Efruxifermin

本文来自微信公众号：医曜，作者：青栎，原文标题：《MNC 半年豪掷 107 亿美元，这个脂肪肝靶点终于爆了》，题图来自：AI 生成早在 2023 年底的时候，我们就曾推断：脂肪肝将是减肥药后的下一个千亿战场。如今 MNC 正用真金白银，让这一推断渐渐落地。10 月 9 日，诺和诺德突然宣布重磅交易，以 52 亿美元收购 Akero Therapeutics 公司，获得后者研发的 FGF21 类似物 Efruxifermin。这是一款每周注射一次的治疗代谢功能障碍相关脂肪性肝炎（MASH）的创新药物，目前已经进入到临床 III 期。值得注意的是，FGF21 药物并非诺和诺德一家的心头好，这已经是半年内第三起针对 FGF21 靶点的大型交易。此前葛兰素史克（GSK）和罗氏早已相继入局，分别以 20 亿美元和 35 亿美元收购了同类靶点资产。医药行业上一次出现如此盛况还是在 GLP-1 靶点爆发之时。FGF21，这个曾经默默无闻的靶点，正迅速成为代谢性疾病治疗领域的黄金赛道。代谢冠军的关键拼图FGF21 全称成纤维细胞生长因子 21，是一种主要由肝脏分泌的代谢调节激素，能够调控葡萄糖、脂质和能量代谢参与机体稳态的维持。作为 FGF 超家族中的内分泌成员，与其他促增殖型生长因子截然不同，它不依赖肝素发挥作用，却能精准锚定代谢调节的核心通路，是代谢疾病的"全能调节者"。从生物学机制来看，FGF21 需与靶器官表面的 FGFR1、FGFR2 或 FGFR3 受体，以及共受体 β-Klotho 形成三元复合物，才能激活下游信号通路，而 β-Klotho 主要分布在肝脏、脂肪组织、胰腺等代谢关键器官，这让 FGF21 的作用范围天然聚焦于代谢紊乱相关组织。在生理状态下，当身体处于饥饿、高脂饮食等应激场景时，肝脏和脂肪组织会分泌 FGF21，通过促进脂肪分解、增强胰岛素敏感性、调节糖脂代谢等方式维持能量稳态；而在肥胖、2 型糖尿病、非酒精性脂肪性肝病（NAFLD）等病理状态下，FGF21 的表达或功能会出现异常，这也是其能成为治疗靶点的生物学依据。图：FGF21 结构，来源：国泰海通证券尽管原理较为清晰，但 FGF21 的成药之路却充满波折。天然 FGF21 蛋白半衰期极短，仅为 1 — 2 小时，且在体内易被蛋白酶降解，需频繁注射才能维持药效，这让它长期停留在实验室阶段难以商业化落地。直到近年蛋白质工程技术的突破，才彻底改写了它的命运。通过 PEG 化修饰，可将其半衰期延长至数天，实现每周一次给药，被罗氏收购的 89bio 公司的 pegozafermin 便采用了这一技术；而 Akero 的 Efruxifermin 则通过氨基酸序列突变优化蛋白结构，在增强稳定性的同时，还保留了天然 FGF21 的多靶点调节能力。这些技术改进让 FGF21 从"实验室分子"中脱颖而出，也为其在 MASH 治疗中崭露头角奠定了基础。当前 MASH 治疗格局中，GLP-1 类药物（如诺和诺德的司美格鲁肽）和 THRβ 激动剂（如 Madrigal 的 Rezdiffra）虽已获批用于 F2-F3 期中重度肝纤维化患者，但二者均存在局限：GLP-1 对晚期肝纤维化效果有限，THRβ 激动剂则无法覆盖肝硬化患者。对比之下，FGF21 类药物则展现出全疾病阶段覆盖的潜力。以 Akero 的 Efruxifermin 为例，其公布的 IIb 期临床数据显示，经过 96 周治疗，F2 — F3 期 MASH 患者的肝纤维化改善率接近 50%，F4 期肝硬化患者的改善率也达到 29%，远超安慰剂组的 24% 和 11%；更重要的是，它在改善肝纤维化的同时，还能降低甘油三酯、提升高密度脂蛋白胆固醇，对心血管代谢指标产生正向调节，这恰好弥补了其他疗法的短板。正因为在 MASH 治疗领域的独特优势，FGF21 成为填补 GLP-1 与 THRβ 激动剂空白的"第三极"，也让 FGF21 从曾经的"冷门靶点"，一跃成为跨国药企争相布局的黄金赛道。此外，临床前研究显示，FGF21 类药物在改善非酒精性脂肪性胰腺炎（NAFP）、肥胖合并代谢紊乱等疾病中也有积极表现，适应症边界还将进一步扩大。MNC 的必争之地FGF21 靶点的科学机制与治疗潜力背后，是不言而喻的巨大商业价值。作为全球增长最快的代谢性肝病，MASH 的发病与肥胖、2 型糖尿病高度关联，据弗若斯特沙利文报告，2030 年全球患病人数将达 4.9 亿人，对应的药物市场规模将攀升至 322 亿美元，这一规模与当年 GLP-1 爆发前的市场预期相当。随着 Madrigal 旗下全球首个 MASH 治疗药物 Rezdiffra 的商业化放量持续超预期，其开辟的市场空间正吸引越来越多 MNC 入局。当前已获批的 GLP-1 类药物与 THRβ 激动剂均局限于 F2 — F3 期患者，无法覆盖占比约 20% 的 F4 期肝硬化群体，而 FGF21 类药物逆转肝硬化的独特疗效，恰好填补了这一临床空白。这种不可替代的治疗价值，让其商业化前景被业内广泛看好，也使其成为 MNC 争相抢夺的核心资产。2025 年 5 月，GSK率先行动，以总额高达20 亿美元的现金对价收购了 Boston Pharmaceuticals 的核心资产，FGF21 类似物 Efimosfermin alfa。该药最初由诺华研发，通过 Fc 融合蛋白技术将半衰期延长至 21 天，实现每月一次给药，显著优于竞品的周给药方案。对于在 GLP-1 赛道布局相对滞后的 GSK 而言，Efimosfermin alfa 的加入迅速填补了其在 MASH 领域的空白。GSK 还计划将其与在研 siRNA 疗法 GSK4532990 联用，以覆盖脂肪性肝病（SLD）的更晚期阶段，形成"抗纤维化 + 基因调控"的互补组合，在细分市场建立竞争优势。紧随 GSK 之后，罗氏也在今年 9 月高调宣布，以最高 35 亿美元的价格收购生物制药公司 89bio，获得其核心资产 FGF21 类药物 pegozafermin。该药采用独特的糖基 PEG 化技术，优化了其生物活性和半衰期，目前已进入 III 期临床阶段。罗氏近年来在减重药物领域连续布局：2023 年 12 月，以 31 亿美元收购了美国制药公司 Carmot Therapeutics（GLP-1 双靶点激动剂）；2025 年 3 月，又同意以 53 亿美元获得丹麦 Zealand Pharma 公司一款在研创新减重疗法的相关权益。此次将 Pegozafermin 收入囊中，将加强其在心血管、肾脏及代谢性疾病领域的产品组合，并为其现有在研项目的潜在联合用药方案打开空间。随着 FGF21 资产不断被收购，业绩遭遇拐点的诺和诺德也终于坐不住了。2025 年 10 月，诺和诺德宣布以最高 52 亿美元的价格收购美国生物技术公司 Akero Therapeutics，获得其 FGF21 类似物 Efruxifermin。该药 III 期 SYNCHRONY 研究预计于 2026 年二季度读出数据，较竞品具备先发优势，也与自研的 NN9499 形成互补之势。图：全球领先 FGF21 管线一览，来源：国盛证券这笔交易是其新任首席执行官 Mike Doustdar 自 7 月上任以来的首个重大交易，也是其继宣布裁撤 9000 个岗位后推出的重要动作，体现了其"简化结构、减少重复、集中资源"的战略决心。