Asciminib Hydrochloride

吴妮 | 撰文 王晨 | 编辑 在一众疯狂追逐ADC和GLP-1的MNC大军中，诺华显得像个异类——即便没有这两条大热管线，2025年股价涨幅却跑赢了礼来。更让人印象深刻的是，这家成立百年的药企，至今仍以纯创新药物公司自居。 过去五年，专利悬崖的阴影一直追着诺华跑。心衰重磅炸弹Entresto、血液疾病药物Promacta和肿瘤药Tasigna已经相继失去专利保护。2025年的财报里，仿制药的冲击已经肉眼可见，Entresto全年销售额77亿美元，同比下滑1%；Promacta/Revolade跌去26%，仅剩16亿美元；Tasigna更是骤降34%，收于11亿美元。 但2025年诺华的整体业绩却稳住了，Kisqali、Kesimpta、Pluvicto、Leqvio正一点点填补专利过期留下的窟窿。根据诺华2025年财报，公司净销售额达到545.32亿美元，同比增长8%（按固定汇率算），核心营业利润率首次站上40%的关口。 真正的考验在2026年。这一年，仿制药的冲击会更加猛烈，诺华自己给出的预期也颇为谨慎：销售额低个位数增长，核心营业利润甚至可能出现低个位数下滑。这是一道必须跨过去的坎。 接下来的悬念是：新一代产品能否继续提速？诺华在核药和小核酸这些“小众赛道”布下的棋局，又能发挥多大的作用？ 对诺华来说，2025到2030年是一段Gap Years，而2030到2040年则是Growth Decade。只有Gap填平，Growth才能起飞。 诺华几年前埋下的管线，正集体走向最严酷的考场。 -01- 小众的神 当行业巨头在PD-1、ADC和GLP-1赛道上演贴身肉搏时，诺华闯进了两条当时来看小众且高壁垒的路径：核药与小核酸。 核药曾被认为是医药界典型的“高门槛、难放量”领域，但诺华凭借两款RDC（核药偶联药物）Pluvicto和Lutathera实现了商业化突破。2025年，Pluvicto跻身20亿美元分子俱乐部，同比增长42%，其增长关键来自年初适应症的拓展，从mCRPC的后线治疗推进至化疗前早期治疗，适用患者群体预计扩大三倍。 这一放量能力的背后，是诺华基建狂魔式的投入。由于Pluvicto的核心成分镥-177半衰期仅6.647天，药物从出厂到注入患者体内必须在约120小时内完成。为此，诺华在美国本土密集布局生产基地，2月25日又宣布了第五个RLT制造工厂的建设计划。在诺华颇为重视的中国市场，也投资了6亿元在浙江海盐建设国内首个核药生产基地。 而在小核酸领域，诺华则展现了另一种耐力。与Alnylam合作开发的“半年一针”降血脂药物Leqvio（英克司兰）在2025年销售额飙升至11.98亿美元，成为首款在常见慢病领域突围的小核酸药物。诺华还计划让小核酸发力神经科学领域，斥资120亿美元收购小核酸biotech Avidity，计划让小核酸发力神经科学领域。 目前，诺华在蛋白降解剂（PROTAC/分子胶）、环状多肽等领域的投入已超百亿美元，试图复刻核药与小核酸的成功路径。 当然，诺华并非天生偏爱小众，主要还是碰壁太多。PD-1抑制剂spartalizumab联合BRAF/MEK抑制剂一线治疗黑色素瘤的III期临床未能达到主要终点，引进自百济神州的替雷利珠单抗也未通过FDA上市批准。在ADC领域，诺华与ImmunoGen、Morphosys合作开发的CDH3、CDH6等ADC项目也相继折戟临床。 正是这段屡战屡败的经历，让诺华对热门赛道的技术门槛与安全性风险有了更深的理解。以ADC为例，诺华认为，某些ADC药物引发的间质性肺病等严重副作用，在RDC中理论上可以规避，因射线作用范围更可控。同时，RDC通过物理杀伤机制攻击肿瘤，不易产生耐药性，且同一靶向分子可实现“诊疗一体”，这是区别于ADC的独特优势。 核药也好，小核酸也罢，作为新兴的治疗 modality，从来都不是能一夜爆发的品类。2025年，Pluvicto 迈进20亿美元门槛，Leqvio 也首次突破10亿美元大关——放在任何一家biotech身上，都值得开香槟庆祝。 然而，在诺华这样的MNC体量下，它们的销售额距离Entresto、Promacta和Tasigna这些“重磅中的重磅”，仍有相当的距离。如今，小核酸和核药的热度已经点燃，接下来就看它们能否真正突破天花板，迈入下一个量级。 -02- 创新的代价 都说“大船难掉头”，但在诺华这里，这句话只能说明决心还不够大。 2018年至今，诺华几乎清空了所有与创新药无关的业务：疫苗、动物保健、消费者保健、眼科器械（爱尔康）、仿制药（山德士）。最狠的一点在于，它剥离的很多业务在当时并不是“垃圾资产”。爱尔康是全球眼科器械的王者，山德士是仿制药巨头，但它们不符合诺华“百分之百聚焦创新药”的终极愿景。 在中国的逻辑也在变化，2025年底，市场传出消息，诺华中国区县域团队将整体解散，诺华的说法是“将对县域业务运营模式进行调整”。2025年，诺华还将两款眼科药物在中国的独家进口,商业推广和分销权转让给康哲药业。 这些选择的背后，是资本市场逻辑的根本转变。市场不再奖励规模，只奖励增长。对一家多元化集团来说，任何一个增长放缓的业务板块，都会成为整体估值的拖累。 而剥离低增长业务，带来的不只是现金流。更重要的是，它能将原本分散的资源，全部集中到回报率最高的核心赛道上。诺华的研发管线不再追求面面俱到，而是锁定在肿瘤、免疫、心血管、神经科学这四个核心领域。 诺华并不是唯一看懂这个趋势的公司，很多跨国药企都在做类似的事，只是选择不同。比如像强生这样的巨头虽然也在剥离骨科等业务，但整体依然保留了庞大的医疗科技板块。 在后续的收购中，诺华也保持着克制与精准。2025年10月，诺华斥资120亿美元收购Avidity，是公司十多年来规模最大的一笔收购。诺华并没有对Avidity的资产照单全收，而是只拿走了自己最需要的神经科学项目，至于那些同样颇具价值的早期精准心脏病学资产，则被果断分拆，独立为新公司Atrium Therapeutics。 当然，这条路并不好走，创新药风险高，诺华也付出了不少代价。 比如在CGT领域。最近，诺华正式放弃了NK细胞疗法管线QEQ278，这是一款NKG2D融合蛋白药物。QEQ278的临床数据实在太过惨淡，在去年10月公布的一项针对晚期实体瘤的早期试验中，30名患者无一例出现疗效反应，更糟的是，半数患者出现了严重不良事件，还发生了两例剂量限制性事件。这个结果，几乎没有任何回旋余地。 -03- 如履薄冰的纯创新之路 对于任何一家跨国药企来说，专利悬崖都是一道绕不开的关卡。诺华虽然通过激进的战略收缩完成了瘦身，但在核心产品的生命周期管理上，依然面临着严峻的考验。锁定在肿瘤、免疫、心血管、神经科学这四大领域之后，各个板块的储备厚度和面临的挑战开始呈现出明显的分化。 