Nivolumab

关注并星标CPHI制药在线2024年，肿瘤学药物市场继续稳居全球制药行业的核心位置，销售额已突破新的里程碑，显示出前所未有的增长潜力。随着精准医疗和免疫肿瘤学的不断推进，靶向疗法和免疫检查点抑制剂等创新药物在全球范围内取得了卓越的商业成功。领先的抗癌药物不仅在销量上持续攀升，还在推动肿瘤治疗领域的技术革新，造福众多癌症患者。通过对2024年销售额排名前十的肿瘤学产品进行分析，我们可以深入探讨这些药物如何塑造未来的癌症治疗格局，同时揭示它们对制药企业及整个医疗体系的重要意义。图1显示了2024年全球销售额前十的肿瘤学产品的销售额及同比变化。　　图1. 2024年全球销售额前十肿瘤学产品。011.Keytruda（pembrolizumab）　● 开发商：默沙东　　● 模态：单抗　　● 作用机制：PD-1抑制剂（免疫检查点抑制剂）　　● 首批时间：2014年9月14日　　● 适应症：黑色素瘤、转移性、非小细胞肺癌、头颈癌、霍奇金淋巴瘤、尿路上皮癌、胃癌、宫颈癌、肝细胞癌、默克尔细胞癌、肾细胞癌、食道癌、子宫内膜癌、鳞状细胞癌、肝细胞癌、乳腺癌、胆道肿瘤、恶性胸膜间皮瘤　　● 2024年销售额：294.8亿美元（同比增长18%，下同）　　● 市场表现分析：2023 年Keytruda坐上了药王的宝座，2024年其全球销售额逼近300亿美元。 Keytruda是一款典型的PIP（Pipeline-in-a-pill）药物，这与之前的药王Humira如出一辙。Keytruda仍在在不断地获取新的适应症批准，包括被批准作为可切除 NSCLC 手术的新辅助辅助疗法，使其成为首个获准用于术前和术后的 PD-1/L1 抑制剂方案。此外，它还被批准与安斯泰来和辉瑞的 Padcev（enfortumab vedotin）联合用于治疗局部晚期或转移性尿路上皮癌的一线治疗，并与化疗联合用于治疗局部晚期不可切除或转移性 HER2 阴性胃或胃食管连接部 (GEJ) 腺癌的一线治疗。Keytruda目前最大的挑战者是时间，其专利独占期将于 2028 年到期，而它的峰值销售可能在2027年到来。022.Darzalex（daratumumab）● 开发商：强生/Genmab　　● 模态：单抗　　● 作用机制：抗CD38抗体　　● 首批时间：2015年11月16日　　● 适应症：多发性骨髓瘤　　● 2024年销售额：116.7亿美元（20%）　　● 市场表现分析：多发性骨髓瘤是第二常见的血液癌症，仍然无法治愈，现有的治疗方法主要针对延长患者生存期并改善生活质量。2024年，美国预计有超过35000例新病例被诊断。强生的Darzalex和Darzalex Faspro通过靶向CD38跨膜糖蛋白，彻底改变了多发性骨髓瘤的治疗。CD38在骨髓瘤细胞表面大量表达。Darzalex靶向CD38创新机制不仅直接杀死癌细胞，还增强了免疫系统的抗肿瘤反应。而Darzalex Faspro采用皮下给药方式，提高了患者依从性。这些优势，使得Darzalex疗法可显著改善无进展生存期并提高总生存率。Darzalex在2024的销售额同比增长率达到20%，强生和Genmab都预计Darzalex和Darzalex Faspro将继续保持这种良好的增长势头，这是建立在它们在多发性骨髓瘤治疗中的重要地位，以及不断涌现出来的潜力基础之上的。033.Opdivo● 开发商：百时美施贵宝　　● 模态：单抗　　● 作用机制：PD-1抑制剂（免疫检查点抑制剂）　　● 首批时间：2014年12月22日　　● 适应症：黑色素瘤、转移性、非小细胞肺癌、肾细胞癌、霍奇金淋巴瘤、头颈癌、尿路上皮癌、结直肠癌、肝细胞癌、食道癌、恶性胸膜间皮瘤、胃癌　　● 2024年销售额：93.04亿美元（7%）　　● 市场表现分析：2023 年，Opdivo 的全球销售额突破了100 亿美元，其中 90.09 亿美元归属于 BMS，1455 亿日元（约合 10.36 亿美元）归属于小野制药。Opdivo也是一款PIP产品，2024年获得了两项FDA批准，包括与顺铂和吉西他滨联合用于不可切除或转移性尿路上皮癌成人患者的一线治疗，以及对于可切除的非小细胞肺癌（NSCLC）的围手术期治疗方案。尽管 Opdivo 的专利独占期将于 2028 年到期，但 BMS 正在积极寻求更多机会。目前正在进行 III 期试验，以评估 Opdivo 在肌层浸润性尿路上皮癌、肝细胞癌 (HCC) 和辅助治疗期间 NSCLC 中的作用。Opdivo的皮下注射版本Opdivo Qvantig也已获批，赶在老对手Keytruda之前成为为美国首个皮下制剂形式的 PD-1/L1 抑制剂。BMS 的目标是将美国 Opdivo 市场的 30% 至 40% 转化为皮下注射剂型。044.Tagrisso（osimertinib）● 开发商：阿斯利康　　● 模态：小分子　　● 作用机制：表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂（TKI）　　● 首批时间： 2015年11月13日　　● 适应症： 非小细胞肺癌（NSCLC）　　● 2024年销售额：65.8亿美元（12%）　　● 市场表现分析：非小细胞肺癌（NSCLC）是全球最常见的癌症之一，且EGFR突变型非小细胞肺癌患者的比例较高。Tagrisso在治疗携带EGFR突变的非小细胞肺癌患者中表现出了显著的临床疗效，尤其是对具有T790M耐药突变的患者。Tagrisso被批准用于不同阶段和类型的非小细胞肺癌患者，特别是针对EGFR突变的患者。随着多项临床研究和新适应症的不断扩展，Tagrisso的应用范围不断增加，进一步扩大了其市场。除此之外，Tagrisso作为第三代EGFR酪氨酸激酶抑制剂具有明显的创新性。相比第一代和第二代EGFR酪氨酸激酶抑制剂，Tagrisso具有更好的选择性和耐药突变应对能力，因此在市场中有更强的竞争力。2024年Tagrisso收获了全球65.8亿美元的年销售额，同比增长高达12%。055.Imbruvica（Ibrutinib）● 开发商：强生/艾伯维　　● 模态：小分子　　● 作用机制：布鲁顿酪氨酸激酶 (BTK) 抑制剂　　● 首批时间：2013年11月13日　　● 适应症：慢性淋巴细胞白血病、瓦尔登斯特伦巨球蛋白血症、移植物抗宿主病　 ●2024年销售额：33.47亿美元（艾伯维，-6.9%），30.38亿美元（强生，-6.9%）　　● 市场表现分析：Imbruvica是一种激酶抑制剂，靶向布鲁顿酪氨酸激酶（BTK），这一蛋白在B细胞受体信号通路中起着关键作用。BTK在恶性B细胞的存活和生长中起到了至关重要的作用。通过抑制BTK，Imbruvica能够减缓或阻止癌细胞的扩散。尽管Imbruvica的2024年销售额同比下降7%（艾伯维和强生的销售均下降7%），但仍然首获了将近64亿美元的表现，说明其仍然具有强劲的市场影响。Imbruvica仍然是艾伯维重要的肿瘤学资产，对于公司具有非常重要的意义。066.Xtandi（Enzalutamide）● 开发商：辉瑞/安斯泰来　　● 模态：小分子　　● 作用机制： 雄激素受体抑制剂　　● 首批时间：2012年8月31日　　● 适应症：前列腺癌　　● 2024年销售额：辉瑞：20.4亿美元（23%）；安斯泰来2024财年数据尚未公布（2023财年Xtandi总销售额为59.7亿美元）　　● 市场表现分析： Xtandi 最初于 2012 年获得 FDA 批准用于治疗转移性去势抵抗性前列腺癌 (mCRPC)，现已成为治疗前列腺癌多个阶段的关键治疗选择。2018 年，Xtandi获批用于治疗非转移性去势抵抗性前列腺癌，随后于 2019 年获批用于治疗转移性去势敏感性前列腺癌。2023 年 11 月，Xtandi 获批用于治疗生化复发且转移风险较高的非转移性去势敏感性前列腺癌。此次批准使 Xtandi 成为首个获批用于非转移性去势敏感性前列腺癌且无需促性腺激素释放激素治疗的雄激素受体信号抑制剂。Xtandi目前仍然保持着明显的上升势头，辉瑞2024财年的Xtandi销售额同比增长了23%，并将继续产生可观的收入。Xtandi受美国专利保护至2027 年 8 月，因此仍然有两年黄金增长期。077.Revlimid（lenalidomide）● 开发商：百时美施贵宝　　● 模态：小分子　　● 作用机制：免疫调节：通过改变细胞因子的产生、调节T细胞共刺激、增强自然杀伤细胞介导的细胞毒性等途径实现　　● 首批时间：2005年12月27日　　● 适应症：骨髓增生异常综合征、多发性骨髓瘤、淋巴瘤、滤泡性淋巴瘤　　● 2024年销售额：57.73亿美元（-5%）　　● 市场表现分析：Revlimid 长期以来一直是多发性骨髓瘤的一线治疗药物，也是 BMS 的重要资产，它长期优异的市场表现主要得益于Revlimid多年来是唯一治疗选择的地位。其专利保护使其在市场上占据主导地位超过十年。但2022 年，Revlimid专利到期，仿制药的推出导致市场占有率下降，去年销售额同比下降了5%。088.Verzenio（abemaciclib）● 开发商：礼来　　● 模态：小分子　　● 作用机制：选择性抑制CDK4和CDK6　　● 首批时间：2017年9月28日　　● 适应症：乳腺癌　　● 2024年销售额：53.07亿美元（37%）　　● 市场表现分析：大约 70% 的乳腺癌属于 HR+ HER2- 亚型。作为CDK4/6抑制剂，Verzenio能够有效抑制肿瘤细胞的增殖，特别是在HR+ HER2-乳腺癌患者中，显示出显著的疗效。其能够延缓疾病进展，改善患者生存期。与其他CDK4/6抑制剂相比，Verzenio在选择性和耐受性方面具有优势，特别是在对CDK4的选择性更高，有助于提高疗效并降低副作用。099.Lynparza（olaparib）● 开发商：阿斯利康/默沙东　　● 模态：小分子　　● 作用机制：聚 ADP 核糖聚合酶 (PARP) 抑制剂　　● 首批时间：2014年12月19日　　● 适应症：卵巢癌、输卵管癌、腹膜癌、乳腺癌、胰腺癌、前列腺癌　　●2024年销售额：36.72亿美元（阿斯利康，7%）; 13.11亿美元（默沙东，9%）　　● 市场表现分析：Lynparza是首个获得批准的PARP抑制剂，专门针对BRCA突变（包括BRCA1和BRCA2）患者进行治疗，特别是对于卵巢癌、乳腺癌和前列腺癌等具有BRCA突变的患者。它通过抑制PARP酶的作用，破坏癌细胞的DNA修复机制，进而诱导癌细胞死亡。其独特的机制使得它在肿瘤治疗中具备了差异化的优势。 Lynparza的有效性在多项临床试验中得到了充分验证，尤其是在治疗卵巢癌、乳腺癌和前列腺癌的患者中，展示了显著的疗效。其在延长无进展生存期和提高患者生活质量方面表现出色，得到了广泛认可。而且Lynparza的适应症逐渐扩大，目前已经获得了九项FDA批准，涵盖了多种癌症，包括卵巢癌、乳腺癌、前列腺癌等，这大大增加了其市场潜力。随着其在不同癌种中的适用范围不断拓展，市场需求不断增加。Lynparza由阿斯利康和默沙东强强联手，全球范围内的市场合作以及双方强大的营销网络使其能够迅速渗透到全球市场，2024年保持了7-9%的销售增长率。1010.Imfinzi（durvalumab）● 开发商：阿斯利康　　● 模态：单抗　　● 作用机制：PD-L1抑制剂　　● 首批时间：2017年5月1日　　● 适应症：非小细胞肺癌、小细胞肺癌、胆道肿瘤、肝细胞癌、子宫内膜癌　　● 2024年销售额：47.17亿美元（9%）　 ● 市场表现分析：Durvalumab作为PD-L1抑制剂，已被批准用于多种癌症的治疗，包括非小细胞肺癌（NSCLC）、膀胱癌、头颈癌等。随着越来越多的适应症和联合治疗方案获得批准，Durvalumab的适用范围不断扩大，市场需求上升。Durvalumab在多项临床试验中显示了显著的疗效，尤其是在非小细胞肺癌等癌症的治疗中。在临床数据的支持下，Durvalumab被越来越多的医院和医生采纳为标准治疗方案之一，促进了销售增长。除此之外，Durvalumab与其他抗癌药物的联合治疗方案展示了其潜力，尤其是在与化疗、靶向治疗等组合使用时，可以增强治疗效果。这种联合治疗的优势使其在多个癌症治疗方案中占据了一席之地。从模态数量对比图来（图2）看，前十名肿瘤学产品中小分子占据微弱优势。前十的肿瘤学产品的榜单中，有6款小分子药物和4款单抗类药物。其它模态，包括细胞与基因疗法，暂时无法跻身前十榜单。而且该6款小分子药物也是绝 对意义上的小分子，不包括多肽和寡核苷酸。　　图2. 2024年销售额前十肿瘤学产品模态数量对比图。虽然小分子药物在数量上占据微弱优势，但榜单的前三名均为单抗模态，而且销售额接近或超过100亿美元。销售额最高的小分子肿瘤学产品Tagrisso的销售额为66亿美元，不足榜首Keytruda的四分之一。从总量来看，前十名中小分子药物2024年总销售额为351亿美元，而单抗药物的销售额达到552亿美元（图3）。　　图3. 2024年销售额前十肿瘤学产品模态销售总额对比图。从适应症肿瘤额分类角度来看（图4），前十产品中绝大多数针对的是实体肿瘤（7）。血癌产品有3款，分别是排名第二的Darzalex （多发性骨髓瘤，117亿美元)，第5的Imbruvica（慢性淋巴细胞白血病，64亿美元）和第7的Revlimid（多发性骨髓瘤，58亿美元）。从销售总额的角度来看（图5），前十名肿瘤学产品中实体肿瘤药物的2024年总销售额达到664亿美元，是血液肿瘤产品总销售额的将近三倍（239亿美元）。从Darzalex取代Opdivo成为肿瘤学产品中销售量榜眼的情况，以及实体瘤销售额方面的巨大领先优势来看，血液肿瘤市场存在这较大未满足的现状和明显的开发潜力，未来可能会有更多的细胞基因疗法进入这个领域并发挥更重要的作用。　　图4. 2024年前十肿瘤学产品适应症对比图。　　图5. 2024年前十肿瘤学产品适应症销售总额对比图。参考资料：1.U.S. Food and Drug Administration Approves Opdivo Qvantig™ (nivolumab and hyaluronidase-nvhy) Injection, for Subcutaneous Use in Most Previously Approved Adult, Solid Tumor Opdivo® (nivolumab) Indications. BMS Press Release. 27. 12. 2024.　　2.Rashid, A. et al. Top 10 Cancer Drugs to Watch in 2024 Based on Recent Sales Data. Xtalks. 26. 11. 2024.　　3.Financial reports of various pharmaceuticals.END2025金笔奖征文活动开启，来投稿吧！领取CPHI & PMEC China 2025展会门票智药研习社课程预告来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

