Infliximab

自免「药王」的争夺，只是 MNC 争夺市场蛋糕的一个缩影。 2024 年，赛诺菲的 Dupixent（度普利尤单抗）脱颖而出，成功摘得新一任自免「药王」桂冠，力压艾伯维的 Humira（修美乐，阿达木单抗）、Skyrizi（利生奇珠单抗）以及强生的 Stelara（乌司奴单抗）。 然而，一花独放不是春，市场格局并未因此改变：艾伯维依然稳居自免业务收入榜首，强生从 2021 年到 2024 年一直排名第二，赛诺菲则紧随其后。 但强生不甘心每次都屈居第二，一直在狠狠发力追赶。这种不认输的劲头，给「自免一哥」之争带来了不少看点。 左搏艾伯维，右击赛诺菲 自免领域是大药集中营，全球制药巨头都对其趋之若鹜。 从市场格局看，赛诺菲、艾伯维和强生形成了三足鼎立的局面。2024 年，三大巨头的自免业务收入规模均超过 100 亿美元。尤其是艾伯维实现收入高达 266.82 亿美元，以断层第一的优势牢牢占据自免市场的霸主地位。强生、赛诺菲则分别以 178.28 亿美元、146.39 亿美元位居第二、第三名。 就强生而言，自免板块对其业绩的贡献十分突出，仅次于肿瘤业务（207.81 亿美元），是未来发展的主战场之一。 回望 2024 年，由于大单品乌司奴单抗和其他自免产品销售额出现下滑，强生自免板块收入同比微降 1.2%。其中，乌司奴单抗因专利到期和生物类似药竞争，销售额同比下降 4.6% 至 103.61 亿美元；Simponi（戈利木单抗）、Remicade（英夫利西单抗）分别实现销售额为 21.9 亿美元（-0.3%）、16.05 亿美元（-12.8%）。 乌司奴单抗历年销售额 来源：Insight 数据库 乌司奴单抗与曾经的药王修美乐面临着相似的困境，强生和艾伯维需要新的产品来填补自免业绩缺口。 众所周知，修美乐贡献了艾伯维自免板块大部分市场份额，对业绩影响较大。2023 年，由于修美乐销售额大幅下滑，艾伯维免疫学业务营收同比下降约 10%。 修美乐历年销售额 来源：Insight 数据库 然而，随着新药 IL-23 单抗 Skyrizi 和 JAK1 抑制剂 Rinvoq（乌帕替尼）实现强劲销售，抵消了修美乐收入下滑的影响，艾伯维的自免营收重回增长轨道（2024 年同比增长 2.1%）。其中，Skyrizi 销售额同比增长 50.9% 至 117.18 亿美元，Rinvoq 同比增长 50.4% 至 59.71 亿美元，两者收入规模合计远超修美乐，完成了交棒。 对比来看，强生的 Simponi 和 Remicade 体量较小，对业绩贡献有限。目前，有望接棒乌司奴单抗、填补业绩缺口的是 IL-23 抑制剂 Tremfya（古塞奇尤单抗）。2024 年，古塞奇尤单抗继续保持两位数的增长，实现销售额同比增长 16.6% 至 36.7 亿美元，机构预测 2026 年销售峰值可达 61 亿美金。 古塞奇尤单抗历年销售额 来源：Insight 数据库 但是，强生要想赶超艾伯维，拿下自免一哥宝座，仅依靠现有产品显然还不够。更何况，还有赛诺菲这一劲敌在虎视眈眈。 2024 年，赛诺菲的自免业务收入与强生仅相差 31.89 亿美元，几乎相当于一个「Tremfya」。而且，尽管目前赛诺菲的自免产品不多，但由于 Dupixent（度普利尤单抗）正值当打之年，市场预测其销售额峰值有望超过 200 亿美元大关，再加上未来将陆续上市新产品，赛诺菲的实力不容小觑。 但强生不想认输，为了打破困局，正在不断壮大自身力量。 利剑出鞘 多年保持两位数增长的古塞奇尤单抗，是强生重点打造的一把利剑。 作为首个也是唯一的全人源、具有双重作用机制、可选择性中和白介素 23 的抑制剂，古塞奇尤单抗对强生意义重大：一是，百亿美元畅销药物乌司奴单抗的荣光正逐渐暗淡，亟待新产品接棒填补；二是，古塞奇尤单抗在治疗克罗恩病的头对头试验中击败了乌司奴单抗，霸气展现出「接班人」气势。 目前，强生正在加速拓展古塞奇尤单抗的适应症范围，2025 年预计将有 6 个新适应症获批上市，包括溃疡性结肠炎（皮下诱导）、克罗恩病（皮下诱导）、儿童银屑病、克罗恩病、幼年型银屑病关节炎、溃疡性结肠炎，意味着未来有望进入加速放量期。 来源：强生 2024 年财报 PPT 可见，强生在自免领域的开发重点，转移到了差异化的炎症性肠病（IBD）上。IBD 由溃疡性结肠炎（UC）和克罗恩病（CD）组成，全球约有 600-800 万患者，存在巨大未被满足的临床需求。 不过，从竞争格局看，强生在 IL-23 靶向药领域要面对两大劲敌：艾伯维的 Skyrizi（利生奇珠单抗）、礼来的 Mirikizumab（米吉珠单抗），此前两者接连在治疗克罗恩病的头对头研究中击败了乌司奴单抗。 来源：Insight 数据库 尤其是 Skyrizi，得益于斩获银屑病、克罗恩病等大适应症，2024 年销售额同比增长 50%，成功跻身百亿美元营收俱乐部。另外，分析师预测，米吉珠单抗将在 2028 年达到 12 亿美元的年销售量。 强生不甘落后，为了巩固自免市场领先地位，采用了引进和收购的布局策略。 针对 IL-23 靶向注射剂患者顺应性不足的局限性，强生斥资近 10 亿美元从 Protagonist 引进了具备 BIC 潜力的口服 IL-23R 拮抗剂 Icotrokinra，通过自我进化予以反击。 目前，Icotrokinr 治疗银屑病的 III 期研究已成功完成，计划 2025 年提交上市申请（US/EU），而且治疗溃疡性结肠炎的Ⅱb 期研究也取得积极顶线结果，加上全球在研的口服 IL-23R 靶向药物较少，强生预计 Icotrokinra 的年峰值销售额有望达到 50 亿美元以上。 另外，强生在 2024 年也有大动作：先以 8.5 亿美元收购双抗公司 Proteologix，获得多款针对特应性皮炎和哮喘的自免双抗疗法，之后又以 12.5 亿美元收购 Yellow Jersey（Numab 子公司），获得一款治疗特应性皮炎的 FIC 双抗 NM26 的全球权益。 这表明，强生在自免领域的研发重点已经发生转变，从过去主要聚焦 IL-17 和 IL-23 两个靶点开发，转而布局差异化的自免双抗产品组合。 值得一提的是，上述管线并不是强生打造的所有利剑。 后手棋 即将获批上市的 Nipocalimab（尼卡利单抗），是强生祭出的「后手棋」。 尼卡利单抗是强生豪掷 65 亿美元收购 Momenta Pharmaceuticals 获得的潜在 BIC 的 FcRn 单抗，已于 2024 年 8 月在美国提交治疗重症肌无力（MG）的上市申请。