心血管、肾脏及代谢领域处境较为紧迫。核心产品Entresto（沙库巴曲缬沙坦）年销售额达77亿美元，但已受专利到期影响出现小幅下滑，所幸在美国以外市场仍保持增长，为调整期提供缓冲。接替重任落在降血脂药物Leqvio（英克司兰）和IgA肾病药物Fabhalta身上，预期峰值分别为40亿和30亿美元。 但目前接棒产品放量速度远追不上失速：Leqvio 2025年销量接近12亿美元，Fabhalta虽接近三倍增长至5亿美元，距离峰值仍有差距。后续看点，还得指望心血管储备管线中的小核酸药物Pelacarsen（Lpa ASO）。 自免领域处境更为微妙。重磅产品Cosentyx（司库奇尤单抗）即将专利到期，正进行最后冲刺（2025年67亿美元，预期峰值80亿）。Xolair（奥马珠单抗）17亿美元年销售额也即将面临仿制药冲击。Ilaris（卡那单抗）保持25%增长（19亿美元），但体量有限。 增量来自2025年获批的BTK抑制剂Rhapsido（瑞米布替尼），已拿下慢性自发性荨麻疹适应症，并拓展至重症肌无力、多发性硬化等自免疾病。但后备力量仍显薄弱——除在研的ianalumab外，自免管线远不及肿瘤和神经科学领域充实。 肿瘤领域是当前业绩支柱。Kisqali（瑞波西利）是最亮眼增长引擎，凭借乳腺癌生存获益，销售额达47亿美元（同比+58%）。尽管2027年专利到期，但预期峰值可达100亿美元，目前已跃居CDK4/6抑制剂市场前三，快速追赶礼来和辉瑞。 Pluvicto销售额近20亿美元（+43%），预期峰值50亿。Scemblix凭借慢性髓系白血病差异化优势，销售额近13亿美元（+87%），有望冲击40亿峰值。加上pelabresib等储备，肿瘤领域接力相对连贯。 神经科学板块的销量2025年增长最快（+26%），净销售额60亿美元。核心驱动力来自Kesimpta（奥法妥木单抗），这款多发性硬化症B细胞疗法凭借便利性和疗效优势，实现44亿美元销售额（+37%），美国专利2031年到期。Kesimpta身后的可能性，押注在收购Avidity获得的神经肌肉疾病管线上。 现在回头看诺华的五年“纯创新之路”，从财务和市值看是初步成功的，在没有热门管线的情况下稳住基本盘，且股价跑赢大盘。而且避免了在同质化竞争中消耗资源，提前卡位了核药、基因疗法、RNA这几个技术门槛足够高的赛道。 但未来五年的“Gap Years”，公司处境来看依然如履薄冰，心血管和自免领域存在明显的断层焦虑，Leqvio们必须跑得更快，Pelacarsen们必须证明自己不仅仅是看点而是爆点。 ...... 加入读者群欢迎添加： 吴妮：nora4409

Pfizer’s urgency to quickly expand the clinical program of its PD-1xVEGF bispecific antibody highlights a thrilling race to develop a successor to displace Keytruda, the current immuno-oncology king.\n Oncology projects currently take up about 40% of Pfizer’s overall R&D budget. Behind this construction is Jeff Legos, Ph.D., who became the firm’s chief oncology officer last year following a high-profile move from Novartis.After steering positive key pivotal readouts for a trio of Novartis’ blockbusters—Kisqali, Pluvicto and Scemblix—Legos is now tasked with fleshing out Pfizer’s $43 billion Seagen acquisition into an antibody-drug conjugate empire while accelerating a PD-1xVEGF bispecific licensed from 3SBio toward 2028 readouts.For the closely watched PD-1xVEGF competition, Legos’ strategy for Pfizer is anchored by three pillars: speed, breadth and novel combinations.“We are operating under very expedited timelines in terms of the first wave of studies,” Legos said in an interview with Fierce Biotech. Slamming the gasPfizer cleared regulatory requirements and completed the licensing agreement for 3SBio\'s PD-1xVEGF bispecific toward the end of July 2025. For an upfront payment of $1.25 billion and potential milestones of up to $4.8 billion, Pfizer gained ex-China rights to SSGJ-707, now also known as PF-08634404.By the end of 2025, Pfizer would have had regulatory discussions with the FDA and launched seven clinical trials, including three phase 3 studies, for the PD-1xVEGF drug. And the company plans to start another five studies by June this year. Normally, it would take about a year from clinical ideation to a study start, Legos noted.As to breadth, Pfizer is examining all of the existing indications of Merck & Co.’s Keytruda, trying to figure out where the PD-1xVEGF inhibitor can go, with additional considerations paid to disease prevalence and unmet medical need, Legos said.  