Step back from the multitude of details that go into every big pharma pipeline, and you’ll see the influence that blockbusters have on the entire field. These days, making your mark in R&D at the level the top 15 spenders play requires not just one, two or three experimental drugs that can earn a billion dollars a year. It’s typically about a slate that includes candidates that can bring in $3 billion to $5 billion a year, preferably more. The numbers keep getting bigger. When Merck execs look at the $30 billion-plus hole they have to fill once Keytruda goes off-patent, they know that anything under a billion won’t count for much. And you can see the same math dominating discussions at J&J, Pfizer, Bristol Myers Squibb and more. On the plus side, the drive to move the dial on sales includes changing standards of care for large numbers of patients. That can open up some hard targets that have defied investigators for years. The hunt for first- and best-in-class drugs inspires truly innovative development work. But for patients — including me — who suffer from diseases that aren’t among the major league targets, it can be hard to find much interest among a set of companies that have to think big in order to survive. These days, with IPOs still out of favor, the blockbuster strategy of the big cap players is more influential than ever. Those R&D alliances that can sustain a biotech will be skewed to the companies that are breaking new ground where pharma sees the biggest upsides. And it will bend an entire global industry’s decision-making process. Success breeds success in this field. AstraZeneca, which once struggled to turn around the industry’s weakest pipeline, can now devote close to $14 billion a year for drug research in a variety of fields. And that has helped alter the landscape of the R&D 15, which once was long dominated by Roche. Other key themes emerge here. One of the most important is the emergence of China as a force in drug discovery. BD teams looking for R&D shortcuts have begun picking up drug candidates in bulk in China, presenting a thorny new reality for US and European biotechs that aren’t able to move as quickly. This year, I’m concentrating on public pharma companies, which have always dominated the list. But it excludes the privately-owned Boehringer Ingelheim, where it’s harder to find details on the pipeline. Takeda also drops off this year’s list, falling just short of the dollar mark needed. And Regeneron marks its arrival as the big biotech invests heavily in its pipeline. — John Carroll The big picture: During 2023, Merck bulked up on M&A deals that pumped up its R&D budget line to a whopping $30.5 billion. In 2024, the pharma giant continued shelling out the big bucks, but without a scale-tipping deal like the $10.8 billion Prometheus acquisition we saw included in the R&D line in 2023. Nevertheless, Merck easily held on to the top spot among the 15 biggest public company R&D spenders on the planet. By the end of last year, Merck had once again dwarfed the old R&D spending leaders like Basel-based Roche, where budget discipline remains a constant. Merck has been shoveling cash into the R&D engine because it’s three years away from a titanic collision with a key patent loss for Keytruda, the $30 billion — and counting — PD-1 behemoth that went a long way to changing the way cancer is treated. Merck continues to rack up big annual increases in Keytruda revenue, which has been essential as the company’s other big earner — Gardasil — fizzled in the face of some ambitious sales projections for the China market. There’s one ace in the hole, with analysts arguing over just how much Merck can make from their late-stage subcutaneous version of Keytruda, which will come with a whole new patent life to profit off of. But whether it’s $6 billion or $7 billion a year, that still leaves a Grand Canyon-sized gap in the budget that must be filled. And the rep of CEO Rob Davis and R&D chief Dean Li will be made or lost on their pipeline strategy for a Keytruda replacement. Or replacements. “The future is less monolithic Keytruda,” Davis said . “It’s going to be a lot of smaller, precision-based therapies aimed at specific tumors or indications.” It’s going to take a lot of smaller drugs to mend a rip that size. That means a long string of deals, including a move to elbow its way to the future of immunotherapy with a rival to Summit’s PD-1/VEGF combo. And that required a turn to China, following what is now a well-beaten path for new drugs that they’ve bet big on. Merck kept the focus on China when it inked a deal just days ago for an oral Lp(a) inhibitor from Hengrui . Novartis recently delayed the timeline for wrapping its Phase 3 study for an antisense candidate for Lp(a) (partnered with Ionis), pushing the results for data on 8,000 patients to the first half of 2026. Merck put up a $200 million down payment on a $2 billion deal for an oral treatment that will need to go through a global program. That’s a low-cost deal in front of a major trial expense, and it offers a chance to leap into a race where orals may well end up ruling the franchise. But it’s no Keytruda. Investors don’t care much for the overall picture. Merck’s shares have dwindled more than 21% over the past year, even as sales kept climbing. Wall Street wasn’t crazy about Merck’s decision