强生预计，尼卡利单抗的销售峰值将达到 50 亿美元。 FcRn 靶点在自免领域的实力已得到市场验证。Argenx/再鼎医药的全球首款 FcRn 拮抗剂 Efgartigimod（艾加莫德），仅凭成人全身性重症肌无力（gMG）这一个适应症，销售额从 2022 年的 3.29 亿美元迅速飙升至 2024 年的 21.86 亿美元。 除了 MG，尼卡利单抗还在开展多个适应症的临床研究，包括干燥综合征（SjD）、类风湿关节炎、胎儿和新生儿溶血病（HDFN）、温热型自身免疫性溶血性贫血（wAIHA）等。其中，用于 wAIHA 的上市申请（US）有望在 2025 年递交。 此外，尼卡利单抗已获得 FDA 授予突破性疗法认定，用于治疗成人中度至重度 SjD。据统计，全球约 400 万 SjD 患者‌，但目前还没有批准治疗 SjD 的潜在和全身性的疗法。尼卡利单抗已在Ⅱ期研究读出积极结果，有望成为 FcRn 靶点首个用于治疗 SjD 的药物。 后期管线中，自免双抗组合也是强生争夺「自免一哥」的一大助力。强生免疫学全球副总裁 Candice Long 表示，「差异化的双抗产品组合是强生在免疫领域的下一个创新篇章。」 来源：Insight 数据库整理 目前，强生收购 Proteologix 获得的 PX128（IL-13/TSLP 双抗）、PX130（IL-13/IL-22 双抗），即将进入 Ⅰ 期研究。其中，PX128 主治中度至重度特应性皮炎（AD）和中度至重度哮喘；PX130 主治中重度 AD。这两种药物的用药间隔都不太频繁，为患者提供了更多便利。 强生创新医学全球免疫学治疗领域负责人 David Lee 表示，「大约 70% 使用现有标准护理疗法的患者未达到缓解。目前针对 AD 的先进疗法要么针对单一途径且疗效有限，要么具有更广泛的免疫抑制作用，导致严重的安全问题。我们看到了 PX128 和 PX130 获得最佳疾病疗效的机会，因为每种双抗都针对介导 AD 患者异质亚群皮肤炎症的两种不同的疾病驱动途径组合。」 另外，强生收购 Yellow Jersey 获得的 NM26（IL-31/IL-4Rα双抗），正在开展治疗 AD 的临床 II 期研究，有可能为皮肤炎症伴有剧烈瘙痒的患者提供针对性的治疗。 可以预见，未来随着这些管线成功上市，或有望为强生填补业绩缺口。 结语 MNC 巨头在自免领域的角逐，本质上是管线布局的终极比拼。 例如，艾伯维采取「狙击式」策略重点突破（IL-23+JAK1），捍卫霸主地位；强生编织起「网状式」攻防体系，通过多靶点协同形成紧密的风险分散网，彰显长线思维；赛诺菲则以「尖刀式」超级单品战略，带来短期的爆发力。 这种战略分化背后，折射出不同发展阶段药企的风险博弈。这场自免霸主之争，似乎已升维为药物开发范式的路线之争。 封面来源：视觉中国 免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。 编辑：月牙 PR 稿对接：微信 insightxb 投稿：微信 insightxb；邮箱 insight@dxy.cn 多样化功能、可溯源数据…… Insight 数据库网页版等你体验 点击阅读原文，立刻解锁！

iStock, SvetaZi With Keytruda, the best-selling drug in the world, facing the end of exclusivity in 2028, BioSpace looks at five drugs that have taken the leap off the patent cliff. Big Pharma is staring down the barrel of blockbuster patent expirations over the next few years. Merck’s Keytruda, for example, is far and away the best-selling drug on the planet at the moment, clocking in at nearly $30 billion in worldwide sales in 2024 , but will go off patent in 2028, and the industry is now racing to develop biosimilars to get a piece of the enormous PD-1 market share. Like many companies facing substantial loss of revenue due to loss of exclusivity, Merck is doing what it can to protect Keytruda. The pharma company has filed at least 129 patents since Keytruda’s initial approval in 2014, most of which cover new indications and formulations for the drug, rather than the drug itself. This so-called patent thicket could theoretically push its protection into 2036. The company’s patent dance has prompted investigation from the office of U.S. Sen. Elizabeth Warren, D-Mass., to investigate what she called Merck’s “ monopoly power .” Meanwhile, Novo Nordisk is taking a similar tack, building out a complex web of nearly two dozen patents for its blockbuster diabetes drug Ozempic, which came in second on last year’s list of top-selling drugs with nearly $17 billion in sales. Novo has a little more breathing room