Enoblituzumab

正文共：2491字 7图预计阅读时间：6分钟ADC的火热无需赘言，辉瑞430亿美元买下Seagen，国内药企2023年相关资产出海十余笔。但在新药研发领域，却是冰与火共存，黑天鹅与灰犀牛横行的复杂光景。美东时间9月5日，MacroGenics公布B7H3 ADC vobra duo（原MGC018）最新临床进展。在其用于治疗转移性去势抵抗性前列腺癌（mCRPC）患者的II 期 TAMARACK研究中，出现5例死亡事件，MacroGenics股价应声大跌77%，收盘价为3.31美元/股。在这5起死亡病例中，有2人被MacroGenics判为与vobra duo无关，1人死于急性心肌梗死，另1人死于心脏骤停。其余病例死因则为肺炎（2人）和3级胸腔积液，是否与vobra duo相关，需等待进一步调查结果。I期试验中，就出现了患者死亡vobra duo是一款以人源化B7H3单抗为靶头、缬氨酸-瓜氨酸（vc）为可裂解连接子、前药seco-DUBA为载荷的ADC药物，DAR值约为2.7。早在其I期研究中，就因不良事件导致了高比例的剂量调整和治疗提前终止。该研究共纳入40名mCRPC、21名NSCLC、16名三阴乳腺癌和9名黑色素瘤患者。86名患者中有78 名（91%）至少经历了一次任何级别的TRAE；有43名（50%） 经历了≥3级TRAE；以及两起死亡病例：一起原因不明，另一起由SARS-CoV-2引起。不过好在vobra duo作为单药在治疗mCRPC患者时，显示出了不错的抗肿瘤活性。其（3mg/kg，Q3W）剂量组的ORR达25%（4/16），PSA水平降低50%以上的患者比例为54%（21/39）。故，只要降低起始剂量，改善耐受性，延长治疗时间，vobra duo在mCRPC中理应有良好的治疗前景。TAMARACK研究采用的便是接近（3mg/kg，Q3W）剂量的（2.0mg/kg，Q4W）与（2.7mg/kg，Q4W）两个剂量组。患者死亡时间为近5个月值得注意的是，2024年4月3日，MacroGenics刚公布了该试验的中期安全性数据，但并未报患者死亡，数据截止日期为2024年1月4日。也就是说，5起死亡病例接连发生在近5个月内。据统计，TAMARACK研究中共有182名mCRPC患者入组，其中177名接受了vobra duo治疗。入组患者的年龄在46至89岁之间（中位数70.5岁），ECOG评分≤2。截止2024年1月4日前，无论剂量如何，治疗期间最常见的（≥10%）TEAE，包括虚弱（40.7%）、恶心（27.7%）、疲劳（20.3%）等不良反应。在接受治疗≥12周或在12周内停止研究治疗的TAMARACK患者子集（n = 95）中，TEAE导致了12名（12.6%）患者药物中断和5名（5.3%）患者停药。这要比I期研究中3mg/kg剂量组，在12周时观察到的药物中断率（58.5%）和停药率（14.6%）更为有利。而如今5位患者死亡，2.0mg/kg剂量组1例，2.7mg/kg剂量组4例，三级及以上不良事件发生率较日前大幅增加。反观疗效方面，两剂量组中PSA下降超过50%的患者双双过半。同时，缓解效果也较为明显，ORR分别为24.4%、43.8%（2.7mg/kg），DCR分别为91.1%（2.0mg/kg）、87.5%。借于此，MacroGenics想要继续拓展vobra duo的研发，计划2024年中在TAMARACK研究中增加NSCLC、SCLC、黑色素瘤等患者，并探索与PD-1/CTLA-4双抗Lorigerlimab（MacroGenics/吉利德）联用的可及性。不过在此之前，还需要先明确另外三起死亡病例是否与药物相关，以及FDA介入后的态度。研发之路虽坎坷，但火热目前，尚无B7H3靶向药物获批上市，原本进展最快的是Y-Mabs/赛生药业的omburtamab（一种放射性核素碘131标记的靶向B7H3单克隆抗体），后因试验设计问题于2022年遭FDA拒批。同年，MacroGenics终止了其B7H3×CD3双特异性抗体的开发。至于B7H3单抗，MacroGenics也“受过伤”，旗下Enoblituzumab（天境生物拥有大中华区权益），在一项治疗头颈部鳞状细胞癌的II期临床试验中，出现7名患者死亡，该试验后被停止。即便多次受挫，MacroGenics的在研管线中还有三款B7H3资产：2款B7H3 ADC（vobra duo、MGC026），以及一款B7H3单抗Enoblituzumab。以小见大，B7H3的研发之路虽坎坷，但火热。当MacroGenics仍在平衡疗效与安全性之时，第一三共的B7H3 ADC已经率先进入临床III期，并在小细胞肺癌等适应症取得了优异的疗效数据；翰森制药的B7H3 ADC于去年以17.1亿美元的交易总价成功出海GSK；宜联生物、迈威生物、信达生物等众多本土药企均在B7H3领域紧追不舍……避无可避ADC的大部分毒性由连接子-有效载荷复合物决定，即便采用了相同的有效载荷和连接子，也会因抗体靶向性、非肿瘤毒性，可能出现截然不同的副作用或非预期反应。而特定靶标的参与或有效载荷在表达ADC靶标的非恶性组织中的积累，可能是此次患者死亡的原因之一。（即毒素的蓄积导致毒性的出现）说回MacroGenics，当初选择差异化开发前列腺癌适应症，便是为了规避锋芒，如今安全性再次生疑，vobra duo的前景逐渐变得扑朔迷离。是继续鉴于其疗效的初步优效性，另辟蹊径；还是回到NSCLC等大适应症中，与第一三共等药企“硬刚”，药时代将持续关注。参考资料：1.MacroGenics官网2.雪球3其他公开资料封面图来源：pixabay版权声明/免责声明本文为原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cnFDA主任Peter Marks：把基因疗法的价格打下来！11个月婴儿恢复听力，再生元、礼来均有布局，国内药企领跑CAR-T疗法新突破：一名15岁少女的重生点击阅读原文，了解更多！

