同行致遠 | 里程碑：首款MASH療法已獲批，新藥開發還有哪些挑戰？| Bilingual

編者按：代謝相關脂肪性肝炎（MASH）是當前最常見的慢性肝病之一，且發病率正快速上升，日益成為全球公共健康的重大威脅。近年來，MASH治療領域迎來重要突破：首款MASH療法已獲批上市，多款基于不同作用機制的在研療法也已進入臨床后期開發階段。為了加速MASH藥物的開發，藥明康德旗下生物學業務平臺（WuXi Biology）已建立多款MASH疾病相關模型，并配套開發了組織學、生物標志物和臨床終點的評估技術。本文將介紹WuXi Biology科學團隊如何助力合作伙伴突破MASH藥物早期發現和開發方面的關鍵挑戰。

MASH藥物研發的難點

2024年3月，美國FDA批準Madrigal Pharmaceuticals公司開發的Rezdiffra（resmetirom，MGL3196）上市，用于治療成人MASH患者，標志著全球首款MASH藥物的正式問世。這一里程碑激發了業界對MASH治療領域的關注，目前已有多款基于不同作用機制的MASH在研療法處于3期臨床開發階段。今年8月，諾和諾德（Novo Nordisk）的重磅療法Wegovy（2.4 mg司美格魯肽）也獲得FDA的加速批準，成為首個獲批用于治療MASH的胰高血糖素樣肽-1（GLP-1）療法。

▲處于3期臨床開發階段的MASH療法（圖片來源：參考資料[2]）

然而，MASH藥物的研發之路并不平坦。在Rezdiffra獲批之前，已有多家藥企和生物技術公司的候選藥物在臨床試驗中表現不佳。其核心挑戰之一在于MASH的致病機制復雜，目前尚未被完全闡明。已知肝臟脂肪沉積最終可引發炎癥反應與纖維化，且MASH發病機制與代謝異常密切相關，不同患者的疾病進程差異顯著，受環境和遺傳等多種因素的影響。這種高度復雜性和異質性也為動物模型的構建帶來了巨大挑戰[1]。目前雖然已經有數十種MASH小鼠模型被開發，但尚無一種模型能全面、準確地反映患者的臨床表現。因此，如何選擇合適的動物模型已成為MASH新藥臨床前研究的關鍵問題之一。對此，WuXi Biology的科學家針對多種MASH小鼠模型的臨床相關性進行了系統評估。

如何選擇合適的MASH小鼠模型評估藥效

MASH患者的典型特征包括肝組織學改變和整體代謝改變兩方面。其中，肝組織學改變包括脂肪變性、肝細胞氣球樣變、肝小葉炎癥和肝纖維化。代謝改變主要包括體重上升、胰島素抵抗和高血脂。因此，臨床前動物模型能否準確預測候選藥物在肝組織學和整體代謝上的改善效果，成為評價模型有效性的關鍵標準。

在此次研究中，WuXi Biology科學家選取了多種MASH小鼠模型，并結合多款已進入臨床階段、在公開試驗中展現療效的在研藥物，系統評估各模型對候選藥物臨床表現的預測能力。結果顯示，WuXi Biology肝病平臺的多種模型能夠有效重現不同候選藥物在臨床試驗中的療效表現。

▲主要在研MASH療法在多種MASH模型中的表現

具體實驗結果顯示，現有的常用模型，如高脂飲食（HFD）聯合四氯化碳（CCl?）誘導的小鼠模型、膽堿缺乏飲食（CDHFD）誘導的模型以及甘氨酸-精氨酸-硝酸鹽（GAN）飲食模型均可有效模擬NAS評分和纖維化評分，且resmetirom和司美格魯肽等化合物在這些模型上均可顯著改善MASH特征，這與其在臨床試驗中的積極結果相吻合。

然而，這些模型均存在不同的局限性，例如HFD+CCl?模型缺乏代謝異常背景，CDHFD模型缺乏肥胖特征，而GAN飲食模型誘導周期過長。盡管有些MASH動物模型與患者的臨床癥狀具有較高相關性，但藥效評估模型的選擇需要與候選藥物的作用機制高度匹配。2024年發表在