before Ozempic, also marketed as Wegovy for weight loss, faces generic competition. While the first round of core patents are set to expire in 2026, a secondary group will give Novo exclusivity until 2033. But if history is any guide, losing exclusivity is not always the death knell of a drug’s profitability. Here, BioSpace explores the sales trajectories of recent blockbuster drugs, before and after they lost their patent, to search out a pattern in the post-exclusivity drug world. GSK’s Advair Indication: COPD and asthma Peak Sales: $7.9 billion in 2013 Year of Patent Expiry: 2010 A new generation of asthma and COPD treatment arrived in the 1990s and 2000s, with Boehringer Ingelheim and AstraZeneca scooping up billions of dollars in sales with their inhalers. But GSK’s multi-blockbuster treatment Advair beat them all when it hit the market in 2000, becoming the best-selling asthma drug on the marke t at its peak. The drug lost its patent in 2010 but kept selling steadily for years afterward, hitting peak sales of about £5.27 billion ($7.9 billion) in 2013. GSK’s secret sauce was the specialized Diskus device for administering the drug that had its own separate patent kept generics out until 2019 . Generic drugmakers had to find their own device to match with the medicine, which proved difficult for several years. Because of that, “it’s not going to be a classic generic collapse,” analyst Paul Diggle predicted to Reuters in 2010, but rather a “fairly slow collapsing pack of cards.” The data show exactly that. AbbVie’s Humira Indication: Rheumatoid arthritis, psioriasis, ulcerative colitis, other immune-related diseases Peak Sales: $21.2 billion in 2022 Year of Patent Expiry: 2022 Before the earth-shaking numbers that Keytruda put up, AbbVie’s arthritis drug Humira was the reigning champ. After gaining approval in 2008, AbbVie racked up indications in immunology and ran up to peak sales of more than $21 billion in 2022. The drug’s original patent was set to expire in 2016, but AbbVie for years fought off biosimilars through a blizzard of patents—totaling more than 250 for a variety of indications beyond its original intended use in arthritis. That extended the drug’s runway to 2022, when it finally lost exclusivity in the U.S. That extra time gave AbbVie the opportunity to set up two successor drugs: Skyrizi, which AbbVie bought from Boeringer Ingelheim in 2016 for $595 million, and Rinvoq, which AbbVie developed in-house. Together, Skyrizi and Rinvoq have almost made up for Humira’s dive off the patent cliff, totaling about $19 billion in sales in 2024. AbbVie expects Skyrizi and Rinvoq to hit a combined $27 billion in sales by 2027. Amgen’s Neulasta Indication: Immune stimulation in chemotherapy patients Peak Sales: $5.8 billion