在面对礼来等竞争对手压力时，诺和诺德积极拓展司美格鲁肽联合疗法，希望找到新的业绩增长点，以巩固其代谢领域的霸主地位。这三笔交易共同体现了 MNC 的战略逻辑：通过收购成熟后期资产快速切入 FGF21 赛道，依托自身管线资源实现协同效应。MNC 拼命在百亿级 MASH 市场中抢占先机，而这种布局也让 FGF21 靶点的竞争逐渐白热化。新的赶超机会？跨国药企在 FGF21 靶点上的密集布局与重金投入，预示着这一靶点极有可能复刻 GLP-1 的成功路径，成为下一代代谢疾病治疗的基石。与 GLP-1 类似，FGF21 不仅靶向明确的巨大临床需求，更可突破单一疾病边界，向减重、心血管保护、血脂代谢等领域延伸。独特的抗纤维化能力，尤其在对晚期肝硬化（F4 期）患者的逆转效应上，构建了难以替代的临床价值与市场壁垒。其"代谢调控"与"组织修复"的双重机制，为未来 GLP-1 与 FGF21 的联合疗法奠定基础，这也是 FGF21 估值飙升的核心逻辑。在跨国药企抢占 FGF21 靶点的浪潮中，中国药企凭借前瞻性的布局与差异化的研发策略，正成为 FGF21 赛道上不可忽视的力量。与跨国药企聚焦单靶点 FGF21 类似物不同，国内企业更聚焦于通过多靶点激动剂探索协同增效的潜力。东阳光药的 HEC88473 是一款 GLP-1/FGF21 双靶点激动剂，通过将两种代谢调节机制结合，在改善糖脂代谢的同时展现出抗肝纤维化潜力。2024 年 11 月，东阳光药就 HEC88473 与 Apollo Therapeutics 达成了总价高达 9.38 亿美元的海外授权协议。该药在国内已进入 II 期临床，早期研究数据显示其在降低肝脏脂肪含量和改善血糖控制方面具有显著疗效。同时，中国生物制药子公司正大天晴通过与安源医药达成合作协议，获得后者 AP025 和 AP026 在中国和部分亚洲地区的独家合作与许可协议，BD 总金额最高为 3.42 亿元另加个位数销售分成。其中 AP025 为单靶点 FGF21，目前处于国内 II 期阶段；AP026 为 FGF21/GLP-1 双靶点药物，目前处于国内申报临床阶段。除已经实现 BD 的东阳光药、安源医药外，华东医药亦是 FGF21 靶点的重要参与者。华东医药旗下控股子公司道尔生物研发的 DR10624，是一款靶向 FGF21R、GLP-1R 和 GCGR 的长效三靶点激动剂。这种"多靶点覆盖"的设计，使 DR10624 成为 FGF21 赛道中极具差异化的候选药物。该药物已在海外完成针对肥胖合并高甘油三酯血症的 Ib/IIa 期研究，并正在中国推进针对代谢相关脂肪性肝病的 II 期临床试验。2025 年 5 月公布的 Ib/IIa 期临床数据显示，DR10624 治疗 12 周后最优剂量组肝脏脂肪含量降幅达到 79%，显著优于安慰剂组的 26%。展望未来，FGF21 赛道的交易热潮预计将持续升温。巨大的 MASH 市场容量以及明确的联合疗法方向，将继续推动 MNC 们对该领域优质资产的追逐。考虑到目前全球范围内进入临床后期的 FGF21 资产仍属稀缺资源，那些已经通过早期临床数据验证了概念、并进入 II 期及以上阶段的在研药物，无疑将成为下一波资本角逐的焦点。FGF21 靶点的百亿并购狂潮，是 GLP-1 传奇在代谢领域的延续与升华。从司美格鲁肽到替尔泊肽，GLP-1 类药物从降糖药跃升为全球"药王"，彻底点燃了全球药企对代谢疾病赛道的热情与期待。而中国药企凭借在多靶点药物上的抢先布局，有潜力在这场全球竞赛中实现追赶，甚至超越。

GSK, Roche and Novo jumped into MASH with a multi-billion-dollar deal spree. Now the phase 3 data have to deliver. For years, MASH was where drug development dreams went to die. One trial after another failed. Companies bowed out. The field earned a reputation as one of biopharma’s most intractable challenges: a complex disease marked by numerous contributing factors that seemed too complicated to crack. Patients with a severe form of fatty liver disease called metabolic dysfunction-associated steatohepatitis—formerly known as nonalcoholic steatohepatitis (NASH)—were left with advice about diet and exercise, and doctors could offer little more than watchful waiting as inflammation and scarring progressed. Then, in March 2024, the narrative cracked. The FDA approved Madrigal Pharmaceuticals’ daily pill Rezdiffra for adults with noncirrhotic MASH and F2-F3 fibrosis. It was the first FDA-approved therapy for the disease, signaling that the bar could be met.Seventeen months later, in mid‑August 2025, Novo Nordisk’s Wegovy—already a blockbuster obesity drug—gained a label expansion to be used as a weekly treatment for adults with noncirrhotic MASH and moderate to advanced fibrosis. With a GLP-1 agonist in the mix, what had been a hepatology problem suddenly belonged to cardiometabolic medicine. Obesity drugs already have the prescribers and patient familiarity plus established ties with payers and PBMs that can speed coverage. That existing distribution network may aid in moving patients toward treatment for