SC-DARIC33

The new head of Regeneron Cell Medicines Phil Gregory talked about the integration of 2seventy on the sidelines of the American Society of Gene and Cell Therapy annual meeting in Baltimore Wednesday. Phil Gregory’s new gig looks a whole lot like his old gig. It’s just that, under the umbrella of Regeneron, things have gotten a bit bigger. “The integration is going great. My head's practically exploded three or four times to assimilate all the information,” Gregory joked in an interview on the sidelines of the American Society of Gene and Cell Therapy (ASGCT) annual meeting Wednesday in Baltimore. “The main challenge has been like neuronal strength to understand everything that's happening.” Now head of Regeneron Cell Medicines, Gregory came over to the famed Big Biotech with the sale of 2seventy’s cell therapy pipeline. The deal, announced in January, did not include financial details beyond a $5 million upfront payment and a $10 million milestone to be paid by Regeneron for the first market approval of the first program resulting from the transaction. 2seventy and Regeneron had worked together before when the cell therapy biotech was still a part of bluebird bio. The two signed a deal in 2018. “We weren’t coming in cold,” Gregory said of the prior partnership. “A lot of the players on the Regeneron side were well known to us and vice versa. So, as integrations go, I think it's really benefited from that familiarity. Everybody kind of knows each other.” Snapping up long-term partners is kind of Regeneron’s thing. See Decibel Therapeutics, another Regeneron acquisition, which was the talk of the ASGCT meeting Wednesday with data showing the restoration of hearing in two profoundly deaf children with a genetic form of hearing loss. Gregory said the 2seventy integration is well underway—not quite finished but moving along. His colleague, 2seventy Chief Medical Officer Steve Bernstein, M.D., also joined Regeneron.  “Now we can kind of put that [partnership] on steroids because we now get access to the full suite of technologies on the other side of the fence because there is no fence. We’re all part of the same thing,” Gregory said. That doesn’t mean things were seamless, mind you. Gregory said the biggest issue for him has been the immense learning curve required to get up to speed on Regeneron’s technologies. “The issues are really more on the other side of, we now have to catch up with everything that's happening in Regeneron. And that's really part of the secret sauce here,” Gregory said. Regeneron executed the deal for the cell therapy pipeline that 2seventy had, but Chief Scientific Officer George Yancopoulos, M.D., Ph.D., signaled shortly after the deal that the goal is to someday blend Regeneron’s antibody capabilities with 2seventy’s cell therapy approach to create something new in biologics. So this is not a plug-and-play acquisition. “The cell therapy component by itself, we think, of course, had tremendous value, but the value of that in combination with everything that's happening on the Regeneron side is really the one plus one equals seven,” Gregory said. Over the next year, Gregory said the focus is on driving toward the inflection points for the original 2seventy pipeline. That includes the dual-targeted CAR T cell therapy bbT369 in B-cell non-Hodgkin lymphoma, SC-DARIC33 in acute myeloid leukemia, a MUC16-targeted CAR-T for ovarian cancer, a MAGE-A4 TCR program in solid tumors and therapies aimed at automimmune indications and several unnamed targets. Longer term, the company will work in Regeneron’s biologics, so antibodies and bispecifics, as well as some that haven’t been disclosed yet. “All that stuff needs to get brought into the cell therapy world where we think there’s one of those synergistic opportunities,” Gregory said. And Regeneron is still keeping an eye on other technologies that could match this ambitious new program, Gregory noted. “We're also trying to make sure that we're always looking for the next opportunity, both technologically from things that are happening inside both sides of the company as well as externally. We always keep our eyes open as to what could come in and really sort of fuel the future,” he said.

