Ervogastat

MASH治疗已从“长期无获批药物”进入多机制并行时代。除THR-β和GLP-1通路外，直接干预肝细胞甘油三酯合成、脂滴储存和脂毒性的肝靶向策略正在加速，其中DGAT2和CIDEB分别代表“减少甘油三酯生成”与“重塑脂滴及脂质处理”的两类方向。 01 从MASLD到MASH：庞大患者基数催生持续治疗需求 代谢功能障碍相关脂肪性肝病（MASLD）以肝脏脂肪变性并伴至少一项心代谢危险因素为主要特征；当疾病进一步出现肝细胞损伤和炎症时，则进入代谢功能障碍相关脂肪性肝炎（MASH）阶段。持续进展可导致显著纤维化、肝硬化及肝细胞癌。 疾病负担仍在扩大。全球系统性分析估计，成人MASLD患病率约为30%，并呈持续上升趋势；相关模型预测，到2040年成人患病率可能超过55%[1,2]。 MASLD并不等同于MASH，但前者构成后者庞大的高风险人群池。MASH患者中，纤维化程度是预测肝脏相关结局的关键指标，因此F2–F3人群已成为当前药物开发和监管审批的核心对象。 治疗格局也发生了结构性变化。2024年3月，FDA加速批准THR-β激动剂Resmetirom，用于非肝硬化、伴中重度纤维化的成人MASH；2025年8月，Semaglutide获得相同疾病阶段的MASH适应证加速批准[3,4]。两项批准验证了MASH药物市场的临床与监管可行性，但疾病的代谢、炎症和纤维化驱动因素高度异质，单一机制难以覆盖全部患者。未来市场更可能呈现分层治疗、肝靶向治疗及联合用药并行的发展格局。 02 MASH不是一条单线通路：脂质失衡驱动多重打击 MASH的发生并非简单的“肝内脂肪增加”。游离脂肪酸输入增加、肝脏新生脂肪生成增强、甘油三酯合成与输出失衡，可共同造成脂质负荷。随后，脂毒性、线粒体与内质网应激、氧化应激及细胞损伤进一步激活Kupffer细胞和其他免疫反应；炎症介质又可驱动肝星状细胞活化和细胞外基质沉积，最终形成纤维化。 病理环节 代表机制/靶点 研发价值 代谢输入与食欲 GLP-1R、FGF21 降低全身代谢负荷并改善肝脂 肝脂合成与处理 THR-β、ACC、FASN、DGAT2、CIDEB 减少脂质生成、储存与脂毒性 炎症与细胞损伤 CCR2/5、ASK1等 缓解炎症放大和肝细胞损伤 纤维化 HSC活化、胶原沉积相关通路 抑制或逆转纤维化 表1:MASH药物研发的主要干预层级 03 同属肝脂代谢网络，DGAT2与CIDEB作用环节不同 DGAT2：把住甘油三酯合成的“最后一关” DGAT2是位于染色体11q13.5的关键酰基转移酶，在肝脏、脂肪细胞和小肠中高表达，主要定位于内质网和脂滴。它通过催化脂酰辅酶A与二酰甘油结合，完成甘油三酯合成的最后一步。抑制DGAT2可减少肝脏甘油三酯合成、脂肪蓄积和炎症，为MASH治疗提供新的干预方向。 图1:DGAT2的相关机制[5]CIDEB：通过增强脂肪酸氧化减轻肝脏脂质负担 研究发现，部分ALD和MASLD患者存在CIDEB体细胞突变，可能通过减少肝脏脂质过载，为突变肝细胞带来生存和扩增优势。 机制上，Cideb 缺失可提升 ATGL 介导的脂解作用，释放游离脂肪酸并激活 PPARα 信号，进而增强脂肪酸 β‑氧化，减少肝脏脂质蓄积。因此，抑制 CIDEB 具备脂肪肝治疗潜力。 图2:CIDEB的相关机制[6] 04 从获批药物到新靶点：MASH管线走向多机制与联合治疗 获批机制方面，Resmetirom通过选择性激活肝脏THR-β改善脂质代谢；Semaglutide则通过GLP-1R通路改善体重和代谢状态。两者获批标志着MASH治疗进入可药物干预阶段，但其批准均基于组织学替代终点，长期临床获益仍需确认性研究验证[3,4]。 DGAT2已有较成熟的人体概念验证。ION224是一款靶向DGAT2的反义寡核苷酸。在一项51周、随机双盲、安慰剂对照的Ⅱ期研究中，90 mg和120 mg剂量均改善了主要组织学终点；120 mg组达到组织学改善的比例为59%，安慰剂组为19%，并观察到MASH缓解及纤维化改善信号[7]。另一款口服DGAT2抑制剂Ervogastat已完成Ⅱ期研究；2026年Madrigal获得其全球许可，并明确提出与Resmetirom开展互补机制联合开发的方向[8]。 CIDEB则正从遗传学验证进入临床检验。ALN-CIDEB为肝靶向RNAi候选药，NCT06836609正在MASLD/MASH成人中评价安全性、耐受性、药代/药效及肝脂变化；截至2026年8月，Alnylam公开管线已将其列入MASH临床项目[9,10]。此外，GalNAc-siCIDEB在多种小鼠MASH模型中显示了降低脂滴形成、炎症、肝脂和纤维化的临床前活性，为该机制提供了补充证据[11]。 05 面向肝靶向核酸药研发：两款人源化模型提供体内验证工具 核酸药通常具有严格的序列和物种特异性。常规野生型小鼠可能无法准确评价针对人DGAT2或人CIDEB设计的siRNA/ASO。百奥赛图分别构建B-hDGAT2和B-hCIDEB人源化小鼠，在保留体内组织环境的同时表达相应人源靶标，可用于靶向核酸药的药效、剂量探索、组织学和转化标志物评价。 B-hDGAT2 mice：支持DGAT2靶向核酸药与GAN诱导MASH评价 人DGAT2 mRNA与蛋白表达分析 表达验证：RT-PCR显示，人DGAT2 mRNA仅在纯合B-hDGAT2小鼠肝脏中检出；蛋白层面在肝脏和脂肪组织中可检测到DGAT2，但所用抗体同时识别人鼠蛋白，因此种属特异性主要由mRNA结果支持。 靶向人DGAT2的核酸药物抑制效率 小核酸敲降验证：单次皮下给予人DGAT2靶向核酸药后，肝脏中人DGAT2 mRNA显著下降。 B-hDGAT2小鼠GAN诱导模型的体内药效评价 药效验证：GAN饮食诱导19周后开始每3周一次给药、共9周，靶向siRNA降低人DGAT2表达，并在组织学上改善肝脏病变及NAS评分，显示该模型可用于DGAT2靶向药物的体内药效评价。 B-hCIDEB mice：覆盖脂肪变、炎症与纤维化多维终点 人CIDEB mRNA表达分析 表达验证：RT-PCR显示，人CIDEB mRNA仅在纯合B-hCIDEB小鼠中检出。 靶向人CIDEB的核酸药物抑制效率 小核酸敲降验证：单次皮下给予人CIDEB靶向siRNA后，肝脏中人CIDEB mRNA显著下降。（客户共享数据） B-hCIDEB小鼠CDAA-HFD诱导模型的体内药效评价 药效验证：在CDAA-HFD诱导体系中，自诱导开始每2周皮下给药一次、共8次。CIDEB靶向siRNA降低肝脏人CIDEB表达及肝TG水平，并改善H&E所见病变和NAS评分；Sirius Red、F4/80及α-SMA结果进一步显示纤维化、巨噬细胞浸润和肝星状细胞活化相关指标下降。该模型适合对CIDEB靶向核酸药进行“靶点沉默—肝脂—炎症—纤维化”的连续评价。 MASH研发正在从广义代谢改善走向更精细的肝脏机制分层。DGAT2通过调控甘油三酯合成，CIDEB则参与肝脏脂质负荷与脂肪酸氧化，均为MASH治疗提供了新的干预方向。随着DGAT2临床证据不断积累、CIDEB靶向药物加速开发，以及联合治疗成为行业趋势，能够表达真实人源靶标并重现脂肪变、炎症和纤维化特征的动物模型，将为候选药物筛选、药效评价及临床转化提供有力支持。 