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氨基观察-创新药组原创出品作者 | 武月吃尽新冠疫苗红利之后的BioNTech，靠着肿瘤布局和中国管线，一举逆袭成为mRNA新王。凭借来自中国的PD-L1/VEGF双抗BNT327，BioNTech更是与百时美施贵宝（BMS）达成超百亿美元的合作。就在6月11日，BMS的CEO Chris Boerner在高盛全球健康医疗峰会上，首次回应了与BioNTech关于PD-L1/VEGF双抗的合作，表示十分看好BNT327的潜力，并抛出一个震撼业界的信号：公司将寻求具有战略意义的收购，例如收购BioNTech。这一潜在收购涉及金额可能超过300亿美元，甚至更高。因为，BioNTech目前市值超过250亿美元，其账上还拥有100多亿美元的现金等价物。退一步来说，仅拿到BNT327全球50%的权益，BMS就需要付出上百亿美元，要收购BioNTech，势必要付出更大的代价。值得玩味的是，就在BMS释放收购信号的后一天，BioNTech宣布将以12.5亿美元全股票交易收购竞争对手CureVac。这被BioNTech称之为，“标志着其肿瘤学战略执行的下一个里程碑”，同时也会终结这两家mRNA公司长达3年的专利拉锯战。一边是来自MNC的巨额收购诱惑，一边是癌症治疗的星辰大海。成立超十年、靠新冠疫苗名利双收的BioNTech，正站在命运的十字路口。/ 01 /BMS越来越急BMS的焦虑肉眼可见。早在今年初JPM大会，Chris Boerner便透露，公司2025年的排他性损失LOE风险敞口将继续增大。尤其是Revlimid，3月份将面临一系列新的仿制药，然后在2026年面临一个完整的仿制药市场。而去年前三季度，Revlimid创造了44亿美元的收入，BMS预计到2025年将进一步下降至20亿至25亿美元。此外，Boerner直言，Pomalyst和Sprycel也将面临仿制药冲击，因此预计今年将出现“叠加效应”。换句话说，情况相当不容乐观。当然，BMS也没有坐以待毙，Boerner介绍了公司产品管线进展，目前有40个项目处于中后期开发阶段。“从今年开始，以及在接下来的24个月内，下一波催化剂的交付是我们的一大重点领域。”在BMS预期中，未来五年，将推出10种新药和30个适应症扩张来带动增长。其中，就包括收购而来的精神分裂症新药KarXT，BMS计划每年都公布其新适应症上的临床数据。不仅如此，Boerner更是立下了一个flag：到2030年实现持续的顶级增长。而在一季度电话会议上，其也将并购列为首要任务。而面对PD-(L)1-VEGF双抗超越药王K药的潜力，全球大药企都在抢位，就连默沙东也跑来中国,买下了一款PD-1/VEGF双抗，BMS也坐不住了。当然，其收购也并非是一时冲动，BNT327的临床表现是最好的解释。在其针对NSCLC的I/II期研究中，BNT327与紫杉醇联用在不同PD-(L)1表达水平人群中均显示良好疗效：疗效不受PD-(L)1表达状态限制，即便是在CPS<1的患者中，ORR依然达到76.9%，18个月生存率也维持在76.9%。适应症的广泛同样是PD-(L)1-VEGF估值通胀的另一因素。PD-(L)1-VEGF双抗不仅能用于非小细胞肺癌，在乳腺癌、肾癌、黑色素瘤等领域也表现出潜力。正是基于BNT327的临床数据和广阔的适应症前景，BMS选择与以15亿美元预付款，并承诺在2028年前支付20亿美元无或有周年付款，以及高达76亿美元的里程碑付款，获得BNT327的开发与商业化权利。在高盛全球健康医疗峰会上，Chris Boerner首次回应了与BioNTech关于PD-L1/VEGF双抗的合作，表示十分看好BNT327改变癌症治疗格局的潜力，正在加紧努力将其推向市场。“至于机会，我们正在与 BioNTech 合作开发一个广泛的CDP，目前正在进行多项III期研究。”Chris Boerner表示，这正是从O药身上的经验中得到的关键教训。显然，这一次BMS不想落后K药一步。在谈及并购战略方面，Chris Boerner强调肿瘤学是BMS非常了解的领域，“因此，我们会寻求具有战略意义的收购，例如收购BioNTech”。显然，面对专利悬崖，BMS正在加快自己的收购步伐，甚至愿意斥巨资收购BioNTech。/ 02 /BioNTech的动作对于BMS来说，如果要在这场PD-(L)1-VEGF双抗浪潮中，彻底领先默沙东，买下Summit无疑来得更直接。但是，从BMS的选择和最新表态来看，相比只有一款AK112的Summit，BioNTech似乎是一个更具性价比的战略选择。在市场看来，能将Summit价值最大化的路径，必然是被MNC收购，但其目前市场超百亿美金，还是令不少大药企选择观望。曾视为最有可能买下Summit的默沙东，买下了同样来自中国的PD-1/VEGF双抗LM-299；曾经的绯闻对象辉瑞，也选择买下了来自中国的PD-1/VEGF双抗SSGJ-707……考虑到Summit太贵，以及其他中国资产过于早期，BMS最终选择以35亿美元预付款+76亿美元里程碑款，与BioNTech达成合作。毕竟，BNT327进度足够快，且临床数据也够看。考虑到这还仅是一款管线的50%权益，若是想要进一步将BioNTech收入麾下，BMS势必要拿出更大的诚意、花更多的钱。目前，BioNTech市值超250亿美元，即使仅给予一定溢价，也很容易创造一个大deal。当然，钱或许不是问题。Chris Boerner在高盛全球健康医疗峰会谈及未来并购战略时，曾强调，BMS拥有足够的财力来开展对公司有意义的交易。对于BMS来说，BioNtech的资产更多元化，账上有100多亿美元现金，还有能创造收入的新冠疫苗，以及20+处在临床后期的mRNA疫苗管线，以及诸多mRNA专利。这似乎与强调在肿瘤学更进一步寻求战略意义收购的BMS，更契合。然而，当BMS抛出橄榄枝时，BioNTech的选择令人玩味。6月12日，BioNTech宣布将以12.5亿美元全股票交易收购竞争对手CureVac，较其前一交易日收盘价溢价55%。这笔收购绝非一时兴起。CureVac作为mRNA领域先驱，在天然序列优化、LNP递送系统等方面积累了大量专利和经验，在欧洲的专利数量与BioNTech并驾齐驱；同时，CureVac在德国图宾根的研发和生产中心也颇具吸引力。BMO表示：“CureVac灵活且可扩展的mRNA生产系统将有益于BioNTech在mRNA治疗领域的增长计划。”换句话说，BioNTech此番收购CureVac，看重的不仅是后者账面上的资产（早期癌症资产，包括CureVac目前处于I期开发阶段的基于mRNA的胶质母细胞瘤疗法），更是长远的战略协同价值。与此同时，这也将消除潜在的专利纠纷隐患。CureVac曾于2022年7月起诉BioNTech，声称其在mRNA技术方面的工作对后者的COVID-19疫苗有所贡献，构成专利侵权。在这场专利战中，BioNTech处于下风，分析师们也曾普遍不好看BioNTech。BioNTech则将这次收购，称之为执行其肿瘤战略方面的下一个重要里程碑，也是对肿瘤医学未来的投资。