their liver disease. Despite the progress, a huge patient gap remains. In the U.S., there are roughly 22 million adults who have MASH, with about 9 million at clinically significant fibrosis (F2/F3)—the very segment Rezdiffra and Wegovy target—leaving many outside treatment today. Even within the label, a gap remains: In the phase 3 Maestro-NASH trial, once-daily Rezdiffra 80 mg and 100 mg achieved MASH resolution with no worsening of fibrosis in 25.9% and 29.9% of patients, respectively, compared to 9.7% with placebo at 52 weeks. Notably, roughly 14% of participants were already on GLP-1 agonists—underscoring the pull toward combination therapy.Against that backdrop, recent acquisitions exceeding $10 billion indicate that major pharma players continue to see a sizable opportunity in MASH. GSK, Roche and Novo stake their claims  GSK moved first among the latecomers. In May 2025, the company agreed to acquire efimosfermin from Boston Pharmaceuticals for $1.2 billion upfront and up to $800 million in milestones. The once‑monthly FGF21 analogue has since changed hands and is being positioned for phase 3 in steatotic liver diseases including MASH. The dosing cadence could give GSK an adherence and convenience case, provided efficacy holds up in late-stage trials. Roche followed in September. The company—long synonymous with cancer care—agreed to acquire 89bio for up to $3.5 billion, capturing pegozafermin, an engineered FGF21 analogue now in phase 3 trials. CEO Thomas Schinecker, Ph.D., framed the deal as portfolio expansion and a bridge to combination approaches across cardiovascular, renal and metabolic diseases. Novo Nordisk, the GLP-1 trailblazer, then announced plans to acquire Akero Therapeutics for about $4.7 billion upfront ($54 per share) plus a $6‑per‑share contingent value right tied to full U.S. approval of efruxifermin in compensated cirrhosis by June 30, 2031—bringing a plausible fibrosis partner to graft on to Wegovy’s newly minted MASH label, if late‑stage data cooperate.  Behind the deal math sits a new clinical reality. Rezdiffra opened the regulatory door and has outpaced early sales projections—more than 17,000 patients were on the therapy by March 31, 2025—and Wegovy’s new label pulled liver disease into one of the most powerful distribution networks in modern medicine. A Spherix Global Insights survey conducted in August—shortly after Wegovy’s MASH label expansion—found that nearly two-thirds of gastroenterologists and hepatologists planned to prescribe the Novo drug within three months, with many anticipating combining it with other therapies for patients with advanced fibrosis. The stack emerges   If the first wave of MASH therapies showed what was possible, the second wave shows what companies believe is necessary. FGF21 analogues—including pegozafermin (Roche/89bio), efruxifermin (Novo/Akero) and efimosfermin (GSK)—aim to reach fibrosis and inflammation in ways incretins may not, especially in patients further along the disease arc. Midstage trials have shown reductions in liver fat and