編者按：代謝功能障礙相關(guān)脂肪性肝炎（MASH）是一種影響全球數(shù)百萬(wàn)人的進(jìn)展性肝病，早期常無(wú)明顯癥狀，甚至在患者無(wú)癥狀的情況下悄然惡化。若未能及時(shí)干預(yù)，疾病可進(jìn)一步發(fā)展為嚴(yán)重的肝硬化和肝癌，甚至危及生命，這使得尋找安全有效的治療方案刻不容緩。當(dāng)前，除瑞司美替羅（resmetirom）外，在代謝領(lǐng)域廣受關(guān)注的胰高糖素樣肽-1受體激動(dòng)劑（GLP-1 RA）司美格魯肽（semaglutide）也獲批MASH適應(yīng)癥，成為第二種獲美國(guó)FDA批準(zhǔn)的MASH療法。隨著新一輪MASH藥物創(chuàng)新熱潮的到來(lái)，創(chuàng)新藥的研發(fā)需求尤為迫切。藥明康德旗下的生物學(xué)業(yè)務(wù)平臺(tái)（WuXi Biology）所建立的肝病研究平臺(tái)正積極回應(yīng)這一挑戰(zhàn)，憑借多樣化的臨床前模型與高質(zhì)量的科研服務(wù)，幫助全球合作伙伴將潛力候選藥物高效推進(jìn)至臨床。以下案例顯示，WuXi Biology建立的MASH臨床前模型中，司美格魯肽與替爾泊肽（tirzepatide）均展現(xiàn)出與臨床試驗(yàn)一致的療效，驗(yàn)證了該平臺(tái)的科學(xué)價(jià)值與臨床轉(zhuǎn)化潛力。

MASH是代謝功能障礙相關(guān)脂肪性肝?。∕ASLD）的更嚴(yán)重階段，已成為醫(yī)學(xué)創(chuàng)新的重點(diǎn)領(lǐng)域。隨著全球肥胖、胰島素抵抗及代謝綜合征人群的持續(xù)增加，數(shù)以百萬(wàn)計(jì)的患者正受到MASH的影響。若不及時(shí)治療，MASH可能進(jìn)展至肝硬化、肝癌等嚴(yán)重階段。近年來(lái)，科學(xué)認(rèn)知的不斷深化與新療法的涌現(xiàn)為改善MASH患者預(yù)后提供了前所未有的機(jī)遇。

在治療探索領(lǐng)域，GLP-1 RA正展現(xiàn)出強(qiáng)大的潛力，不僅有望減輕肝臟炎癥和纖維化，還能改善潛在的代謝風(fēng)險(xiǎn)。在一項(xiàng)3期臨床試驗(yàn)中，司美格魯肽相較安慰劑在脂肪性肝炎消退和纖維化改善方面均顯示出顯著優(yōu)勢(shì)。今年8月，該療法正式獲得美國(guó)FDA批準(zhǔn)用于治療MASH，成為首款在該適應(yīng)癥上獲批的GLP-1 RA療法，具有里程碑意義。與此同時(shí)，另一款雙重GIP/GLP-1受體激動(dòng)劑替爾泊肽也在一項(xiàng)2期臨床試驗(yàn)中展現(xiàn)出突出的療效，進(jìn)一步印證了此類藥物在MASH管理中的廣闊前景。

為助力全球合作伙伴加速創(chuàng)新療法研發(fā)，藥明康德旗下WuXi Biology體內(nèi)藥理學(xué)團(tuán)隊(duì)建立了多種MASH的小鼠和大鼠模型，這些臨床前模型已通過(guò)在臨床中展現(xiàn)顯著療效的創(chuàng)新療法（例如瑞司美替羅、司美格魯肽和替爾泊肽）的驗(yàn)證，從而搭建起一座高效的轉(zhuǎn)化橋梁，為全球合作伙伴開展嚴(yán)格的候選藥物評(píng)估和創(chuàng)新研發(fā)提供有力支持。

