Abstract

Purpose

To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction.

Methods

A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses.

Results

Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m²) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects.

Conclusions

In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted.

ClinicalTrials.gov Identifier

NCT03466203

中文翻译：

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LLF580 是一种 FGF21 类似物，可降低患有中度高甘油三酯血症的肥胖成年人的甘油三酯和肝脏脂肪

摘要

目的

评估 LLF580（人类成纤维细胞生长因子 21 的基因工程变体）在降低甘油三酯、减轻体重和减少肝脏脂肪方面的安全性和潜在功效。

方法

一项针对肥胖、轻度高甘油三酯血症的成人进行的多中心、双盲、平行设计试验，随机 (1:1) 接受 LLF580 300 mg 或安慰剂，每 4 周皮下注射 3 剂。

结果

在 64 名随机研究参与者中，61 名（平均值 ± SD：年龄 45 ± 11 岁，49% 男性，80/15/5% 白种人/非洲裔美国人/其他，体重指数 36.1 ± 3.8 kg/m ²）接受 LLF580（n = 30) 或安慰剂 (n = 31) 在美国的 7 个研究地点。与安慰剂相比，LLF580 使血清甘油三酯降低 54%（安慰剂调整后的最小二乘变化），总胆固醇降低 7%，低密度脂蛋白胆固醇降低 12%，高密度脂蛋白胆固醇升高 36%（均P < 0.001） 12 周。与安慰剂相比，肝脏脂肪显着减少 52%（P< 0.001）在改善肝功能测试（包括丙氨酸氨基转移酶、天冬氨酸氨基转移酶和碱性磷酸酶、复合增强肝纤维化评分和 N 端 III 型胶原前肽）的设置中也得到证实（所有P < 0.05）。与安慰剂相比，LLF580 治疗的胰岛素和 C 肽水平以及通过稳态模型评估的胰岛素抵抗均较低，脂联素较高，而空腹血糖和糖化血红蛋白没有变化。观察到骨形成的生物标志物减少，而骨吸收标志物没有差异。LLF580 通常是安全的且耐受性良好，除了一般轻度至中度胃肠道不良反应的发生率较高。

结论

在肥胖、轻度高甘油三酯血症的成年人中，LLF580 通常是安全的，并显示出对血脂、肝脏脂肪和肝损伤生物标志物的有益作用，这表明它可能对治疗某些代谢疾病（包括高甘油三酯血症和非酒精性脂肪肝疾病）有效。有必要对长期安全性和有效性进行评估。

ClinicalTrials.gov 标识符

NCT03466203