to withdraw guidance on Gardasil, at all. And the Keytruda dilemma has created a narrative that has dominated the company for years now. Merck execs can project confidence, but R&D spending illustrates a high level of anxiety. The big picture: You can bet that Roche execs were paying particularly close attention to AstraZeneca’s recent release of a positive, preliminary slice of late-stage data for camizestrant, its oral SERD for hormone receptor-positive, HER2-negative breast cancer. The Basel-based pharma giant has been angling — alongside Eli Lilly — to beat a path to the market with a best-in-class oral SERD that can be expected to rack up billions a year, provided they get in early on a field that has been a primary concern for years. Roche CEO Thomas Schinecker has pegged giredestrant as one of its top late-stage drugs, putting it in the pole position of a chart of potential blockbusters as it waits for late-stage data from their persevERA and evERA trials. It’s in a group of seven pipeline therapies that Roche believes can pave the way to new franchises worth $3 billion or more. AstraZeneca has pegged its rival as a $5 billion-plus earner, offering some added insight here on where the market is focused. But the others include some high flyers that face daunting odds in the clinic, as well as a cluster of rivals that Roche has to race for best-in-class status. Take, for example, the amyloid buster trontinemab, which recently offered an early picture of its ability to target the plaque — cognition was not part of that study, though. And the road for Alzheimer’s drugs is long and frequently twisted, with a questionable marketing future if it fails to do more than slow progression. Prasinezumab has failed a couple of mid-stage studies for Parkinson’s, as investigators try to find a population where it works. Parkinson’s remains one of the toughest targets in the industry, with repeated setbacks for key players — including a rival with the mechanism as Roche’s drug. Trontinemab and prasinezumab are both up for Phase 3 enabling readouts this year. Astegolimab is a dark horse Phase 3 candidate in a group of drugs aimed at taking on Dupixent’s dominant role in COPD. That drug — which inhibits the IL-33 receptor ST2 — was flagged for pivotal readouts this year from the ALIENTO and ARNASA trials. A couple of years ago, Roche fronted $310 million to partner with Alnylam on the RNAi drug zilebesiran for hypertension, which has posted positive mid-stage data. That makes the cut as a major potential player. NXT007 offers a new shot at hemophilia A after Roche took a hit on its gene therapy out of the Spark buyout. Long term, Roche wants to keep building around the Hemlibra franchise, which brought in $5 billion in 2024. In the follow-up category of potential blockbusters, Roche counts four drugs with $2 billion to $3 billion in peak sales potential. That group includes their BTK inhibitor fenebrutinib, which has reportedly done well in Phase 2 for MS. That’s up for a pivotal readout this year, along with vamikibart, which is in two studies called SANDCAT and MEERKAT for uveitic macular edema. As one of the biggest R&D operators in the world, Roche can afford a big pipeline with a number of misses. It’s the one or two big successes in each group of contenders that sustain a company of this size, as it proved yet again with their Regeneron rival Vabysmo, which broke through the $4 billion barrier last year as Tecentriq flattened out and exhibited signs of erosion. Polivy also jumped into the blockbuster club, marking a key marketing success. The key thing for Roche R&D is putting up a slate of credible contenders, with a group of late-stage candidates tackling big diseases and at least one big prospect that looks competitive in the multibillion-dollar class. To that end, Roche continues to selectively snap up new candidates and forge new alliances around the globe. In recent months we’ve tracked an antibody pact with UK biotech Oxford BioTherapeutics, heavily weighted to biobucks as is common in discovery deals. And they went back to the China well for a new deal with Innovent on small cell lung cancer that cost $80 million in upfront cash. Paying $1 billion for the off-the-shelf CAR-T tech at Poseida amounted to a small bolt-on in this world. Roche paid $2.7 billion for Carmot, and had some positive early data to exhibit last year. A lot of this will sour or fizzle out. TIGIT was once a hot prospect, but it’s all been bad news on that front. You win some, you lose some in Big Pharma. Roche has been winning enough to stay on top, but the pressure is always on. The big picture: Pascal Soriot took plenty of painful shots during his early years as CEO of a woeful AstraZeneca — including more than a couple from me — with each setback cause for fresh concern. Slowly building a slate of giant franchises in oncology, and buying Alexion to beef up earnings, ended the fretting. By the end of 2024, AstraZeneca’s top execs could boast of full-year revenue growth of 21%. Industry buzz has Soriot spending big chunks of every year in China, where the company has been working to make a confrontation with the government into a commercial speed bump, hoping to continue to romp and stomp while using its international status and UK headquarters to steer clear of the showdown between the US and China. And it recently underscored the connection by unveiling plans for an expansion of its R&D work in China. Its growing commercial success with proven oncology drugs has spurred Soriot to invest heavily in the pipeline, stretching past cancer into other fields, like obesity. Five years ago, AstraZeneca shelled out $6 billion for R&D in 2019. In 2024, that tally had more than doubled as AstraZeneca surged from a cash-strapped player to an industry leader in research, trailing only Merck as the US outfit urgently tries to