此，首款用于宫颈癌治疗ADC，由Seagen和Genmab公司合作开发的Tivdak®，于2021年取得加速批准在美国上市。 今天，我们就来了解一下。   01   首个靶向组织因子（TF）的宫颈癌ADC 图1：Tivdak®包装，来源：Tivdak官网 Tivdak® (tisotumab vedotin）最早由Seagen和Genmab公司联合开发，2021年9月20日获得FDA加速批准上市。2024年4月被完全批准用于治疗化疗期间或化疗后疾病进展的复发性或转移性宫颈癌。 它是首个批准用于宫颈癌的ADC，也是目前唯一一款靶向组织因子（TF）的上市ADC。 Tivdak®(tisotumab vedotin）为注射用无菌、不含防腐剂的白色至灰白色冻干粉末，规格为40mg/瓶，稀释后输注。 每毫升含非活性成分：d-甘露醇30mg、l-组氨酸2.11mg、1-组氨酸单盐酸盐3.44mg和蔗糖30mg，pH值为 6.0。 推荐剂量为2mg/kg，体重≥100kg的病人，最高剂量为200mg；每3周一次，每次静脉滴注超过30分钟，病情恶化或出现不可接受的毒性调整用药或停药。   02   为什么选择组织因子（TF）为靶点？ 组织因子（TF，Tissue Factor）：又称凝血因子Ⅲ，是一个由263个氨基酸残基组成的跨膜单链糖蛋白。许多研究文献报道，TF在多种实体瘤中存在阳性表达，宫颈癌阳性率100%，非小细胞肺癌为34%-88%，子宫内膜癌为14%-100%，前列腺癌47%-75%，卵巢癌75%-100%，食管癌43%-91%，膀胱癌78%。TF的这种高表达可能有助于肿瘤细胞的生长和存活、血管生成和转移。因此，被认为是一个极具潜力的肿瘤治疗靶点。 图2：tisotumab vedotin结构图，来源：Tivdak说明书 Tivdak® (tisotumab vedotin）由单抗tisotumab和小分子毒性药物vedotin（MMAE），通过可切割连接子偶联而成。 Tisotumab：人源抗TF的IgG1κ单抗，在哺乳动物细胞群中国仓鼠卵巢中产生。 lvedotin（MMAE）：是一种天然的微管蛋白抑制剂，系Dolastatin 10的衍生物单甲基auristatin E，具有破坏细胞微管的作用。 连接子：采用了蛋白酶敏感的可切割连接子缬氨酸-瓜氨酸（Val-Cit）。 Tivdak分子量约153kDa，每个抗体平均结合的4个MMAE。 作用机制：Tivdak与表达TF的肿瘤细胞结合，随后ADC-TF复合物内化并通过蛋白水解裂解释放 MMAE。MMAE破坏活跃分裂细胞的微管网络，导致细胞周期停滞和凋亡细胞死亡。   03   临床研究 2021年9月，Tivdak的首次批准基于一项开放标签、多中心、单臂临床II期试验（innovaTV204）。 研究在101名复发性或转移性宫颈癌患者中进行，评估Tivdak的疗效和安全性。这些患者既往接受过不超过两种全身性治疗方案，包括至少一种含铂化疗方案。 临床研究显示，Tivdak的客观缓解率（ORR）为24%，中位反应持续时间（DOR）为8.3个月，基于上述结果，FDA给予加速批准上市。 图3：innovaTV204结果，来源：FDA 2023年10月，Seagen和Genmab宣布了一项全球性、随机、开放标签的临床3期试验（innovaTV 301）结果。在一线治疗期间或治疗后疾病发生进展的复发性或转移性宫颈癌患者中，与单独化疗相比，接受Tivdak治疗的患者死亡风险降低了30%，表现出显著的统计学意义和临床意义。该研究数据公布在2023年欧洲肿瘤内科学会(ESMO)年会主席专场上。 该试验纳入502名既往接受过一种或两种全身治疗方案的复发性或转移性宫颈癌患者。研究显示，中位总生存期（OS）Tivdak组为11.5个月，化疗组为9.5个月，中位无进展生存期（PFS）Tivdak组为4.2个月，化疗组为2.9个月，客观缓解率（ORR）Tivdak组和化疗组分别为17.8%和5.2%。 基于上述结果，2024年4月，FDA完全批准Tivdak用于治疗化疗期间或化疗后疾病进展的复发性或转移性宫颈癌患者。 Tivdak最常见的不良反应（≥25%），包括实验室异常在内是血红蛋白减少、周围神经病变、疲劳、淋巴细胞减少、恶心、脱发、鼻出血、结膜不良反应、出血、白细胞减少、肌酐增加、干眼症、凝血酶原国际标准化比率增加、活化部分促凝血酶原激酶时间延长、腹泻和皮疹。   04   市场表现 2022年9月，再鼎医药与Seagen达成合作，获得Tivdak®在中国内地、香港、澳门和台湾地区的独家授权。 2023年Tivdak®销售额为0.64亿美元。同年3月，Seagen被辉瑞收购，Tivdak®连同另两款ADC产品Adcetris®、Padcev®，一并纳入辉瑞麾下。 据贝哲斯咨询发布的市场调研报告，全球宫颈癌药物市场规模在2022年达到374.58亿元人民币，预计至2028年这一规模将会达到587.12亿元人民币。 接下来，我们选出几个同样靶点TF的ADC产品，来看看它们的异同。   05   TF靶点ADC相关竞品 5.1 MRG004A 原研：乐普生物 靶点：组织因子（TF） 有效载荷：MMAE（微管抑制） 连接子：BCN-Val-Cit 适应症：胰腺癌、宫颈癌、乳腺癌 研究状态：临床1/2期 MRG004A由乐普生物子公司上海美雅珂开发，这是国内首款靶向TF的创新ADC，由靶向TF单抗与抗微管毒性药物MMAE，通过蛋白酶可切割连接子偶联而成。 MRG004A采用了GlycoConnect定点偶联技术及HydraSpace极性间隔技术，将MMAE共价连接至TF靶向单抗的Fc区域，药抗比（DAR）为3.8。相比传统偶联技术，MRG004A的均一性和稳定性更好。 就在前不久，2024年5月，美国芝加哥举行的美国临床肿瘤学会（ASCO）年会上，乐普生物公布了MRG004A治疗晚期实体瘤1/2期临床最新数据。 数据显示，MRG004A在胰腺癌患者（PC）中显示出显著的抗肿瘤活性，在2.0mg/kg剂量组的12名既往已接受中位3线治疗的可评价PC患者中，有4例部分缓解（PR）及6例病情稳定（SD），客观缓解率（ORR）为33.3%（4/12），疾病控制率（DCR）为83.3%（10/ 12）。其中，5名患者PC的TF表达为50%或以上、强度水平为3+，且先前已接受2线或以下治疗。以2mg/kg剂量接受MRG004A，其中4名患者达到PR，1名患者达到SD。因此，高TF表达PC的ORR为80%（4/5），DCR为100%（5/5）。 此外，MRG004A对三阴性乳腺癌（TNBC）及宫颈癌（CC）患者亦显示出疗效。在4名接受过多线治疗的TNBC患者中，ORR和DCR分别为25%（1/4）和50%（2/4）。在2名接受过四线治疗的CC患者中，1名患者达到PR，1名患者达到SD。7.9%（5/63）的患者曾出现严重不良事件。 且MRG004A在多次预先治疗的情况下，对多种肿瘤类型显示出可控的毒性以及显著的抗肿瘤活性。剂量扩展阶段的评价仍在进行中。 