The urgency to quickly expand PF-08634404’s clinical program highlights a thrilling race to develop a successor to displace Keytruda, the current immuno-oncology king. To justify its price tag, Pfizer has talked about how PF-08634404 is differentiated from other candidates from a chemistry and biological mechanism perspective. But the phase 3 programs that Pfizer has outlined so far appear similar—if not identical—to what its rivals Summit Therapeutics/Akeso and BioNTech/Bristol Myers Squibb are undertaking for their PD(L)1xVEGF candidates.Some of the same settings where Pfizer is running phase 3 include a first-line non-small cell lung cancer study pitting PF-08634404 against Keytruda in their respective combinations with chemotherapy across both squamous and nonsquamous histologies, against Roche’s Tecentriq and chemo in first-line extensive-stage small cell lung cancer, and phase 3 tests in first-line gastric cancer and first-line colorectal cancer. PF-08634404 is a tetravalent antibody with four binding domains, two each for PD-1 and VEGF. The structure provides more robust cooperative binding and create a so-called “daisy chain” effect that could bring more cancer-killing T cells to the tumor microenvironment, Legos explained.“Despite that [scientific rationale], it does come down to clinical data, and that’s why we are required to test it in these very well-defined patient populations,” Legos said.Even though Keytruda has established itself as the standard of care in first-line NSCLC, only about 30% of patients benefit from immunotherapy, and only 30% of those patients benefitting experience long-term, durable responses, Legos observed. And in colorectal cancer, immunotherapy remains less effective in microsatellite-stable tumors. The unmet need prompted Pfizer to study whether PF-08634404 can improve patients’ outcomes, he said.  Can PD-1xVEGF live up to its promise?Despite billions of dollars being poured into the PD-(L)1xVEGF space, the main criticism against the class is its seemingly weak ability to turn slowing tumor progression into prolonging patients’ lives. Summit and Akeso’s first-in-class ivonescimab recently showed a 26% death risk reduction in Chinese patients with previously treated EGFR-mutated NSCLC at the final analysis of the phase 3 HARMONi-A trial. But when it comes to the global HARMONi trial, the overall survival data failed to meet statistical significance.Legos argues that those data shouldn’t discount the broader potential of the PD-1xVEGF mechanism. Neither PD-1 nor VEGF inhibitor works very well separately in EGFR-mutated NSCLC, so it’s “not so surprising that the overall survival data is more borderline,” he said.And the problem may not be PD-1xVEGF anyway.