engineer a replacement set of drugs for an aging Keytruda franchise. Quite a few analysts are ready to offer their thumbs-up for AstraZeneca’s progress, but the question now is likely to center on whether AstraZeneca can keep its winning streak on track. Case in point: Camizestrant has been built into a $5 billion+ annual prospect. Some observers are ready to sign off on a blockbuster future for the oral SERD drug, especially after a recent Phase 3 win, but temper the enthusiasm with somewhat lower sales expectations. Baxdrostat also gets star billing, as Soriot touts “more than 90 late-stage trials underway with an average non-risk adjusted peak year revenue per trial of $1 billion.” The focus now is on performance in the clinic, but AstraZeneca’s financial results give it considerable range to consider more deals. Soriot picked up baxdrostat — exploring a new mechanism of action for hypertension that investigators have been exploring for close to 20 years — in a $1.8 billion deal for CinCor two years ago. And the pharma giant has helped blaze the BD path through China, leaving it in a position to scoop up fresh assets at discount prices. R&D risk is always huge, but investors have liked the odds. $AZN is up 16% over the past year. The big picture: With biosimilar competition ramping up this year for Stelara, one of J&J’s mainstay mega-franchises ($10.4 billion in 2024), the pharma giant needs to rack up some regulatory wins from the late-stage pipeline. The company’s R&D group breathed a sigh of relief when icotrokinra, its big program for IBD brought in from Protagonist, recently delivered — at least on the major points we could see in the company statement — in an important mid-stage trial of the oral IL-23 therapy. J&J execs, who have been slowly unfolding a pipeline-in-a-product strategy for this drug, believe icotrokinra can be a $5 billion-a-year earner, putting it at the tip of the big phalanx of R&D projects now in the pipeline. Another late-stage drug that gets a lot of attention at J&J is nipocalimab for generalized myasthenia gravis, which has nabbed breakthrough drug status at the FDA as it looks for an OK. And there’s a new fast-track designation for this drug in moderate-to-severe Sjögren’s disease. J&J is a behemoth with a long list of marketed drugs, a fact that comforts risk-averse investors. But the churn tends to deter anyone looking for some quick upside. Its medtech group spent $3.7 billion on R&D last year, helping maintain a stable of products that deliver on the bottom line. That helps keep the numbers steady. And it helps when one-time blockbusters-to-be — I’m talking about aticaprant here — flounders in its Phase 3. J&J had slated the anti-depressant in the $1 billion to $5 billion category, up until a few weeks ago when the drug giant wrote it off for insufficient efficacy. Anyone who’s been following depression R&D for the past 20 years wouldn’t have been too surprised to see yet another Phase 3 fail here. But neuro is still surging on increased confidence that scientists can deliver major drugs for unmet needs. For J&J, the belief helped inspire the Intra-Cellular Therapies buyout for $14.6 billion during JPM, finally breaking the year-plus drought of M&A deals that broke the $5 billion barrier. That deal, like the top drugs in its pipeline, underscores a well-known fact about J&J. The company is a global player in R&D — helping break the mold on China deals when it picked up the cancer drug Carvykti. But while the company can be a world-class drug picker, it’s not known for discovery work. J&J has also long been operating under a cloud brought on by its talc settlement talks, where the numbers people have set aside billions and appear to be close to finally completing a deal to shunt talc into a subsidiary and settle up with the bulk of the lawsuits. It’s manageable, but after 16 years and thousands of suits, J&J’s investors would like to move on. Following its spinout of the consumer division, J&J is on an R&D path — sticking with diseases its researchers understand well — it’s likely to follow for years. And that will keep BD busy. The big picture: AbbVie’s story in recent years has centered primarily around its fierce development and then commercialization of Rinvoq and Skyrizi to bridge its way past the revenue gorge created by Humira’s slow-motion loss of exclusivity. Once the biggest drug in the world, Humira is being steadily eclipsed by biosimilars, but the R&D group has kept the ball rolling with new studies to expand their pair of cash cows. The Botox buyout remains another key storyline as AbbVie proves yet again that it has an excellent set of marketing skills. Mission accomplished on the big moves, which isn’t to be underestimated. That may not add up to be the most exciting R&D story in biopharma in 2025, but it has certainly kept investors happy as AbbVie worked through a top-level executive transition and began to try kickstarting some fresh enthusiasm with a few ambitious deals. AbbVie took a major stab at neuroscience when it bought out Cerevel a couple of years ago for $8.7 billion , landing a lead asset in the field. But that strategy largely came a cropper recently with the failure of emraclidine, once intended to help change the standard for treating schizophrenia. Big Pharma has been making a few careful moves in neuro, but the unknowns are still legion, and the risks are extremely high. Roche’s setback on prasinezumab for Parkinson’s in late 2024 underscored that universal truth. AbbVie is still talking up the prospects of tavapadon as it racks up Phase 3 wins, but the upside isn’t as great, as far as the analysts are concerned. AbbVie was a late arrival to the obesity scene, talking up its potential for less frequent dosing and relatively competitive weight loss data with Gubra’s amylin drug. The BD team brought that in for $350 