5.2  XB002（ICON-2） 原研：Exelixis、Iconic Therapeutics和Zymeworks 靶点：组织因子（TF） 有效载荷：zovodotin（微管抑制） 连接子：缬氨酸-瓜氨酸（Val-Cit） 适应症：前列腺癌、宫颈癌、卵巢癌等 研究状态：临床I期 XB002由Exelixis、Iconic Therapeutics和Zymeworks合作开发，系将靶向TF的人单克隆抗体与有效载荷zovodotin通过蛋白酶可切割连接子偶联组成。 Zovodotin是一种新型auristatin类微管蛋白抑制剂，与同类细胞毒药物相比，它的脱靶性更低、耐受性更好。 2024年1月，在ASCO泌尿生殖系统癌症研讨会上，公司公布了XB 002在晚期实体瘤患者中临床I期研究（JEWEL-101）剂量递增阶段的初步结果。 初步结果显示，XB 002在多个剂量水平下耐受性良好，具有较低的眼部毒性，且没有出血事件或治疗相关的周围神经病变（PN）。 2024年公司会继续推进XB 002的临床I期研究（JEWEL-101），进一步探寻单药治疗和联合治疗的潜力，优选出对XB 002敏感的实体瘤类型。   写在最后   这一期我们了解到，Tivdak®是全球已上市ADC中，首款用于宫颈癌的ADC，也是首款靶向组织因子（TF）的ADC。2021年它以FDA加速批准上市，今年2024年4月终于获得完全批准。 未来Tivdak®能否在硝烟四起的宫颈癌市场抢占一席之地呢？我们拭目以待。  上市ADC系列往期文章 第一期：上市抗体偶联药物（ADCs）系列第一期：全球首款ADC Mylotarg 第二期：全球首款批准用于一线治疗的ADC——Adcetris 第三期：迄今商业化最成功ADC：Kadcyla 第四期：Besponsa：辉瑞的第二款ADC，这次“命运”会好点吗？ 第五期：阿斯利康Lumoxiti，20年来首款批准用于毛细胞白血病的新药 第六期：罗氏第二款ADC，能续写Kadcyla的成功吗？ 第七期：Best in Class，“头对头”优效，这款ADC一度颠覆治疗指南 第八期：ADC扎堆HER2，Nectin-4靶点能杀出重围么？ 第九期：全球首款Trop2 ADC：三年，从加速批准到跻身重磅—Trodelvy® 第十期：全球首款靶向BCMA ADC：从加速批准到美国退市，现在进展如何？ 第十一期：全球首款光免疫疗法ADC—Akalux® 第十二期：荣昌生物「维迪西妥单抗」，首款中国原创HER2 ADC 参考资料： 1. ICO/IARC HPV Information Centre. Human Papillomavirus and Related Diseases Report. China, 2023-03-10. 2. 许兰芬, 江荷叶，江莉. 专家与您面对面——宫颈癌. 北京：中国医药科技出版社. 2016.1 3. Tivdak®FDA说明书. 4. Johann S de Bono , Nicole Concin , David S Hong，et al. Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Mar;20(3):383-393. 5. Wungki Park et al.Phase I/II first-in-human study to evaluate the safety and efficacy of tissue factor-ADC MRG004A in patients with solid tumors.JCO 42, 3002-3002(2024). 6. Susanna Varkey Ulahannan et al.Cohort expansion from the phase 1 JEWEL-101 study investigating the tissue factor–targeting antibody-drug conjugate XB002 in patients with advanced solid tumors: Metastatic castration-resistant prostate cancer cohort. JCO 42, TPS237-TPS237(2024). 7. 官网或公开资料. 共建Biomedical创新生态圈！ 如何加入BiG会员？

First Cohort of Participants Dosed in Phase 1 Clinical Trial with Lead Development Candidate AV078 Intended for the Treatment of Seizures Associated with Tuberous Sclerosis Complex (TSC) Leadership Team Strengthened with the Appointment of William Greene, MD, CIO at Hevolution, and Justin Gover, Former CEO at GW Pharmaceuticals to the Board of Directors, and Micah Zajic Appointed as CFO $50M Financing Led by Hevolution BERKELEY, Calif., March 28, 2024 /PRNewswire/ -- Aeovian Pharmaceuticals, a clinical-stage biopharmaceutical company developing novel and highly selective therapeutics that potently inhibit the mTORC1 pathway, today announced that it has dosed the first cohort of participants in a Phase 1 clinical trial for its lead development candidate AV078, a first-in-class CNS penetrant selective mTORC1 inhibitor. Supporting this transition into the clinic, the company has also expanded its leadership team with the appointment of seasoned industry veterans William Greene, M.D., Chief Investment Officer at Hevolution, and Justin Gover, former Chief Executive Officer of GW Pharmaceuticals, to the company's Board of Directors, and appointed Micah Zajic as Chief Financial Officer. The company also