Nature Metabolism

▲MGL3196在三種常用MASH模型中對肝組織學的模擬效果

為應對MASH疾病復雜性的挑戰，WuXi Biology已構建并表征多種具有不同特征的MASH動物模型，同時通過調整飼料成分和飼養環境開發新的MASH模型，支持研究人員深入理解候選藥物的作用機制，并更準確評估其臨床潛力。此外，平臺還配備了全面的肝組織學和生物標志物檢測技術，并設有通過CAP認證的病理學實驗室，支持各類肝臟病理的定量分析。

除了MASH模型，WuXi Biology還建立了覆蓋多種肝病類型的小鼠和大鼠疾病模型體系，包括酒精性肝炎（ASH）、代謝和酒精相關脂肪變性肝病（MetALD）、肝纖維化、肝硬化、急性/慢性肝損傷、肝功能衰竭、肝癌以及多種膽道疾病。該平臺致力于提供高質量的體內藥理研究服務，加速肝病新療法的開發。目前，團隊已成功為全球合作伙伴開展了涵蓋不同分子類型和治療靶點的藥物測試，其中部分項目已進入臨床階段或獲得FDA批準。

▲WuXi Biology肝病體內藥理平臺動物模型總覽

不僅如此，WuXi Biology還提供覆蓋從靶點發現到候選分子篩選直至臨床推進的全流程研究服務，可靈活支持獨立或一體化項目。展望未來，藥明康德將繼續基于其獨特的CRDMO模式，賦能合作伙伴的創新項目，致力于將更多新藥、好藥帶給全球病患，早日實現“讓天下沒有難做的藥，難治的病”的愿景。

CRDMO: Overcoming Early-Stage Challenges in MASH Drug Development

Metabolic Dysfunction-Associated Steatohepatitis (MASH) has emerged as one of the most prevalent chronic liver diseases globally, with its rising incidence posing a growing public health concern. Recent breakthroughs have renewed optimism in the field—most notably, the U.S. FDA's March 2024 approval of Madrigal Pharmaceuticals’ Rezdiffra (resmetirom, MGL3196), the first approved therapy for MASH. This milestone has catalyzed significant momentum in drug development, with multiple candidates now in late-stage clinical trials across a variety of mechanisms.

However, the road to successful MASH therapy development remains complex and uncertain. Prior to Rezdiffra, numerous promising candidates failed clinical studies. One major obstacle is the multifactorial and poorly understood pathogenesis of MASH. Disease progression is driven by a cascade of interrelated factors—hepatic fat accumulation, inflammation, fibrosis, and systemic metabolic dysfunction—further complicated by high inter-patient heterogeneity shaped by genetics and environment. These challenges underscore the critical need for robust preclinical models to support early-stage discovery and translational success.

Enabling Predictive Preclinical Modeling at WuXi Biology

As a core capability under WuXi AppTec’s CRDMO (Contract Research, Development, and Manufacturing Organization) model, WuXi Biology has built an expansive platform of MASH-relevant in vivo models and translational tools to help partners address early-stage development challenges.

Understanding that no single model can capture the full complexity of MASH, WuXi Biology scientists have systematically evaluated a range of mouse models for their predictive performance using drug candidates already in clinical development. These models were assessed for their ability to replicate key human disease features, including:

• Liver histological changes: steatosis, hepatocyte ballooning, lobular inflammation, and fibrosis

• Metabolic disturbances: insulin resistance, dyslipidemia, and weight gain

In comparative studies, several models—such as the high-fat diet (HFD) plus carbon tetrachloride (CCl?), choline-deficient high-fat diet (CDHFD), and glycine-arginine-nitrate (GAN) diet models—effectively reproduced key clinical endpoints, including NAFLD activity scores (NAS) and fibrosis stages. Investigational compounds such as resmetirom and semaglutide showed concordant efficacy in these models, mirroring their clinical trial performance.