参考资料： [1] Riazi K, et al. The prevalence and incidence of NAFLD worldwide: systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022. [2] Le MH, et al. Forecasted 2040 global prevalence of NAFLD. Clin Mol Hepatol. 2022. [3] FDA. FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease. 2024-03-14. [4] FDA. FDA Approves Treatment for Serious Liver Disease Known as MASH. 2025-08-15. [5] Yen CLE, Stone SJ, Koliwad S, Harris C, Farese RV Jr. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. Journal of Lipid Research. 2008;49(11):2283–2301. doi: 10.1194/jlr.R800018-JLR200. [6] Zeng Q, Patel S, Wang X, et al. Somatic loss-of-function mutations in CIDEB reduce hepatic steatosis by increasing lipolysis and fatty acid oxidation. Journal of Hepatology. 2026;84(1):35–50. doi: 10.1016/j.jhep.2025.06.021. [7] Loomba R, et al. ION224 for MASH: a 51-week randomized phase 2 trial. Lancet. 2025. [8] Madrigal Pharmaceuticals. Global license agreement for ervogastat, a Phase 2 oral DGAT-2 inhibitor. 2026-01-09. [9] ClinicalTrials.gov. NCT06836609: ALN-CIDEB in adults with MASLD/MASH. [10] Alnylam Pharmaceuticals. Product Development Pipeline, updated July 2026. [11] Lin Y, et al. Targeting CIDEB alleviates liver steatosis and fibrosis in mouse MASH models. Mol Ther Nucleic Acids. 2025. 百奥动物 立足全球生物医药行业，从技术创新出发，百奥赛图建立“BioMice百奥动物”子品牌。百奥动物集创新动物模型研发制备、生产供应和实验服务为一体，拥有5600个独特基因编辑动物/细胞系模型，覆盖肿瘤，自免，代谢，心血管等多个疾病领域，包括重度免疫缺陷B-NDG及系列鼠、靶点人源化鼠、疾病模型鼠及基因敲除鼠等，结合优质的药理药效评价服务及转化医学服务平台，针对靶点类型、抗体亚型与作用机制，可订制个性化项目方案，提供具有广泛实验类型或数据分析结果的体内药效、PK/PD、生物标志物评估、Non-GLP毒理学评估、体外免疫细胞和细胞因子分析以及细胞功能测定，完整的体内药效和体外药理学服务能力能够为药物开发提供完整的PoC和MoA。为全球约1500个合作伙伴完成了10000项药物评估项目，已支持了多项IND应用和临床试验。以高标准的3大动物中心为支撑，极大的满足了全球科学研究和药物开发需求。创新的动物模型、高标准的质量管理、多元化的服务平台，助推生物医药创新产业的快速发展。

Not content with navigating Rezdiffra’s trajectory to blockbuster territory, Madrigal Pharmaceuticals has spent 2026 shopping for a range of drugs that the company hopes could work alongside its metabolic dysfunction-associated steatohepatitis (MASH) trailblazer. Madrigal kicked off the year paying $50 million to Pfizer for the rights to a DGAT2i inhibitor, before spending $60 million the following month on six preclinical siRNA programs from China’s Ribo Life Science and its Swedish subsidiary Ribocure Pharmaceuticals that Madrigal wants to use to silence genes implicated in MASH. The company explained at the time that both deals were aimed at securing therapies that could be combined with Rezdiffra. The biopharma was back at the dealmaking table in May, paying $25 million upfront to Arrowhead Pharmaceuticals for a phase 1-stage RNA interference therapeutic that had previously been rejected by Johnson & Johnson. Early clinical data had suggested the asset could reduce liver fat in a mutation found in 30% of MASH patients, including high prevalence in Hispanic populations. Combined with a preclinical GLP-1 agonist licensed from China’s CSPC Pharmaceutical for $120 million upfront last year, Madrigal now has a diverse array of MASH assets coming up behind Rezdiffra. So what’s the strategy behind this rapid pipeline expansion? “The question early on was what