million upfront. There are some ADCs that the R&D group thinks highly of and a host of low-cost early-stage deals intended to raise its prospects for the future. For now, though, AbbVie is clearly relying on its marketing muscle and experienced research groups to keep building key franchises — which it is really, really good at. The jury’s out on whether AbbVie can add some major new franchises to grow the company faster. But they have time now. The big picture: Every time a CEO or biotech investor starts making the case for more M&A, often on background, they inevitably point to Bristol Myers as the poster child for Big Pharma pipeline demand. It faces huge looming patent losses — let’s start with Opdivo — and has a couple of years to wait for the kind of registrational data needed for its most promising late-stage drugs. The pharma giant has certainly been a player in the M&A club, snapping up Karuna ( $14 billion ), RayzeBio ( $4.1 billion for a radiopharmaceutical drug in a hotly contested arena) and Mirati ( $5.8 billion for KRAS) along the way. But recent moves aimed at cutting costs while boosting work in Phase 3 underscore just how tricky this can be. And all the buzz about its need for pricey buyouts hummed right along through a muted year of dealmaking in 2024. By all accounts, a few analysts on the Street seem satisfied that Cobenfy — out of Karuna — is on track to a blockbuster future, starting with schizophrenia and potentially expanding into Alzheimer’s. But its launch late last year didn’t come close to satisfying the skeptics rooting for more BD — which has been encouraged by a set of execs ready and willing to talk up their expectations on the acquisitions side of the business. Among the drugs in late-stage work, you’ll find new multiple myeloma therapies, which Samit Hirawat talked up in the last quarterly run-down. “ … It is very important to continue to develop small molecules, which are easy to deliver and can be combined with the standard of care therapies. And that’s exactly where iberdomide, mezigdomide sit,” he added, highlighting head-to-heads with pomalidomide (Pomalyst) — facing near-term generic competition — and Revlimid — already losing ground to copycats. Overall, costs have been headed up in R&D at Bristol Myers, and with all hands on deck for a Phase 3 revival of the portfolio, the pharma giant is poised to keep pouring money into drug development. The big picture: The CEO/R&D chief duo of David Ricks and Daniel Skovronsky took home the big prize with the successful launch of the drug juggernaut Zepbound/Mounjaro, which has emerged as the leading obesity/type 2 diabetes treatment in a world hungry for effective fat busters. They aced the main prize in the GLP-1+ field with their own particular take, and they are following up with additional studies to prove efficacy where it can gain reimbursements — while following up with an oral that is aimed at cementing this category in its favor for years to come. That storyline has proved enormously persuasive with investors, as Eli Lilly’s share price has grown 64% over the past two years and its biggest supporters among the analysts glow with enormous projections. But with that much money on the table, it’s no major surprise to see Novo Nordisk double down on its own obesity franchise — a story that’s had a few problems — while the competition aims at doing it better with fewer side effects and a more appealing form of administration has grown into a mob of biopharma companies. It does make you wonder where peak obesity lies. But Lilly is determined to hold onto the lead, no matter how rough this ride may get. And it promises to pay off in the tens of billions per year. To that end is a prospective 2026 launch of orforglipron, an oral GLP-1. Analysts have been on high alert for upcoming T2 data, which Lilly forecasts should look good in comparison to Novo’s semaglutide. That’s the key competitive number they’re looking for. There’s also the multi-targeted retatrutide in the pipeline to consider, where investigators tracked a 12% weight loss in a mid-stage study. Novo certainly has, inking a deal with China’s United Laboratories for an early-stage rival treatment as it looks to be competitive in a range of targets aside from GLP-1. That deal also underscores how Big Pharma can steal a march on a rival drug by scouting R&D programs in China. There’s also remternetug for Alzheimer’s, a quarterly injection to remove amyloid plaque, versus the monthly injection their approved drug donanemab (Kisunla) uses. Analysts once projected billions in upside for the new Alzheimer’s drugs making their way into the market, but skeptics wonder if their modest benefits for patients will win doctors and large numbers of patients over. Lilly’s late-stage cardio drug lepodisiran often earns a mention from leadership, along with their oral follow-up muvalaplin. Then there’s the KRAS contender olomorasib. Add in the occasional buyout — like Morphic — and you’ll get a picture of an ambitious pipeline funded with growing revenue from an effectively marketed drug with the kind of legs that can sustain a company like this for years to come. Given the company’s credibility in drug development, you’re likely to agree that Eli Lilly should never be underestimated. The big picture: By the end of 2022, Pfizer’s rep was pure gold. There was a king’s ransom in revenue for the multinational operation as it capitalized big time on its rapidly successful alliance with BioNTech for their mega-franchise mRNA vaccine to combat Covid. And CEO Albert Bourla basked in the glow of accolades for helping save the world — with the exception of some stray trolls. Then the world turned, vaccine demand plummeted far past most projections and Pfizer was left to pick up the pieces with a revised R&D game plan and revenue that only modestly improved in 2024 after bottoming