Pictured: 3D illustration of antibody-drug conjugate molecules carrying toxic payloads/iStock, Love Employee MacroGenics’ stock dropped by as much as 70% Friday morning after the biotech disclosed five deaths in the Phase II TAMARACK trial for its investigational antibody-drug conjugate vobramitamab duocarmazine in metastatic castration-resistant prostate cancer. The five fatal adverse events included two grade 5 toxicities—one case of acute myocardial infarction and another of cardiac arrest—which were deemed unrelated to the study treatment. Two of the deaths were caused by pneumonitis, or inflammation of lung tissues, while the fifth patient died of pleural effusion, or the build-up of fluids in the pleural cavity. MacroGenics is still investigating these three deaths. TAMARACK is ongoing and follow-up is still incomplete. Despite these fatal toxicities and negative stock reaction, CEO Scott Koenig in an investor call on Thursday struck a positive note, calling the candidate’s side effects “extremely manageable.” Study investigators, he continued, are “very comfortable” with managing these toxicities “and are very encouraged by both the safety and obviously, the activity data they’ve seen.” Vobramitamab duocarmazine, also called vobra duo, is an investigational antibody-drug conjugate (ADC) therapy designed to target the B7-H3 antigen, which is overexpressed in cancer cells. Vobra duo carries the toxic payload seco-duocarmycin hydroxybenzamide azaindole, an alkylating agent that damages DNA in cancer cells and triggers their cell death, according to MacroGenics’ website. The Maryland-based biotech is developing vobra duo as a treatment for various solid tumors, including non-small cell lung cancer, melanoma and squamous cell carcinoma of the head and neck. Its most mature program, however, is in metastatic castration-resistant prostate cancer (mCRPC), for which it is running the mid-stage, open-label TAMARACK study. Data from TAMARACK, which MacroGenics also released on Friday, show that the lower, 2.0-mg/kg dose of vobra duo elicited an overall response rate (ORR) of 24.4%, when counting even unconfirmed instances of treatment response. At the higher, 2.7-mg/kg dose, vobra duo treatment resulted in a 43.8% ORR. Disease control rates were 91.1% and 87.5% for the low and high rates, respectively. With these data in hand, MacroGenics is preparing for a potential Phase III study in mCRPC, slated for 2025. The decision to push through with this late-stage trial will depend on the final analysis of TAMARACK, including progression-free survival data, when available, according to the press release. MacroGenics has had a history of patient deaths in its trials. In September 2021, the biotech posted Phase I data for vobra duo, revealing two fatal grade 5 toxicities—one with an unknown cause and the other attributable to COVID-19. Nearly a year later, in June 2022, MacroGenics reported seven patient deaths, this time in connection with its investigational antibody enoblituzumab, which also targets the B7-H3 antigen, forcing the company to discontinue its Phase II study in head and neck cancer. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.