mechanisms we wanted,” Madrigal CEO Bill Sibold told Fierce in an interview at the company’s office in Waltham, Massachusetts. “My answer was: we want all of them,” Sibold continued. “We want anything that makes sense mechanistically or has proven already to have an effect on MASH.” It’s a sign of just how much Rezdiffra has changed the game since being approved as the first-ever treatment for MASH in 2024. Before that point, Sibold said he had counted 23 drugs across the industry that had failed to treat the fatty liver disease previously known as nonalcoholic steatohepatitis (NASH). This rollcall of failure meant MASH had become “the graveyard of drug development,” lumped in with other difficult-to-treat conditions like sepsis and lupus, he remembered. The disease occurs when fat builds up in the liver, causing inflammation and eventually cell death. It is the leading cause of liver transplants for women and the second biggest cause for men in the U.S. “Industry had been really interested in this area for a long time, but nobody could crack the nut,” Sibold said. Many companies tried and failed to find a breakthrough. Gilead’s ASK1 inhibitor selonsertib and its LOXL2 enzyme-targeting simtuzumab both flopped in the clinic, as did Genfit’s dual PPAR alpha/delta agonist elafibranor and Conatus Pharmaceuticals' pan-caspase inhibitor emricasan. Rezdiffra’s origins go back to Roche. Madrigal founder Rebecca Taub, Ph.D., left the Swiss pharma’s metabolic unit to work for VIA Pharmaceuticals, which licensed the thyroid hormone receptor (THR)-β agonist. Madrigal assumed the rights to that agreement when it was founded in 2011 and continued to develop the therapy. Sibold remembers getting a call from a recruiter about the Madrigal CEO position in 2023 while he was president for North America at Sanofi, having helped launch immunology blockbuster Dupixent. “There's no way I'm going to leave this to go to that,” he remembers of his initial reaction to the offer. But as Sibold dug into the company, educating himself on the trials and the science behind its lead asset, he became convinced that this was a unique opportunity to make a special impact. The year after Sibold joined up, Madrigal had secured Rezdiffra’s historic FDA approval. As well as the company's headquarters in West Conshohocken, Pennsylvania, the company now also has an office in Massachusetts—which Fierce visited—as well as an international outpost in Switzerland. “There were so many Big Pharma companies trying to solve [MASH], and this little Pennsylvania company of very few people had the tenacity, the guts and the grit to get there,” Sibold said. Madrigal reported $958.4 million in annual net sales for the drug in 2025. By the second quarter of this year, Rezdiffra was bringing in $364.3 million, equivalent to year-over-year growth of 71%. Sibold told Fierce that it wasn’t always this way. Early on, a MASH advocate told him: “We didn't know whether to believe you at first because it seemed like such a huge hill to climb that you guys didn't even have an approved product. But you are