由于GLP-1 RAs已知具有抑制食欲的作用，研究團(tuán)隊(duì)設(shè)立了嚴(yán)格的對(duì)照組，以區(qū)分飲食因素與藥物在MASH治療中的直接作用。在小鼠模型研究中，結(jié)果顯示，與未接受治療的小鼠相比，司美格魯肽和替爾泊肽兩種藥物均顯著改善了肝臟健康，減少了脂肪堆積和細(xì)胞損傷。與飲食匹配對(duì)照組相比，兩種藥物均表現(xiàn)出顯著的抗纖維化效果。這些發(fā)現(xiàn)顯示GLP-1 RAs在MASH治療中的潛在益處不僅限于抑制食欲，其療效還可能歸因于藥物本身對(duì)代謝的影響。實(shí)驗(yàn)室檢測(cè)進(jìn)一步印證了這一結(jié)論，結(jié)果顯示，與飲食匹配對(duì)照組相比，司美格魯肽和替爾泊肽均有助于降低肝臟脂肪、膽固醇、肝酶及血脂水平。

▲MASH小鼠模型中GLP-1 RA藥物療效的評(píng)估結(jié)果（圖片來(lái)源：參考資料[1]）

研究團(tuán)隊(duì)還在MASH大鼠模型中測(cè)試了司美格魯肽，并觀察到一致的療效，包括降低肝損傷評(píng)分、減輕纖維化，以及降低血液中關(guān)鍵肝酶和脂質(zhì)水平。

研究還發(fā)現(xiàn)雖然使用同樣的藥物，但是在不同MASH模型中觀察到的療效結(jié)果也會(huì)有些許差異。這一現(xiàn)象進(jìn)一步凸顯出，采用多種動(dòng)物模型進(jìn)行全面評(píng)估能夠更準(zhǔn)確地理解藥物的治療機(jī)制并預(yù)測(cè)潛在獲益。

▲MASH大鼠模型中GLP-1 RA藥物療效的評(píng)估結(jié)果（圖片來(lái)源：參考資料[1]）

MASH之外，WuXi Biology建立了覆蓋多種肝病、適用于小鼠和大鼠的豐富模型體系。這一能力已幫助全球合作伙伴在多種分子類型與靶點(diǎn)領(lǐng)域推進(jìn)候選藥物研發(fā)，其中許多項(xiàng)目已進(jìn)入臨床階段，或獲得監(jiān)管批準(zhǔn)。在藥明康德“讓天下沒(méi)有難做的藥，難治的病”的愿景激勵(lì)下，團(tuán)隊(duì)融合多樣化模型、嚴(yán)謹(jǐn)?shù)难芯吭O(shè)計(jì)與深入的數(shù)據(jù)分析，為全球合作伙伴提供可轉(zhuǎn)化的研究洞見(jiàn)，加速潛力療法的推進(jìn)，以造福更多患者。

▲藥明康德旗下生物學(xué)業(yè)務(wù)平臺(tái)臨床前肝病模型匯總（圖片來(lái)源：參考資料[1]）

Driving Innovation — Advanced Preclinical MASH Models Paving the Way for the Next-Generation Treatments

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of liver disease affecting millions worldwide, often advances quietly with few or no symptoms in its early stages. Without timely intervention, it can lead to significant health complications, making the search for effective treatments increasingly important. Currently, apart from resmetirom, the GLP-1R agonist semaglutide, which has gained widespread attention in the metabolic field, has also been approved for MASH. A new wave of innovation in MASH drug development is underway, underscoring the urgent need for novel therapeutic solutions. As part of WuXi AppTec, WuXi Biology’s liver disease platform is designed to help meet this need, offering a broad portfolio of preclinical models and high-quality research services to support global partners in moving promising drug candidates from concept to clinic. In recent studies, both semaglutide and tirzepatide demonstrated efficacy in WuXi Biology’s MASH preclinical models, consistent with clinical trial outcomes and validating the platform’s scientific value and translational potential.

