Abstract：
OBJECTIVE: This was a randomized, double-blind, placebo-controlled study to assess the effects of pemvidutide, a glucagon-like peptide-1 (GLP-1)/glucagon dual receptor agonist, on liver fat content (LFC) in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD).
METHODS: Subjects with a BMI ≥28.0 kg/m2 and LFC ≥10% by magnetic resonance imaging-proton density fat fraction were randomized 1:1:1:1 to pemvidutide at 1.2 mg, 1.8 mg, or 2.4 mg, or placebo administered subcutaneously once weekly for 12 weeks. Participants were stratified according to a diagnosis of type 2 diabetes mellitus (T2DM). The primary efficacy endpoint was relative reduction (%) from baseline in LFC after 12 weeks of treatment.
RESULTS: 94 subjects were randomized and dosed. Median baseline BMI and LFC across the study population were 36.2 kg/m2 and 20.6%; 29% of subjects had T2DM. At Week 12, relative reductions in LFC from baseline were (1.2 mg) 46.6% [95% CI -63.7 to -29.6], (1.8 mg) 68.5% [95% CI -84.4 to -52.5], and (2.4 mg) 57.1% [95% CI -76.1 to -38.1] versus 4.4% [95% CI -20.2 to 11.3] in placebo subjects (p <0.001 vs. placebo, all treatment groups), with 94.4% and 72.2% of subjects achieving 30% and 50% reductions in LFC and 55.6% achieving normalization (≤5% LFC) at the 1.8 mg dose. Maximal responses for weight loss (-4.3%; p <0.001), alanine aminotransferase (-13.8 IU/L; p = 0.029), and corrected cT1 (-75.9 ms; p = 0.002) were all observed at the 1.8 mg dose. Pemvidutide was well-tolerated at all doses with no severe or serious adverse events.
CONCLUSIONS: In subjects with MASLD, weekly pemvidutide treatment yielded significant reductions in LFC, markers of hepatic inflammation, and body weight compared to placebo.
UNASSIGNED: MASLD, and MASH, are strongly associated with overweight and obesity and it is believed that the excess liver fat associated with obesity is an important driver of these diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists elicit weight loss through centrally and peripherally mediated effects on appetite. Unlike GLP-1R agonists, glucagon receptor (GCGR) agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, potentially providing a more potent mechanism for liver fat content (LFC) reduction than weight loss alone. This study demonstrated the ability of once-weekly treatment with pemvidutide, a dual GLP-1R/GCGR agonist, to significantly reduce LFC, hepatic inflammatory activity, and body weight, suggesting that pemvidutide may be an effective treatment for both MASH and obesity.
BACKGROUND: NCT05006885.
METHODS: Subjects with a BMI ≥28.0 kg/m2 and LFC ≥10% by magnetic resonance imaging-proton density fat fraction were randomized 1:1:1:1 to pemvidutide at 1.2 mg, 1.8 mg, or 2.4 mg, or placebo administered subcutaneously once weekly for 12 weeks. Participants were stratified according to a diagnosis of type 2 diabetes mellitus (T2DM). The primary efficacy endpoint was relative reduction (%) from baseline in LFC after 12 weeks of treatment.
RESULTS: 94 subjects were randomized and dosed. Median baseline BMI and LFC across the study population were 36.2 kg/m2 and 20.6%; 29% of subjects had T2DM. At Week 12, relative reductions in LFC from baseline were (1.2 mg) 46.6% [95% CI -63.7 to -29.6], (1.8 mg) 68.5% [95% CI -84.4 to -52.5], and (2.4 mg) 57.1% [95% CI -76.1 to -38.1] versus 4.4% [95% CI -20.2 to 11.3] in placebo subjects (p <0.001 vs. placebo, all treatment groups), with 94.4% and 72.2% of subjects achieving 30% and 50% reductions in LFC and 55.6% achieving normalization (≤5% LFC) at the 1.8 mg dose. Maximal responses for weight loss (-4.3%; p <0.001), alanine aminotransferase (-13.8 IU/L; p = 0.029), and corrected cT1 (-75.9 ms; p = 0.002) were all observed at the 1.8 mg dose. Pemvidutide was well-tolerated at all doses with no severe or serious adverse events.
CONCLUSIONS: In subjects with MASLD, weekly pemvidutide treatment yielded significant reductions in LFC, markers of hepatic inflammation, and body weight compared to placebo.
UNASSIGNED: MASLD, and MASH, are strongly associated with overweight and obesity and it is believed that the excess liver fat associated with obesity is an important driver of these diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists elicit weight loss through centrally and peripherally mediated effects on appetite. Unlike GLP-1R agonists, glucagon receptor (GCGR) agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, potentially providing a more potent mechanism for liver fat content (LFC) reduction than weight loss alone. This study demonstrated the ability of once-weekly treatment with pemvidutide, a dual GLP-1R/GCGR agonist, to significantly reduce LFC, hepatic inflammatory activity, and body weight, suggesting that pemvidutide may be an effective treatment for both MASH and obesity.