out at $59.5 billion in ’23. Now, instead of continuing accolades for a truly historic vaccine rollout, analysts were reminded of Pfizer’s long track record for hit-and-miss performance in R&D and commercial ops. And it remains a big player in vaccines, where the long reach of the new Trump administration and its vaccine critics has extended to scrubbing out references to mRNA. Those persistent doubts led Pfizer to recruit Citi analyst — and longtime Pfizer doubter — Andrew Baum to help sell the company’s innovation plans. And he likely is more aware than most of just how hard that is as Pfizer looks to largely tread water on the numbers side this year. Buying Seagen set its course for a higher profile in oncology, which was on display as Bourla cheered their late-stage programs in his recent assessment of what’s ahead. Bourla earlier tapped oncology chief Chris Boshoff to take over R&D from Mikael Dolsten, signaling that it’s relying on a slate of cancer drugs to help replace Ibrance and Xtandi as those big blockbusters lose exclusivity in a couple of years — mere ticks of the clock in drug development cycles. So it’s no surprise to see company execs talking up prospects for the CDK4 inhibitor atirmociclib, now in a Phase 3 breast cancer study. But they took a nasty hit a few weeks ago when vepdegestrant, its protein degrader partnered with Arvinas, fell short in another breast cancer study. Baum also has his work cut out for him talking up Pfizer’s big plans for their oral obesity drug danuglipron, with analysts shaking their heads over a twice-daily dosing as rivals make progress on that front with drugs that may be much better positioned. Its cachexia drug ponsegromab, meanwhile, has had its late-stage development plan trimmed. Underscoring the doubts about Pfizer, analysts haven’t liked watching its sales of RSV vaccine Abrysvo plunge in a turbulent market for everyone involved. The pharma player has to perform consistently on sales if it expects to overcome the skeptics at this point. Add it all up and Pfizer looks like it will continue to operate under a cloud for some time to come, needing to establish a solid track record of significant new approvals and reliable marketing success. In the meantime, look for the company to keep shelling out big dividends to keep investors happy. The big picture: Under the watchful eye of chairman Joerg Reinhardt, Novartis CEO Vas Narasimhan has always proved ready to bring out the scalpel — or the axe — to trim away at its enormous global structure. So no analyst would have been surprised to see Novartis cutting away at its commercial ops in anticipation of a looming patent loss for its heavyweight therapy Entresto. A cliff like that would make many pharmas amp up R&D spending in a big way. Novartis actually cut back in 2024. The other Basel-based pharma giant is playing this one carefully for Wall Street, defending what’s left of patent exclusivity while signaling an LOE for Entresto in the middle of the year. It’s boosted revenue from Entresto in advance of the inevitable decline of its star drug — like pumping money from a dying well — and it’s pushing its other portfolio drugs hard, looking to make up for its blockbuster losses. That push includes building the franchises for Fabhalta, which just won its third approval, along with other drugs like Leqvio and Scemblix. Novartis has maintained a big focus in R&D on its radioligand portfolio, along with cell and gene therapies and RNA. Its late-stage pipeline includes OAV101 IT for spinal muscular atrophy, using a new delivery method aimed at widening the patient population for Zolgensma and now lining up for regulatory approvals. And there’s a big emphasis on votoplam (PTC518) for Huntington’s, in-licensed from PTC. Earlier this year Narasimhan and his execs spent a fair amount of time talking up the prospects of votoplam, which has to complete a mid-stage program successfully before Novartis takes over Phase 3. Huntington’s is wide open for anyone who can move the bar on this fatal neurodegenerative disease. But it’s also incredibly difficult to master, as Novartis knows from its own recent failure in the field with branaplam. Sage has also hit the wall here. But Novartis feels it’s learned a lot from its own setback — enough to believe that they can take the command here. Novartis, despite a busy pipeline overall, has a pretty thin set of late-stage drugs to tout, which led the Wall Street Journal to ask where Narasimhan expects to get its next round of drugs as Novartis sets out to perform with annual revenue increases in the mid-single digit range. Novartis spent a billion in cash on its Huntington’s alliance, underscoring just how careful they are with the R&D budget, which fell year-over-year in 2024. Not surprisingly, he centered on “smaller deals” while insisting he won’t make a move in obesity unless the BD team can line up something particularly distinctive. He also counts himself happy with their 2022/2023 reorganization. Happy, though, doesn’t mean content to leave things be. Novartis is always turning over stones to see where else it can cut. It adds up. And it’s shown zero interest in doing anything splashy. Its recent buyouts underscore that careful approach: MorphoSys was on the outer edge of the $1 billion to $3 billion range where Novartis prefers to play in M&A. At Novartis, financial discipline is a core value. And it’s part of the buttoned-down Swiss approach that isn’t expected to change. The big picture: There are a lot of moving parts at GSK, and not all are headed in the right direction. Its RSV vaccine sales have been on a roller coaster ride. The UK pharma’s big bet on Shingrix was dinged by slipping sales last quarter, all while the Trump administration helped cast a pall over vaccines in general that may well endure for four years. The vaccine market in China has