in 2013 Year of Patent Expiry: 2015 Amgen’s blockbuster drug Neulasta—used to stimulate neutrophil growth primarily in patients undergoing chemotherapy—was an annual top 10 best-selling drug for most of its exclusivity period and perennially one of Amgen’s top sellers, going neck-and-neck with Amgen’s arthritis treatment Enbrel. Amgen didn’t use any special legal maneuvers to prolong the drug’s life after the patent dropped in 2015 (aside from suing potential competitor Coherus, accusing it of poaching Amgen employees to learn about Neulasta). Amgen got lucky that companies jostling to produce their copycats struggled to gain FDA approval. Mylan finally got a biosimilar across the line in 2018, taking a bite out of Amgen’s sales. Sandoz followed in 2019, pushing sales down further. Pfizer’s Lipitor Indication: High cholesterol Peak Sales: $12.9 billion in 2006 Year of Patent Expiry: 2011 Lipitor had an outsized impact on the cardiology space. Its class of drugs—statins —were prescribed to more than 800 million people in 2019, with Lipitor and its generics accounting for nearly 300 million of those. After losing its patent back in 2011, Lipitor fell off a nearly picture-perfect patent cliff when generics immediately cut Pfizer’s sales of the drug by two-thirds in a single year. Pfizer spun off Lipitor and another legacy drug, Viagra, into a separate company, Viatris, in 2020, which has reported steady total sales of the drug of around $400 million per year for the last few years. Pfizer began selling its own Lipitor generic starting in 2011 in partnership with Watson Pharmaceuticals. Johnson & Johnson’s Remicade Indication: Crohn’s disease, rheumatoid arthritis Peak Sales: $6.9 billion in 2016 Year of Patent Expiry: 2016 The TNFa-blocking antibody Remicade was a blockbuster year after year for J&J’s pharmaceuticals unit Janssen. It’s one of the top five best selling drugs of all time, and the rheumatoid arthritis treatment hit its peak sales in 2016, going head-to-head with Humira in the space. J&J spent practically the entire lifetime of the drug fighting tooth and nail to maintain patent exclusivity and protect its margins. In 2018, two lawyers from Brinks Gilson & Lione wrote in the National Law Review that J&J had tried and failed to “rewrite history” with the games it played regarding Remicade’s patent. Pfizer, meanwhile, gambled on the drug’s patent expiring as planned in 2018, launching a biosimilar version in 2016 . When a judge temporarily struck down Remicade’s patent, Pfizer sued J&J in 2017 for anti-competitive practices—litigation that was only resolved in 2021 . In the end, Remicade’s patent expired on time in 2018, and a suite of additional biosimilars stepped into the space, sending the Remicade’s sales plummeting.