Precision Model Selection Tailored to Drug Mechanism

Despite their utility, each model has limitations. For instance:

• HFD+CCl?: lacks a background of metabolic abnormalities

• CDHFD: fails to induce obesity

• GAN: requires an extended induction period

As no single model can fully recapitulate the MASH disease landscape, WuXi Biology emphasizes mechanism-matched model selection. This strategy aligns animal model characteristics with the candidate drug’s mode of action, improving translational fidelity. A recent

Nature Metabolism

To this end, WuXi Biology has developed customizable MASH models by fine-tuning dietary compositions and housing conditions. These tools are supported by robust histological, biomarker, and endpoint assessment capabilities, including a CAP-certified pathology lab for quantitative liver pathology analysis.

A Comprehensive Liver Disease Modeling Ecosystem

Beyond MASH, WuXi Biology’s platform spans a broad range of liver diseases in both mice and rats, including:

• Alcohol-associated steatohepatitis (ASH)

• Metabolic and alcohol-associated liver disease (MetALD)

• Liver fibrosis and cirrhosis

• Acute and chronic liver injury

• Liver failure and hepatocellular carcinoma

• Biliary tract diseases

This full-spectrum capability enables partners to explore diverse therapeutic mechanisms and molecular modalities. To date, the platform has supported numerous global drug discovery programs, some of which have advanced into clinical development or achieved regulatory milestones.

Empowering Innovation Through Integrated CRDMO Solutions

WuXi Biology also offers end-to-end research services, encompassing target validation, hit discovery, lead optimization, and preclinical evaluation—flexibly supporting both standalone studies and integrated CRDMO programs. This seamless infrastructure accelerates candidate progression from discovery to IND-enabling studies.

Looking ahead, WuXi AppTec remains committed to driving innovation in liver disease research through its integrated CRDMO model. By providing scientific insight, advanced technologies, and tailored model systems, WuXi Biology helps global partners de-risk early-stage development and bring transformative therapies to patients worldwide, realizing the mission of making drug development easier and diseases easier to treat.

參考資料：

[1] CLINICAL RELEVANCE OF NASH ANIMAL MODELS. Retrieved June 6, 2025, from https://wuxibiology.com/wp-content/uploads/2023/07/Clinically-Relevant-NASH-Animal-Model_case-study.pdf

[2] The first anniversary of the MASH “market”: looking back and ahead. Retrieved June 9, 2025, from https://www.iqvia.com/locations/emea/blogs/2025/02/the-mash-markets-first-anniversary-looking-back-and-ahead

[3] In Vivo Pharmacology:Liver Disease Models. Retrieved June 9, 2025, from https://wuxibiology.com/biology-services/in-vivo-pharmacology/liver-disease-models/

[4] Guo et al., (2025). Global burden of MAFLD, MAFLD related cirrhosis and MASH related liver cancer from 1990 to 2021. https://doi.org/10.1038/s41598-025-91312-5

[5] Vacca et al., (2024). An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD). Nature Metabolism, https://doi.org/10.1038/s42255-024-01043-6

[6] An effective MASH drug is good, but biotech can make it better. (2025) Nat Biotechnol, https://doi.org/10.1038/s41587-024-02265-5

[7] Hepatobiliary disease platform. Retrieved June 9, 2025, from https://wuxibiology.com/wp-content/uploads/2024/05/Hepatobiliary_Disease-Platform.pdf

[8] Goodman. (2024) No single perfect mouse model of MASH. Nat Metab https://doi.org/10.1038/s42255-024-01052-5

[9] Do et al., (2025). Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nat Rev Drug Discov, https://doi.org/10.1038/s41573-024-01084-2

[10] Emerging Role of GLP-1 Receptor Agonists for the Treatment of MASH. Retrieved July 7, 2025, from https://wuxibiology.com/resource/emerging-role-of-glp-1-receptor-agonists-for-the-treatment-of-mash/

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