Harrison Stephen A, Browne Sarah K, Suschak John J, Tomah Shaheen, Gutierrez Julio A, Yang Jay, Roberts M Scot, Harris M Scott
Department of Hepatology, University of Oxford, Oxford, UK; Pinnacle Clinical Research, San Antonio, TX, USA.
Altimmune, Inc, Gaithersburg, MD, USA.
J Hepatol. 2025 Jan;82(1):7-17. doi: 10.1016/j.jhep.2024.07.006. Epub 2024 Jul 11.
BACKGROUND & AIMS: 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 individuals with metabolic dysfunction-associated steatotic liver disease (MASLD).
Patients with a BMI ≥28.0 kg/m 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. The primary efficacy endpoint was relative reduction (%) from baseline in LFC after 12 weeks of treatment.
Ninety-four patients were randomized and dosed. Median baseline BMI and LFC across the study population were 36.2 kg/m and 20.6%; 29% of patients had type 2 diabetes mellitus. At week 12, relative reductions in LFC from baseline were 46.6% (95% CI -63.7 to -29.6), 68.5% (95% CI -84.4 to -52.5), and 57.1% (95% CI -76.1 to -38.1) for the pemvidutide 1.2 mg, 1.8 mg, and 2.4 mg groups, respectively, vs. 4.4% (95% CI -20.2 to 11.3) for the placebo group (p <0.001 vs. placebo, all treatment groups), with 94.4% and 72.2% of patients 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.
In patients with MASLD, weekly pemvidutide treatment yielded significant reductions in LFC, markers of hepatic inflammation, and body weight compared to placebo.
Metabolic dysfunction-associated steatotic liver disease, and its progressive form steatohepatitis, are strongly associated with overweight/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 agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, potentially providing a more potent mechanism for liver fat content reduction than weight loss alone. This study demonstrated the ability of once-weekly treatment with pemvidutide, a dual GLP-1R/glucagon receptor agonist, to significantly reduce liver fat content, hepatic inflammatory activity, and body weight, suggesting that pemvidutide may be an effective treatment for both metabolic dysfunction-associated steatohepatitis and obesity.
NCT05006885.
这是一项随机、双盲、安慰剂对照研究，旨在评估胰高血糖素样肽-1（GLP-1）/胰高血糖素双重受体激动剂佩米度肽对代谢功能障碍相关脂肪性肝病（MASLD）患者肝脏脂肪含量（LFC）的影响。
体重指数（BMI）≥28.0kg/m²且通过磁共振成像-质子密度脂肪分数测定LFC≥10%的患者按1:1:1:1随机分组，分别接受1.2mg、1.8mg或2.4mg的佩米度肽或安慰剂皮下注射，每周1次，共12周。参与者根据2型糖尿病诊断进行分层。主要疗效终点是治疗12周后LFC较基线的相对降低百分比（%）。
94例患者被随机分组并给药。研究人群的基线BMI中位数和LFC分别为36.2kg/m²和20.6%；29%的患者患有2型糖尿病。在第12周时，佩米度肽1.2mg、1.8mg和2.4mg组的LFC较基线的相对降低率分别为46.6%（95%CI -63.7至-29.6）、68.5%（95%CI -84.4至-52.5）和57.1%（95%CI -76.1至-38.1），而安慰剂组为4.4%（95%CI -20.2至11.3）（与安慰剂相比，所有治疗组p<0.001），在1.8mg剂量时，94.4%和72.2%的患者LFC降低30%和50%，55.6%的患者LFC恢复正常（≤5%）。在1.8mg剂量时观察到体重减轻（-4.3%；p<0.001）、丙氨酸氨基转移酶（-13.8IU/L；p=0.029）和校正cT1（-75.9ms；p=0.002）的最大反应。所有剂量的佩米度肽耐受性良好，无严重不良事件。
在MASLD患者中，与安慰剂相比，每周一次的佩米度肽治疗可使LFC、肝脏炎症标志物和体重显著降低。
代谢功能障碍相关脂肪性肝病及其进展型脂肪性肝炎与超重/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）激动剂通过对食欲的中枢和外周介导作用引起体重减轻。与GLP-1R激动剂不同，胰高血糖素受体激动剂直接作用于肝脏，刺激脂肪酸氧化并抑制脂肪生成，可能提供一种比单纯体重减轻更有效的降低肝脏脂肪含量的机制。本研究证明了每周一次使用双重GLP-1R/胰高血糖素受体激动剂佩米度肽治疗能够显著降低肝脏脂肪含量、肝脏炎症活性和体重，表明佩米度肽可能是治疗代谢功能障碍相关脂肪性肝炎和肥胖的有效药物。
NCT05006885。