also been wobbly, as Merck can attest to with Gardasil. On the other hand, GSK once again has high hopes for Blenrep, which was yanked from the market in 2022 after flunking a confirmatory study. The IL-5 therapy depemokimab has excited great expectations for £3 billion in annual sales, following up on the success of their asthma drug Nucala. All the while the BD group keeps turning up new deals that bolster their case without weighing heavily on the numbers side. And CEO Emma Walmsley, now an eight-year veteran in the top spot, is promising to move its top line to $50 billion, moving from £31.4 billion last year to 40 billion — a 27% increase in seven years. A lot of that increase will depend on how GSK’s commercial arm can capitalize on new therapeutics like their newly approved antibiotic gepotidacin. Commercial chief Luke Miels has cited analysts’ estimates for up to $1.25 billion for that program, but not everyone is nearly that enthusiastic about the near-term chances for a new antibiotic that could take years to gain a firm footing in the market. GSK has never been flashy. The stock is down about 10% over the past year. If you pull back over a three-year timeline, since GSK spun off its commercial group, the stock is down 19%, all of which has some analysts wondering if the large-cap company may once again become a target of the activist crowd. The big picture: I met Paul Hudson in Paris five years ago, when he stepped in as the new Sanofi CEO after a lengthy dry spell in R&D. Since then, he’s proven time and again that he’s ready and willing to invest in drug research, despite the inevitable ups and downs associated with bigger pipelines. A bit more than two years ago he was concentrating on what he called three major blockbuster candidates (€5 billion-plus): The OX40 drug amlitelimab, frexalimab and SAR441566, an oral TNFR1. And he was ready to sacrifice some profitability to move a pipeline where he counted another nine blockbuster candidates, mostly in immunology and inflammation. He kept that promise, with a boost in R&D spending of 14% in 2024 as Sanofi joined the industry migration out of consumer — staking its future on its ability to push new drugs to big futures. A few days ago Leerink noted that Sanofi was still juggling OX40 drugs to see whether amlitelimab, or its OX40L/TNF bispecific nanobody, would go into Phase 3 for hidradenitis suppurativa. That drug is in Phase 3 in atopic dermatitis and in Phase 2 in asthma and several other indications. Frexalimab failed a Phase 2 for Sjögren’s syndrome last year, narrowing its potential. That came with a Phase 3 failure of venglustat — another one of Hudson’s original top prospects — which nicked off part of its attraction as well. The next tier, where Hudson forecasts sales of €2 billion to €5 billion includes: Sanofi had one huge ace in the hole when Hudson took over the hand. It could rely on big sales of Dupixent ($13 billion in global sales last year) to keep it going in search of a new portfolio. And their marketing expertise in the field — built thanks to their alliance with Regeneron, which did the heavy lifting on the innovation side — would benefit any new drugs to warrant a regulatory approval while easing Aubagio out as generics took hold. The big picture: After hustling its way to the front of the GLP-1 line, Novo Nordisk is now all about the fierce rivalry it’s facing from Eli Lilly while positioning itself against any other entries that could sap its brilliant future in obesity. And that is no easy task, as execs have learned over the past year, while its stock plummeted 45% after peaking out as an obesity darling last summer. It turns out that superheating the stock price set up a supercooling series of events. After seeing explosive growth in revenue last year, Novo’s executive team is counseling analysts about a more modest growth path in 2025 as Eli Lilly brings the heat and pricing pressure grows. One of the big jobs they had to complete ASAP was being able to make enough semaglutide to satisfy the market and get off the drug shortage list — battling back against compounders who were carving up market share. While Novo Nordisk hasn’t been keeping up with average R&D spend among the top 15 — which generally comes in around the low 20s as a percentage of revenue — even 16.5% allowed for a 50% hike in R&D spending last year. In recent weeks Novo not only reorganized its growing R&D ops, it also struck back-to-back deals for new obesity drugs in an effort to stay ahead of the mob out to grab a share of the action. Now diabetes/obesity/MASH will be one R&D cluster focus, with cardio/chronic kidney disease and rare diseases making up the other two legs of its three-pronged research strategy. And like every other company in the R&D 15, it will rely on AI to make better bets on experimental drugs. Normally, that might make an intriguing proposition for investors, but analysts have been more focused on repeated setbacks in the clinic than the prospective benefits of a revised strategy. Novo Nordisk recently aired lackluster data for CagriSema, its follow-up drug that is a combination of the amylin analog cagrilintide and GLP-1. One of the big downsides to GLP-1 is the side effects of the drug, which the amylin analog is thought to limit while building weight loss. But it barely edged a high dose of Zepbound, leaving Lilly in the lead of the expectations game. And it earlier fell far short of the company’s stated expectation that it could trigger 25% weight loss. There’s lots more on the way, but Novo Nordisk has a lot riding on a head-to-head between CagriSema and Zepbound. Those data will come later this year, and failure is not an option. The big picture: Amgen has added a meaningful amount to its R&D budget, but it’s still hanging on in the second tier of the R&D 15. As always with CEO Bob Bradway, there’s a