MASH, a more advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), is drawing increasing attention as a key area for medical innovation. Closely linked to rising rates of obesity, insulin resistance, and metabolic syndrome, MASH affects millions of people worldwide. The disease can progress to serious conditions such as cirrhosis and hepatocellular carcinoma if left untreated. In recent years, the deepening scientific understanding and the emergence of new therapies have provided unprecedented opportunities to improve the prognosis of MASH patients.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have rapidly emerged as one of the most promising therapeutic classes for MASH, offering the potential not only to reduce liver inflammation and fibrosis but also to address the underlying metabolic risks driving disease progression. In a pivotal phase 3 trial, semaglutide delivered notable improvements in both steatohepatitis resolution and fibrosis compared to placebo. In August 2025, it received FDA approval as the first GLP-1 RA therapy for MASH, marking a historic milestone in the treatment of this challenging disease. Extending this momentum, tirzepatide—a dual GIP/GLP-1 receptor co-agonist—demonstrated significant efficacy in a phase 2 trial, further reinforcing the transformative potential of this therapeutic class in reshaping MASH management.

To accelerate the development of next-generation therapies,WuXi Biology’s in vivo pharmacology team has established and validated multiple mouse and rat models of MASH. These preclinical models have been benchmarked with approved and investigational drugs that have demonstrated clinical activity, including resmetirom, semaglutide, and tirzepatide, creating a robust translational bridge to support the rigorous evaluation of novel therapeutic candidates.

Because GLP-1 RA therapies are known to reduce appetite, the team established rigorous control groups to distinguish the impact of dietary factors from the direct effects of the drugs on MASH treatment. In a mouse model study, results showed that, compared with untreated mice, both semaglutide and tirzepatide significantly improved liver health by reducing fat accumulation and cellular damage. Moreover, both treatments demonstrated a significant reduction in fibrosis when compared with diet-matched controls.These findings highlight the potential benefits of GLP-1 RAs in treating MASH independent of diet.Laboratory tests also supported this observation, showing that compared to the diet-matched controls, both semaglutide and tirzepatide helped lower liver fat, cholesterol, liver enzymes, and blood lipid levels.

▲Efficacy evaluation of semaglutide and tirzepatide in the MASH Mouse Model (Source: Reference [1])

The team also tested semaglutide in a rat model of MASH and saw consistent benefits, including reduced liver damage scores, less fibrosis, and lower levels of key liver enzymes and fats in the blood.

The study also revealed efficacy variations across different models using the same drugs.Such variations further highlight the importance of using multiple animal models for comprehensive evaluation, to gain a deeper and more accurate understanding of the therapeutic mechanisms of drugs and predict their potential benefits.

▲Efficacy Assessment of Semaglutide in the MASH Rat Models (Source: Reference [1])

In addition to models for MASH, WuXi Biology’s liver disease platform established an extensive portfolio of models covering various liver diseases in both mice and rats.These capabilities have helped global partners advance drug candidates across a wide range of molecular modalities and targets, with many progressing into clinical development or receiving regulatory approval. Guided by WuXi AppTec’s vision—“Every drug can be made and every disease can be treated”—the team combines model diversity, rigorous study design, and in-depth data analysis to provide global partners with actionable insights that help advance promising therapies for patients.

▲WuXi Biology Liver Disease Models (Source: Reference [1])

參考資料:

[1] Emerging Role of GLP-1 Receptor Agonists for the Treatment of MASH. Retrieved August 13, 2025 from https://wuxibiology.com/resource/emerging-role-of-glp-1-receptor-agonists-for-the-treatment-of-mash/

免責(zé)聲明：本文僅作信息交流之目的，文中觀點(diǎn)不代表藥明康德立場(chǎng)，亦不代表藥明康德支持或反對(duì)文中觀點(diǎn)。本文也不是治療方案推薦。如需獲得治療方案指導(dǎo)，請(qǐng)前往正規(guī)醫(yī)院就診。

版權(quán)說(shuō)明：歡迎個(gè)人轉(zhuǎn)發(fā)至朋友圈，謝絕媒體或機(jī)構(gòu)未經(jīng)授權(quán)以任何形式轉(zhuǎn)載至其他平臺(tái)。轉(zhuǎn)載授權(quán)請(qǐng)?jiān)凇杆幟骺档隆刮⑿殴娞?hào)回復(fù)“轉(zhuǎn)載”，獲取轉(zhuǎn)載須知。