该战略即为专注于两个泛肿瘤项目，包括基于mRNA的肿瘤免疫治疗候选药物，和PD-L1/VEGF双抗BNT327。/ 03 /下一个抉择时刻在新冠疫苗退潮后，mRNA三巨头最终走向了不同的命运：Moderna因过度押注mRNA疫苗而深陷困境，CureVac转向癌症免疫疗法后终被收购，BioNTech选择了一条“中间”道路——通过战略收购强化肿瘤管线，并凭借中国管线止住了股价下跌的颓势，一举逆袭成为mRNA新王。这背后，无疑是一场关于战略定力与时代机遇的博弈。2019年之前的mRNA企业，迫切需要的是一个契机，证明mRNA平台技术的契机。暴富、完成阶级跃迁之后，它们更需要的是补足大药企经营之道。不仅是烧钱搞研发，更重要的是，如何通过手中的巨额资本，提高自己的确定性，满足市场的预期。显然，BioNTech更早领悟了这一点。新冠疫苗跻身暴富之后，BioNTech变得激进起来，当然，其BD眼光和运作也值得称赞，押注的ADC、PD(L)1/VEGF双抗等都是时下的大热门。也正是这些管线的潜力和临床预期，支撑了市场对其估值的核心预期。同时，BioNTech也正在加速推进癌症疫苗的研发，进一步证明自己mRNA技术平台的潜力。眼下，BioNTech或许也迎来了一个新的抉择时刻。那么，手握重金、技术领先的BioNTech是否愿意卖身？答案可能藏在两个关键因素中：价格和愿景。从价格角度看，BMS若发起收购，潜在交易总额势必巨大。对于急需转型的BMS来说，愿意为BioNTech的肿瘤管线组合和mRNA技术平台，付出多高的价格，是一个关键因素。毕竟，随着市场再度活跃，但凡有点资源、技术的生物技术公司都不想轻易下牌桌。典型如曾经拒绝默沙东收购要约的MoonLake，公司仅有一条核心管线，靶向IL-17A/F的三抗药物Sonelokimab，其在自免领域显示出不小的潜力。今年早些时候，默沙东曾对MoonLake提出不具约束力的的收购要约，但被拒绝了。当然，在市场看来，随着默沙东报价提高，最终MoonLake最有可能的决定是接受被收购。从愿景角度看，BioNTech创始人夫妇一直怀揣着“用mRNA技术攻克癌症”的梦想。“科学是我们的乐趣。我们愿意在实验室里度过每一分钟”，这是他们关于科研的态度。这种科学家的执着与梦想的召唤，可能比金钱更具驱动力。当然，BioNTech创始人Ugur Sahin也曾表示，有了充裕的资金，他们就能实现所有的梦想。BioNTech的抉择也会影响整个mRNA产业的格局。若选择独立发展，它可能成为继罗氏、诺华之后新一代欧洲生物技术巨头；若接受收购，则将成为BMS对抗专利悬崖的关键武器。最终BioNTech的选择，可能取决于BMS愿意开出怎样的价码，以及双方关于愿景的契合度。PS：欢迎扫描下方二维码，添加氨基君微信号交流。

Bristol Myers has multiple data readouts and new clinical trials for Cobenfy to "maximize the opportunity beyond schizophrenia," CEO Chris Boerner said. Cobenfy, the novel antipsychotic drug that Bristol Myers Squibb obtained from a $14 billion acquisition, could have a problem.The drug recently failed as an adjunctive treatment in a phase 3 trial for inadequately controlled schizophrenia, and, as Goldman Sachs analyst Asad Haider noted, new-to-brand prescription growth appears to be moderating as the second quarter nears its end.But Bristol Myers CEO Chris Boerner and Chief Commercialization Officer Adam Lenkowsky don’t see things that way.“We’ve got very good feedback from physicians in terms of what they’re seeing on positive symptoms, negative symptoms and … the cognitive benefits,” Boerner said at the Goldman Sachs Annual Global Healthcare Conference this week. “What we have now is a number of programs that either will begin reading out or that we’ll be initiating to ensure that we can maximize the opportunity beyond schizophrenia.”BMS continues to interrogate the failed Arise trial to understand why some patients derived benefits in the adjunctive setting, but the trial has “zero impact” on Cobenfy’s commercial uptake “in the short term or in the long term,” Lenkowsky said.BMS has not ascribed any sales projection to Cobenfy’s adjunctive use, and the trial’s investigators are the only doctors who are really aware of the setback, Lenkowsky said. Nevertheless, two “experienced psychiatrists” recently told Leerink Partners that they still expect Cobenfy to be used as an adjunctive schizophrenia therapy, given that no treatments are currently approved in that setting and psychiatrists have limited options, according to a May 5 note. The experts did caution, however, that payers may reject coverage for adjunctive treatment due to the