Abstract：
OBJECTIVE: Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis.
METHODS: This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored.
RESULTS: In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment.
CONCLUSIONS: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis.
UNASSIGNED: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.
RESULTS:
UNASSIGNED: NCT05296733.
METHODS: This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored.
RESULTS: In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment.
CONCLUSIONS: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis.
UNASSIGNED: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.
RESULTS:
UNASSIGNED: NCT05296733.
摘要：
目的：Survodutide是一种胰高血糖素/胰高血糖素样肽-1受体双重激动剂，用于治疗代谢功能障碍相关脂肪性肝炎（MASH）。我们调查了肝硬化患者的survodutide。
方法：这家跨国公司，非随机化，开放标签，第一阶段临床试验最初评估了在Child-PughA级患者中单次皮下（s.c.）剂量的survodutide0.3mg，B或C肝硬化和有或没有超重/肥胖的健康个体与年龄相匹配，性别,和体重；主要终点是从0到无穷大的血浆浓度-时间曲线下面积（AUC0-∞）和最大血浆浓度（Cmax）。随后，超重/肥胖伴或不伴肝硬化和Child-PughA级或B级的患者接受每周一次的皮下注射，剂量在24周内从0.3mg增加到6.0mg，然后维持4周；主要终点是药物相关治疗引起的不良事件，探讨MASH/肝硬化相关终点。
结果：在单剂量队列中（n=41），与健康个体相比,肝硬化患者的平均AUC0-∞和Cmax相似(校正后几何平均比率的90%置信区间跨越1).单剂量后，25.0%的健康个体和≤25.0%的肝硬化患者发生药物相关不良事件，82.4%和87.5%，分别,在28周内的多剂量队列（n=41）。肝脏脂肪含量，肝脏硬度,肝脏体积,体重,和其他肝脏和代谢性疾病标志物一般减少后28周的survodutide治疗。
结论：Survodutide在代偿期或代偿期肝硬化患者中通常是可以耐受的，不需要药代动力学相关的剂量调整，并可能改善肝脏相关的非侵入性检查，支持其对MASH相关肝硬化的调查。临床试验编号；ClinicalTrials.gov标识符：NCT05296733。
■Survodutide是一种胰高血糖素受体/胰高血糖素样肽-1受体双重激动剂，用于治疗代谢功能障碍相关脂肪性肝炎（MASH），这导致了20%的病例发生肝硬化。本试验描述了survodutide在代偿性或失代偿性肝硬化患者中的药代动力学和安全性。并揭示了肝脏脂肪含量的相关减少，肝纤维化和体重的标志物。这些发现对MASH患者有潜在的相关性，包括那些患有失代偿期肝硬化的患者，通常被排除在研究药物的临床试验之外。基于这项研究，舒沃杜肽治疗MASH相关性肝硬化的进一步研究是必要的.
方法：这家跨国公司，非随机化，开放标签，第一阶段临床试验最初评估了在Child-PughA级患者中单次皮下（s.c.）剂量的survodutide0.3mg，B或C肝硬化和有或没有超重/肥胖的健康个体与年龄相匹配，性别,和体重；主要终点是从0到无穷大的血浆浓度-时间曲线下面积（AUC0-∞）和最大血浆浓度（Cmax）。随后，超重/肥胖伴或不伴肝硬化和Child-PughA级或B级的患者接受每周一次的皮下注射，剂量在24周内从0.3mg增加到6.0mg，然后维持4周；主要终点是药物相关治疗引起的不良事件，探讨MASH/肝硬化相关终点。
结果：在单剂量队列中（n=41），与健康个体相比,肝硬化患者的平均AUC0-∞和Cmax相似(校正后几何平均比率的90%置信区间跨越1).单剂量后，25.0%的健康个体和≤25.0%的肝硬化患者发生药物相关不良事件，82.4%和87.5%，分别,在28周内的多剂量队列（n=41）。肝脏脂肪含量，肝脏硬度,肝脏体积,体重,和其他肝脏和代谢性疾病标志物一般减少后28周的survodutide治疗。
结论：Survodutide在代偿期或代偿期肝硬化患者中通常是可以耐受的，不需要药代动力学相关的剂量调整，并可能改善肝脏相关的非侵入性检查，支持其对MASH相关肝硬化的调查。临床试验编号；ClinicalTrials.gov标识符：NCT05296733。
■Survodutide是一种胰高血糖素受体/胰高血糖素样肽-1受体双重激动剂，用于治疗代谢功能障碍相关脂肪性肝炎（MASH），这导致了20%的病例发生肝硬化。本试验描述了survodutide在代偿性或失代偿性肝硬化患者中的药代动力学和安全性。并揭示了肝脏脂肪含量的相关减少，肝纤维化和体重的标志物。这些发现对MASH患者有潜在的相关性，包括那些患有失代偿期肝硬化的患者，通常被排除在研究药物的临床试验之外。基于这项研究，舒沃杜肽治疗MASH相关性肝硬化的进一步研究是必要的.