encouraging signals on fibrosis biomarkers. Akero’s 96-week analysis, presented earlier this year, drew “transformational” praise from some analysts, even after an earlier 36-week readout fell short. But phase 3 trials are the industry's truth serum. Those readouts, expected to begin next year, will test whether the science can support the surge of investment that's flowed into the field.The strategy driving that investment is clear: combination therapy. Roche has assembled a modular metabolic stack: CT‑388, a GLP‑1/GIP dual agonist acquired with Carmot Therapeutics; an amylin analogue partnership with Zealand Pharma (petrelintide), including plans for fixed‑dose combinations with CT‑388; and now an FGF21 anchor via 89bio. The company is building from the outside in, collecting mechanisms to test in combination with one another. Madrigal, the field’s first commercial mover, is preparing for the same future. In July 2025, it licensed global rights to CSPC Pharmaceutical’s preclinical oral GLP‑1, SYH2086, for $120 million upfront and up to $2 billion in milestones—explicitly to pair with Rezdiffra. About 25% of Rezdiffra patients are already on a GLP‑1, Madrigal CEO Bill Sibold pointed out in the company's first-quarter earnings presentation.  Novo Nordisk aims to leverage Wegovy's track record in obesity as it extends its efforts to MASH. The Danish pharma boasts a GLP‑1 backbone with a fresh MASH label, onto which it aims to graft Akero’s FGF21 program if the data hold. GSK adds a once-monthly FGF21 to that mix. If efimosfermin delivers fibrosis and other clinical benefits with fewer injections, the company gains both a differentiated marketing angle and leverage at the combination table. Provisional momentum The crowded landscape belies how provisional it remains. Rezdiffra's early success is notable, but Madrigal is naturally pushing to expand beyond F2-F3 noncirrhotic patients. Wegovy's label gives Novo a foothold among noncirrhotic patients with significant fibrosis, but confirmatory outcome data still hang on the horizon. The FGF21 class must show that biomarker gains translate into fibrosis improvements and real clinical benefit, substantial hurdles proportionate to a disease area that humbled an entire generation of researchers.Yet capital keeps flooding in. Roche's $3.5 billion pact for 89bio and Novo's move on Akero signal serious sales expectations. These large pharma companies with manufacturing scale, market access proficiency and deep pockets are stepping in deliberately. GSK is positioned to challenge both with a monthly FGF21 dosing that could matter to prescribers and payers.The stakes are considerable. The MASH sweepstakes went from unsolvable to inevitable in 18 months, with billions committed betting that GLP-1s and FGF21s can work in combination. Early signals—patient data, prescriber intent, midstage biomarkers—suggest the strategy could work. But if phase 3 trials fail on fibrosis, outcomes or safety, regulators may balk. Add liver diagnostics and specialist referrals, and access gets even tougher.