trial failure. Cobenfy’s launch is tracking against expectations, having surpassed 30,000 total scripts following an FDA approval in late September, according to Lenkowsky.However, a Leerink Partners analysis of IQVIA data showed that Cobenfy’s weekly total scripts stayed largely flat, at 1,800, for most of May, before dipping to about 1,700 toward the end of the month thanks to the Memorial Day holiday.Lenkowsky acknowledged that it’s going to take time to continue to increase the number of prescribers and to get doctors to break the decades-old habit of using generic dopamine D2 receptor antagonists to treat schizophrenia.“We’ve got a very robust plan in place right now,” the commercial chief said. “In the field organization, we’ll be upsizing our teams in the near future as well to make sure we’ve got the right reach and frequency.”The company is also running a study to help inform physicians on the best way to switch patients from traditional antipsychotics and how to manage some of the side effects, he noted.BMS believes Cobenfy will see strong uptake “in the back end of the year,” Lenkowsky said, citing positive feedback from doctors, “particularly around the efficacy profile and, most notably, the cognitive benefits.”But, apparently, not all responses from doctors have been positive. One of Leerink’s experts said he hasn’t observed remarkable efficacy for Cobenfy among patients who haven’t responded to other schizophrenia treatments, the setting in which he has primarily been using the drug because of prior authorization requirements from insurance.“He questioned whether Cobenfy’s real-world efficacy will turn out to be robust enough to justify its [twice-daily] dosing and high cost,” Leerink analysts summarized in the May 5 note, adding that the expert argued that clinical trials tend to cherry-pick patients, making real-world outcomes notably different from clinical results. Meanwhile, looking to expand Cobenfy beyond schizophrenia, BMS currently has three studies in Alzheimer’s disease psychosis—a large market, as about half of the six million patients with Alzheimer’s suffer from hallucinations and delusions, Lenkowsky said.The first of the trio, Adept-2, is expected to read out this year. While doctors have reported a positive surprise on Cobenfy’s real-world tolerability in schizophrenia, Leerink analysts flagged that Alzheimer’s patients are more sensitive to side effects in the digestive system. BMS lowered the trospium component of the two-drug combo in Adept-2, a move that the Leerink team argued could raise gastrointestinal tolerability issues.Beyond Alzheimer’s psychosis, BMS is launching seven new phase 3 trials in Alzheimer’s agitation, Alzheimer’s cognition, bipolar disorder, irritability associated with autism and a new formulation. That means Cobenfy could have a data readout every single year from now to the end of the decade, setting the drug up to be a “meaningful contributor to growth for the company in the back end of the decade and beyond,” Lenkowsky said.