recently completed a $50 million financing, led by Hevolution. "We are delighted to partner with Aeovian's management team and current investors, who have proven track records of success in drug discovery, development, and commercialization. Aeovian has assembled a compelling platform for the development of selective mTORC1 inhibitors," said Dr. Greene, CIO at Hevolution. "By developing novel small molecules to restore cellular metabolic quality control, Aeovian has several opportunities to address major unmet medical needs for indications spanning orphan neurological diseases to highly prevalent diseases of aging." In the $50M financing, Hevolution was joined by existing investors Apollo Health Ventures, Sofinnova Investments, venBio, Evotec and b2venture. This financing will support the completion of the Phase 1 clinical trial in healthy volunteers and prepare for the start of a subsequent Phase 2 clinical trial in adult and pediatric patients with TSC refractory epilepsy. "TSC is a genetic disorder of mTORC1 hyperactivation. We believe that our first-in-class CNS penetrant selective mTORC1 inhibitor, AV078, has the potential to be transformative for patients with TSC refractory epilepsy, a patient population in need of therapeutic options with better efficacy and tolerability. Beyond AV078, we believe that there is vast potential for our library of proprietary compounds in treating mTORC1-mediated rare and age-related diseases," said Allison Hulme, Ph.D., President and Chief Executive Officer, Aeovian Pharmaceuticals. "The entire Aeovian team welcomes Hevolution, and is thankful for the continued support and commitment of our existing investors as we move to this next exciting stage of the company's development." Dr. William Greene brings over 25 years of experience in leadership positions, which have included founder, biotechnology executive, investor, and clinician. As CEO, he built and led Iconic Therapeutics through discovery, clinical development, and venture financing, which culminated in a successful sale of the company. Dr. Greene spent 12 years at MPM Capital where he was a Managing Director and member of its Investment Committee, responsible for biotechnology and medical technology investments worldwide. He was also founding Chairman and head of the Investment Committee at the Global Health Investment Fund, a groundbreaking impact-oriented venture fund in collaboration with the Gates Foundation, which successfully scaled both investment returns and health impact simultaneously. Dr. Greene earned his BA from Wesleyan University and his MD from UCSF. He was a Robert Wood Johnson Clinical Scholar at Yale and a Howard Hughes Medical Institute Research Scholar at the US National Institutes of Health (NIH). Justin Gover brings 25 years of experience in leadership positions in the biotechnology industry. Mr. Gover served as founding CEO and as a director of GW Pharmaceuticals plc from the company's inception in 1999 until its sale to Jazz Pharmaceuticals plc for $7.2 billion in 