well-thought-out strategy that he’s pursuing — and selling to investors as the best path forward. And as always, the stakes are incredibly high. While looking to build on some existing drug franchises, Bradway once again used his Q4/2024 call with analysts to put the spotlight squarely on Amgen’s top prospect in the pipeline. This year it’s MariTide, an obesity drug that is looking to find a patch of marketing sun in the Big Kahuna of all drug rivalries. But it’s one tough sale. A few months ago, in a story covered by Max Bayer at Endpoints News , Amgen saw its stock take a dive on positive mid-stage data that illustrated a 20% weight loss for the drug. Once upon a time, you could have parlayed that into star status on Wall Street. But no more. It looked a little second-rate compared to the megablockbuster leaders in obesity, Novo Nordisk and a romping, stomping Eli Lilly, even if it can be effective at lower dosing. Amgen has a new take on the glucose-dependent insulinotropic polypeptide (GIP) receptor, blocking it instead of activating it. But it may just be the amped-up GLP-1 component that is delivering the benefit. Amgen has a huge Phase 3 for this one to answer all its questions, but you can see a few analysts are taking to the sidelines on this one, not quite won over by the dosing and design. On the upside: Any significant piece of obesity can be huge, even if in this case it’s relatively small compared to the leaders’ market share. On the downside: A big lead counts for a lot when you’re breaking new ground in therapeutic research, and Amgen definitely does not have the lead here. Amgen, though, will stick to its story. While it’s far from the top 10 in terms of R&D spending, the company has always punched above its weight when it comes to touting an experimental drug. So it was no surprise to see ex-Novartis vet Jay Bradner pick up his first Q4 call at Amgen by keeping his sights set on MariTide. But Bradner is also quick to highlight other late-stage prospects, topped by its Lp(a) drug olpasiran — now one of several drugs in the mix for this target — while waiting on the FDA decision for Uplizna. There’s also the Phase 3 program for rocatinlimab in atopic dermatitis, which has the potential to pursue other pathways, provided the data are strong. That could prove a major caveat, though, While Tim Anderson sees Amgen as 12 to 18 months ahead of Sanofi’s rival OX40 mab amlitelimab, he called one of the mid-stage data cuts “underwhelming” compared to Dupixent, hampered by some safety concerns. The big picture: Gilead has been anchored by HIV for years now, able to take multiple hits on the R&D side without triggering too much angst among investors. And Gilead CEO Daniel O’Day — who celebrated six years in the top post — has been winning over some mild converts to the cause recently, including Tim Anderson. Anderson, like the rank-and-file investor group, is comforted by Biktarvy’s big role in the HIV arena, where Gilead mints money. And he’s intrigued by the upside of a couple of late-stage plays, including anito-cel, which Gilead — partnered with Arcellx — believes can cut down Carvykti from J&J and Legend. That depends a lot on the safety profile that has been emerging in clinical trials. But at this stage, Gilead has seen a slate of oncology prospects go down in flames, which hasn’t done much to increase confidence in a cancer drug now. On the other hand, maybe they are due for a win. If they can cut into line with Carvykti, which is linked with Parkinson’s and other serious side effects, it has the potential to earn billions. And that would push them to their goal of getting 30% of revenue from oncology, rather than continue to rely so heavily on its longtime dominance in HIV. But there are some big ifs along the way, including the developers’ plans to look for an accelerated approval of the CAR-T. The big picture: Regeneron was close to making the R&D 15 in 2023, and it made it through last year with a surge of research spending in 2024 that slipped ahead of Takeda, based on their last four quarters. Regeneron arrives as the only company that still counters its two remarkable founders in the top posts: Science chief George Yancopoulos and CEO Len Schleifer. They got to this point by creating a company that is frequently held up as the gold standard of biotech startups, building two giant franchises in Dupixent (partnered with Sanofi) and Eylea. Now Eylea has biosimilar trouble, but Dupixent is still romping and stomping on the numbers side, giving Regeneron a nice runway to build new drugs. Tim Anderson at Bank of America counts two key drugs in the late-stage pipeline, and one to watch now in Phase 2. There’s fianlimab, a LAG3 treatment in frontline melanoma that hasn’t received a ton of attention. Anderson notes that Regeneron is several years behind Bristol Myers in LAG3, with 2030 sales set under the $900 million mark. LAG3 has had a number of problems in the clinic, though, and the jury is definitely out on what the potential is here. And there’s IL-33 mAB itepekimab, also partnered with Sanofi. Not the next-gen successor to Dupixent as once billed, Anderson still sees blockbuster potential. Then there’s trevogrumab — an anti-myostatin — and the anti-activin A garetosmab for obesity, in Phase 2 development with a host of rivals in the clinic. Of more immediate importance commercially, Regeneron has tagged linvoseltamab , its BCMAxCD3 drug delayed for manufacturing reasons, as a likely near-term entry for multiple myeloma. Sales projections are relatively muted, though. There’s also a CRISPR drug partnered with Intellia, NTLA-2001 for ATTR amyloidosis . Of everyone on the R&D 15, Regeneron is reinvesting a larger percentage of its revenue than any other player. Thirty-seven years after the biotech was created, the founders still see themselves on the cutting edge of drug research.