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.
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。