1月30日，再生元（Regeneron Pharmaceuticals）宣布收购2seventy bio，后者除了保留已经获批上市的BCMA靶向CAR-T疗法Abecma（idecabtagene vicleucel）外，将全部在研管线打包卖给再生元。值得一提的是，此次并购，再生元仅以500万美元预付款就收购了2seventy bio的全部在研管线，并将接管与这些项目相关的其它项目以及相关的基础设施和人员成本。除了500万美元预付款外，再生元在交易产生的第一个项目首次获得市场批准后将向2seventy bio支付一笔里程碑付款，具体金额暂未披露。那么2seventy bio为何选择此时抛售CAR-T资产？再生元又在下一盘什么样的棋？拆分出来的优质资产时运不济2seventy bio于2021年11月分拆自细胞治疗先驱Bluebird Bio，拆分后的2seventy bio专注于开发创新的细胞疗法和基因编辑治疗，主要领域是CAR-T细胞疗法和基因编辑技术。分拆初期，2seventy bio继承了优质资产——与BMS合作开发的靶向BCMA（B细胞成熟抗原）的CAR-T疗法Abecma，于2021年3月获FDA批准上市，用于治疗复发性或难治性多发性骨髓瘤（R/R MM）成人患者，是第一个获批上市的以BCMA为靶向的个体化免疫细胞疗法。上市之初，Abecma销售额迅速攀升，2021年第二季度的销售额就达到了2400万美元，甚至一度供不应求。正在Abecma为2seventy bio和BMS带来源源不断收入的时候，2022年，传奇/强生的Carvykti（西达基奥仑赛）获批上市，同样用于R/R MM的治疗。同样作为一款BCMA CAR-T，Carvykti上市后迅速抢占了市场份额。2023年前三季度，Carvykti销售额为3.41亿美元，同比增长332%，仅第三季度的销售额就达1.52亿美元。受Carvykti影响，Abecma在2023年前三季度销售额为3.02亿美元，虽然与Carvykti相差不大，但Abecma在去年第三季度的销售额仅有6900万美元，环比第二季度下滑了40%。以上对比可以看出，Carvykti具有强大的市场竞争力，Abecma面临的挑战巨大。除了遇到劲敌Carvykti外，去年11月，Abecma三线治疗多发性骨髓瘤的补充适应症申请时间，遭到了FDA的推迟。对此，FDA希望看到更多的总生存期数据。另外，2seventy bio的在研管线进展也不顺利。2023年6月，公司一款治疗急性髓系白血病（AML）的CAR-T疗法SC-DARIC33在I期研究中，因发生5级（致命）严重不良事件（SAE）导致1例患者死亡，随后FDA暂停了该临床试验。试验中的SC-DARIC33是一款靶向CD33的CAR-T疗法，该试验正是2seventy bio公司DARIC T技术平台的首次人体临床试验。DARIC T技术平台是2seventy专有的CAR-T活性调控平台，通过雷帕霉素的给药/停药来实现对CAR-T细胞活性的打开/关闭，最大限度地减少副作用。SC-DARIC33临床试验的搁置，也让人们对DARIC T技术平台的可行性产生质疑。“时运不济”的2seventy bio，股价一直下跌。去年9月，该公司为了延长运营跑道的现金流，宣布“战略重组”计划，预计裁员约40%。此次“捡漏”再生元有多赚？对于此次交易金额，不少人感到震惊。我们先来看下再生元将得到什么，两款临床阶段CAR-T疗法：bbT369和SC-DARIC33。bbT369是一款靶向CD79a/CD20 的CAR-T疗法，用于治疗复发和/或难治性B细胞非霍奇金淋巴瘤（B-NHL）。SC-DARIC33就是上文提到的靶向CD33的CAR-T疗法，正处在临床搁置状态，2seventy bio曾打算与FDA沟通并重启。还将获得两款IND阶段的细胞疗法资产：治疗卵巢癌的MUC16和治疗自身免疫性疾病的MAGE-A4 TCR-T细胞疗法。其中关于MAGE-A4 TCR-T项目，早在2022年10月，国内细胞疗法头部企业药明巨诺就已经与2seventy bio围绕该项目达成战略合作，并且为此项目支付了300万美元预付款，后续还有开发相关的7000万美元里程碑付款。对比来看，再生元此次“抄底”的500万美元预付款，简直是白菜价，妥妥赚翻。除了管线资产，再生元还将获得2seventy bio的160名员工以及刚于2023年建成的新GMP级别CAR-T制造工厂。此次交易完成后，再生元将新成立一个研发部门Regeneron Cell Medicines，旨在推进肿瘤学和免疫学领域的细胞疗法和组合方法。毫无疑问，这次并购为再生元持续加码细胞治疗赛道增强了底气与硬实力。