“When you design a study with smaller patient numbers, in order to meet predefined endpoint around progression-free survival, you may not have enough power to sufficiently demonstrate the overall survival benefit,” Legos said.For PF-08634404, Pfizer plans to make overall survival at least a primary endpoint in all its phase 3 trials.“It comes down to the intention of the trial and your statistical analysis plan up front, and then ultimately the patient population that we are studying,” he said. Answers to the question of whether Pfizer’s PD-1xVEGF drug can be the next Keytruda will start to emerge in 2028, when the company expects readouts from the first wave of its phase 3 programs.However, the landscape of cancer care is forever evolving, and PD-(L)1xVEGF is not the only force that has its eyes on the prize. Notably, Merck is investing aggressively in its Kelun Biotech-partnered TROP2 antibody-drug conjugate sacituzumab tirumotecan (sac-TMT) but has been quiet on its own PD-1xVEGF bispecific after licensing the asset from China’s LaNova Medicines—now part of Sino Biopharm—in late 2024.“I’m not sure it’s an either-or, because they’re doing two very different things,” Legos said of a potential showdown between PD-1xVEGF bispecifics and TROP2 ADCs.ADCs, as targeted missiles to deliver a cancer-killing payload, can achieve immediate cytotoxic cell death.“But frankly, we’re not just looking for improvements in response rates,” Legos continued. “Without engaging the immune system, I think the benefit of just a single modality may be limited in terms of its fullest potential.”Merck is already pairing sac-TMT with Keytruda in phase 3 trials in multiple tumor settings. As to whether a TROP2 ADC can be combined with a PD-1xVEGF bispecific, “those experiments would have to be done,” Legos said. Expanding Pfizer’s oncology pipelineCombination with other novel agents, including ADCs, is already on Legos’ agenda, forming the third pillar of his strategy in hopes of truly differentiating PF-08634404 from its peers. One of the phase 3 studies being planned pairs PF-08634404 with Pfizer’s Astellas-partnered ADC Padcev in first-line bladder cancer, a setting where the Padcev-Keytruda combo has recorded standing ovation-worthy data. Following the Seagen buy, questions persist regarding Pfizer’s ability to build a sustainable ADC pipeline while avoiding the path of Gilead Sciences, which has not produced a new ADC beyond the TROP2-directed Trodelvy in the six years since its $21 billion acquisition of Immunomedics. Pfizer discontinued a B7-H4 ADC a year ago and has repeatedly pared back efforts around its RemeGen-partnered HER2 ADC disitamab vedotin.Legos remains optimistic that new ADCs are coming out of Pfizer. Among eight key readouts that Pfizer expects this year across the group, sigvotatug vedotin, an ADC targeting integrin-beta6, is expected to report phase 3 data in second-line nonsquamous NSCLC in the first half of 2026.With its biology experts and partners, Pfizer is profiling novel antigens to target for next-generation ADCs and is examining “a variety of permutations,” such as bispecific antibody constructions and novel payloads, Legos said.