2021. From 2018 to 2021, Mr. Gover served on the Board of Directors of the Biotechnology Innovation Organization (BIO). Mr. Gover currently serves on the Board of Directors for Xenon Pharmaceuticals, CURE Epilepsy and Rady Children's Institute for Genomic Medicine. Mr. Gover holds an M.B.A. from the INSEAD business school in France and a B.Sc. (Hons) from Bristol University, UK. "I am delighted to be joining the Aeovian Board at this exciting time as the company enters the clinic. I have a deep commitment to the epilepsy community and to patients with TSC and believe that AV078 has the potential to be a valuable new treatment option for this high need population," said Justin Gover. "I am impressed by the breadth of potential applications for Aeovian's science and by the caliber of the Aeovian team and look forward to contributing to the company's future." "On behalf of our Board of Directors, I am delighted to welcome William and Justin to our Board as they bring diverse and relevant experience from various leadership roles within the biotechnology industry and we look forward to their contributions as we navigate the company's next phase of growth," said Richard Gaster, M.D., Ph.D., Chairman of the Aeovian Board of Directors. Micah Zajic has been appointed Chief Financial Officer at Aeovian. Mr. Zajic brings nearly 20 years of experience in biotech corporate development, healthcare capital markets and investment banking to the company. Mr. Zajic most recently served as Chief Business Officer and Chief Financial Officer at LEXEO Therapeutics (NASDAQ). Prior to this he served as Chief Financial Officer of SQZ Biotechnologies (NYSE). He began his career at Morgan Stanley in the Global Capital Markets and Healthcare Investment Banking Groups, raising capital and executing strategic transactions for companies across the healthcare industry. In addition, Mr. Zajic worked in corporate development roles at Alexion Pharmaceuticals and MeiraGTx, focusing on the evaluation and execution of external partnerships, license agreements and acquisitions. About Aeovian Aeovian Pharmaceuticals is a clinical-stage biopharmaceutical company developing targeted and highly selective small molecules to restore cellular metabolic quality control, thereby addressing the dysregulated growth and hyperactive signaling found in certain rare genetic and age-related diseases. Our lead development candidate, AV078, is a first-in-class CNS penetrant selective mTORC1 inhibitor being developed for the treatment of TSC refractory epilepsy and is currently being evaluated in a Phase 1 trial. TSC is a rare genetic disorder caused by the hyperactive signaling of mTORC1. Beyond AV078, we have developed a proprietary library of small molecules, which are potent and selective inhibitors of either mTORC1 or CD38 and have the potential to precisely target the underlying biology of multiple rare and age-related diseases. For more information, please visit our website at . Contact: Micah Zajic Chief Financial Officer ir@aeovian.com