向外并购再生元开启新征程再生元成立于1988年，从创立之日起，它就带有深深的“科研”烙印。正是源于对研发二十年磨一剑的专注，再生元拥有了Traps和VelociSuite两大技术平台，在此基础上，公司打造了丰富的产品管线，并收获眼科神药Eylea（阿柏西普）和Dupixent（度普利尤单抗）等重磅炸弹药物。Eylea于2011年获FDA批准上市，适应症为湿性年龄相关性黄斑变性（wAMD）、糖尿病黄斑水肿（DME）、青光眼或高眼压症和视网膜病变等；2022年，Eylea销售收入高达96.47亿美元。Dupixent于2017年获FDA批准上市，是首个治疗中重度特应性皮炎的生物制剂。目前已斩获哮喘、嗜酸性粒细胞性食管炎、结节性痒疹等适应症。2022年，Dupixent共收入86.81亿美元，同比增长40%。除此之外，再生元在靶点挖掘上也没有落后。2016年至今，再生元已经在高甘油三酯血症、肥胖、非酒精性脂肪性肝炎等领域，挖掘了6个创新药潜在靶点。再生元的成功与其两大自研平台密不可分。依靠超强的研发能力，再生元实现了企业的飞跃式发展。不过由于Eylea、Dupixent等重磅炸弹即将迎来专利悬崖，再生元近年来也开始打破从不收购的理念，开始加强对外合作。2023年8月，再生元宣布将以约1.09亿美元收购基因疗法公司Decibel Therapeutics。该公司的主要在研药物为基因疗法DB-OTO，旨在为耳铁蛋白（otoferlin）相关听力损失患者恢复听力。DB-OTO目前正在进行全球I/II期临床试验。2022年5月，再生元以每股10.50美元（约2.5亿美元）的价格全现金收购临床阶段生物技术公司Checkmate Pharmaceuticals。该公司的核心产品是一款新一代 Toll 样受体9（TLR9）激动剂Vidutolimod，旨在治疗黑色素瘤、非黑色素瘤皮肤癌和头颈癌。2019年，再生元与行业领先的RNAi疗法公司Alnylam Pharmaceuticals达成一项合作协议，旨在发现、开发和商业化RNAi疗法，治疗眼科疾病和中枢神经系统，以及肝脏中表达的几种靶标。在这项合作中，再生元合计投资8亿美元。自研和外部并购的相得益彰，使再生元成为Biotech们羡慕的模样。如今再生元又开启新征程，其创新迭代的步伐从不停歇。立足于从源头解决和探索满足真正临床需求的信念，再生元已在眼科、心血管疾病、免疫和炎症、肿瘤等领域打造了丰富的研发管线。抄底CAR-T的时机到了吗？自去年底以来，CAR-T疗法遇到的挫折一波接着一波。2023年11月28日，FDA宣布正在调查已上市的CAR-T疗法是否会在极少数情况下导致T细胞恶性肿瘤。今年开年，FDA正式明确对已经上市的CAR-T疗法加“黑框警告”。根据公开信息，FDA已经确定，T细胞恶性肿瘤风险适用于所有目前批准的靶向BCMA或CD19的自体CAR-T细胞免疫疗法。FDA表示，接受这些CAR-T细胞治疗的患者和临床试验参与者应终生监测新的恶性肿瘤风险，一旦发现，需立即报告。除了安全性问题外，2023年12月，科济药业发布公告，其美国子公司CARsgen收到FDA通知，要求暂停CT053、CT041、CT071三款CAR-T药物的临床试验，等待位于北卡罗来纳州的生产基地进行检查后得出结论。此次科济药业CAR-T产品被暂停临床试验的原因在于CMC问题（CMC即医药产品的开发、许可、制造和持续营销中的化学、制造和控制流程）。安全性、CMC问题无疑为CAR-T赛道泼了一盆冷水，不过我们也不必过于悲观，作为一种新兴疗法，自2017年FDA批准第一款CAR-T产品至今，不过7年时间，CAR-T疗法迭代的空间还很大。此次再生元和2seventy bio的交易，让我们看到现在也许是抄底CAR-T的好时机。参考来源https://www.biospace.com2.https://ir.2seventybio.com/news-releases/news-release-details/2seventy-bio-reports-second-quarter-financial-results-and-0.Regeneron to Acquire Decibel Therapeutics, Strengthening Gene Therapy and Hearing Loss Programs. Retrieved August 10，2023.https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/2024-safety-and-availability-communications.