“Instead of just focusing on traditional cytotoxic payloads, which I think have done very well, we’re now leveraging our small-molecule chemistry, and these could be low molecular weight inhibitors, they could be molecular glues, they could be targeted protein degraders,” Legos said. “These can become the basis of payloads where you can deliver very high dose, high concentration of a specific inhibitor directly to the cancer cells, thereby minimizing any safety or tolerability challenges but optimizing a therapeutic index.”The mix-and-match has already begun. Instead of the vedotin payload, Pfizer is testing another integrin beta6 candidate with a TOPO1 payload in phase 1 dose escalation, and is developing a third intravesical molecule with a unique payload in non-muscle invasive bladder cancer to complement Padcev, according to Legos.“We are working on modifying all of those different variables to bring forward what we believe to be a potentially practice-changing ADC in our priority disease areas,” Legos said. The Pfizer oncology pipeline currently includes traditional small molecules, regular antibodies, ADCs and bispecifics, including T-cell engager. But the company does not have any CAR-T projects. Pfizer Ventures was a top investor in Capstan Therapeutics, an in vivo CAR-T biotech that was recently bought by AbbVie. Legos said he’s “fairly agnostic to” modalities and is “completely open […] to pursue innovation wherever it originates.”“We have all of the building blocks that hopefully helps us accelerate the time to patient, but we are open and interested to explore all types of innovation, irrespective of modality,” he said.While the large deals for Seagen and 3SBio’s PD-1xVEGF drug have put rejuvenation of oncology at the top of Pfizer investors’ mind, obesity has grabbed their attention lately in the forms of Pfizer’s $10 billion takeover of Metsera and a $1.9 billion biobucks deal for new GLP-1 therapies from Fosun Pharma.Pointing to oncology’s 40% allocation of Pfizer’s entire R&D budget, Legos said he’s not worried about competition for resources internally with metabolic diseases but sees potential for mutual lessons sharing.“I’m very hopeful about the potential intersections of cancer and the insulin axis as it relates to the future of care,” Legos said. “For a company that actually can be a leader in obesity and in oncology, it’s an opportunity to think about how cancer care is done on the backbone of GLP-1, amylin, GIP as part of the future.”