BACKGROUND: NCT05006885.
摘要：
目的：这是一个随机的，双盲,安慰剂对照研究，以评估pemvidutide的效果，胰高血糖素样肽-1（GLP-1）/胰高血糖素双受体激动剂，与代谢功能障碍相关的脂肪变性肝病（MASLD）受试者的肝脏脂肪含量（LFC）。
方法：通过磁共振成像-质子密度脂肪分数，BMI≥28.0kg/m2和LFC≥10％的受试者随机分为1：1：1：1：1，以1.2mg，1.8mg,或2.4毫克，或安慰剂皮下给药，每周一次，持续12周。根据2型糖尿病（T2DM）的诊断对参与者进行分层。主要疗效终点是治疗12周后LFC相对于基线的相对减少(%)。
结果：94名受试者被随机化并给药。研究人群的中位基线BMI和LFC为36.2kg/m2和20.6%;29%的受试者患有T2DM。在第12周，LFC相对于基线的相对减少为（1.2mg）46.6％[95％CI-63.7至-29.6]，（1.8毫克）68.5%[95%CI-84.4至-52.5]，安慰剂受试者中（2.4mg）57.1％[95％CI-76.1至-38.1]与4.4％[95％CI-20.2至11.3]（p<0.001与安慰剂,所有治疗组)，在1.8mg剂量下，94.4％和72.2％的受试者实现了LFC的30％和50％的降低，55.6％的受试者实现了正常化（≤5％LFC）。体重损失的最大响应（-4.3％；p<0.001），丙氨酸氨基转移酶（-13.8IU/L；p=0.029），和校正的cT1(-75.9ms;p=0.002)均在1.8mg剂量下观察到。Pemvidutide在所有剂量下都具有良好的耐受性，没有严重或严重的不良事件。
结论：在MASLD受试者中，每周pemvidutide治疗可显著降低LFC，肝脏炎症的标志物，和体重相比安慰剂。
■MASLD,MASH,与超重和肥胖密切相关，据信与肥胖相关的肝脏脂肪过多是这些疾病的重要驱动因素。胰高血糖素样肽-1受体（GLP-1R）激动剂通过中枢和外周介导的食欲作用引起体重减轻。与GLP-1R激动剂不同,胰高血糖素受体（GCGR）激动剂直接作用于肝脏以刺激脂肪酸氧化和抑制脂肪生成，可能提供比单独减肥更有效的肝脏脂肪含量（LFC）降低机制。这项研究证明了pemvidutide每周一次治疗的能力，GLP-1R/GCGR双重激动剂，为了显著降低LFC，肝脏炎症活动，和体重，表明pemvidutide可能是MASH和肥胖症的有效治疗方法。
背景：NCT05006885。
方法：通过磁共振成像-质子密度脂肪分数，BMI≥28.0kg/m2和LFC≥10％的受试者随机分为1：1：1：1：1，以1.2mg，1.8mg,或2.4毫克，或安慰剂皮下给药，每周一次，持续12周。根据2型糖尿病（T2DM）的诊断对参与者进行分层。主要疗效终点是治疗12周后LFC相对于基线的相对减少(%)。
结果：94名受试者被随机化并给药。研究人群的中位基线BMI和LFC为36.2kg/m2和20.6%;29%的受试者患有T2DM。在第12周，LFC相对于基线的相对减少为（1.2mg）46.6％[95％CI-63.7至-29.6]，（1.8毫克）68.5%[95%CI-84.4至-52.5]，安慰剂受试者中（2.4mg）57.1％[95％CI-76.1至-38.1]与4.4％[95％CI-20.2至11.3]（p<0.001与安慰剂,所有治疗组)，在1.8mg剂量下，94.4％和72.2％的受试者实现了LFC的30％和50％的降低，55.6％的受试者实现了正常化（≤5％LFC）。体重损失的最大响应（-4.3％；p<0.001），丙氨酸氨基转移酶（-13.8IU/L；p=0.029），和校正的cT1(-75.9ms;p=0.002)均在1.8mg剂量下观察到。Pemvidutide在所有剂量下都具有良好的耐受性，没有严重或严重的不良事件。
结论：在MASLD受试者中，每周pemvidutide治疗可显著降低LFC，肝脏炎症的标志物，和体重相比安慰剂。
■MASLD,MASH,与超重和肥胖密切相关，据信与肥胖相关的肝脏脂肪过多是这些疾病的重要驱动因素。胰高血糖素样肽-1受体（GLP-1R）激动剂通过中枢和外周介导的食欲作用引起体重减轻。与GLP-1R激动剂不同,胰高血糖素受体（GCGR）激动剂直接作用于肝脏以刺激脂肪酸氧化和抑制脂肪生成，可能提供比单独减肥更有效的肝脏脂肪含量（LFC）降低机制。这项研究证明了pemvidutide每周一次治疗的能力，GLP-1R/GCGR双重激动剂，为了显著降低LFC，肝脏炎症活动，和体重，表明pemvidutide可能是MASH和肥胖症的有效治疗方法。
背景：NCT05006885。