doing exactly what you said you would do.” After establishing itself as the market leader in MASH, what’s next? Does the company stay in its lane, expand into immunology targets or look at new indications? For Sibold, the answer lies in Madrigal’s five-word purpose: leading the fight against MASH. The biopharma wants to continue working with the MASH community it has come to know so well to build out its pipeline with more effective and comprehensive treatments for different subpopulations. Rather than generate data and hope to get bought by a bigger fish, Sibold said he is planning for an independent and sustainable company 10 to 20 years down the line. His vision is for MASH treatments to grow like other specialty markets, such as rheumatoid arthritis, psoriasis or inflammatory bowel disease, with dozens of products that generate tens of billions of dollars in annual sales. “We feel like MASH will emerge like that, and as a result, we want to have the portfolio of products that can best help all or subpopulations of patients,” Sibold said. Unlike a Big Pharma, where MASH may be one of a myriad of indications being focused on, Sibold suggested Madrigal's strength comes from the fact it is committed to the disease. This approach is reflected in trial enrollment and feedback, he said. “The community values expertise, and I think we've made a conscious decision to be experts in MASH,” he said. “Through expertise comes insight into what might be the next best mechanism, or the next best mechanism to combine with your current mechanism, or the best way to design the next trial.” Because reducing liver fat is so important to preventing or treating MASH, GLP-1s are moving into the space and posing a potential threat. Last year, Novo Nordisk’s Wegovy was approved to treat MASH, and some people have warned Sibold that Madrigal could be crushed by GLP-1s in the future. Instead, the CEO insisted more activity in the space is a good thing for Madrigal. “It's great to have another company who's putting resources into diagnosis, awareness and treatment,” he said. “There are some patients that are getting Wegovy, but it is helping to grow the market. It's not to our detriment.” But other Big Pharmas are circling. Last year saw GSK acquire the FGF21 analog efimosfermin from Boston Pharmaceuticals for $1.2 billion upfront, while Roche picked up a similar drug called pegozafermin as part of its $3.5 billion buyout of 89bio . Madrigal may be looking to become the MASH version of what Vertex Pharmaceuticals has achieved in cystic fibrosis, but that doesn’t mean Sibold and his team couldn’t eventually broaden their focus. “Would we look at other diseases? Yes. We would in time, or if the biology takes us there,” he told Fierce. But for now, the company is leaning into MASH specialization, developing relationships with patient groups, clinicians and researchers while raising Rezdiffra’s profile and growing a specialized portfolio of complementary therapies. “It's been fun. It's making a difference. It's helping patients,” Sibold said. “This is as good as it gets.