INTRODUCTION AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. METHODS In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRI-PDFF -22.9% vs -5.7%, HOMA-IR -4.4 vs +0.7, ALT -21.9% vs -7.2%, K-18 M65 -13.6% vs +20.1%, cT1 -69.6 vs +18.3 ms (P < 0.05), and Pro-C3 -13.6% vs -3.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF -8.1%, HOMA-IR +8.4, ALT -20.7%, K-18 M65 6.6%, cT1 -34.7 ms, and Pro-C3 -15.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects.

中文翻译：

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AXA1125 和 AXA1957 在非酒精性脂肪肝患者中的安全性、耐受性和生物活性。

简介 AXA1125 和 AXA1957 是新型口服内源性代谢调节剂组合物，专门设计用于同时支持与非酒精性脂肪肝病 (NAFLD) 相关的多种代谢和纤维炎症途径。本研究评估了 AXA1125 和 AXA1957 在 NAFLD 中的安全性、耐受性和生物活性。方法 在这项多中心、16 周、安慰剂对照、单盲、随机临床研究中，NAFLD 受试者按 2 型糖尿病分层，每天两次给予 AXA1125 24 g、AXA1957 13.5 g 或 20.3 g 或安慰剂。关键代谢（MRI-质子密度脂肪分数 [MRI-PDFF] 和胰岛素抵抗稳态模型评估 [HOMA-IR]）和纤维炎症标志物（丙氨酸转氨酶 [ALT]、校正 T1 [cT1]、角蛋白-18 [K-18] ] M65，和 N 末端 III 型胶原前肽 [Pro-C3]）进行了评估。安全结果包括不良事件和标准实验室评估。结果 102 名入组受试者（其中 40 名患有 2 型糖尿病）的基线特征与假定的非酒精性脂肪性肝炎一致。AXA1125 始终表现出比 AXA1957 或安慰剂更高的生物活性。AXA1125 与安慰剂相比，第 16 周相对于基线的变化：MRI-PDFF -22.9% 与 -5.7%、HOMA-IR -4.4 与 +0.7、ALT -21.9% 与 -7.2%、K-18 M65 -13.6% 与 +20.1% ，cT1 -69.6 vs +18.3 ms (P < 0.05)，Pro-C3 -13.6% vs -3.6%。AXA1957 20.3 g 与基线相比第 16 周的变化：MRI-PDFF -8.1%、HOMA-IR +8.4、ALT -20.7%、K-18 M65 6.6%、cT1 -34.7 ms 和 Pro-C3 -15.6%。使用 AXA1125 治疗的受试者中有更大比例达到了临床相关阈值：≥30% MRI-PDFF，第 16 周时 ALT ≥17-IU/L，cT1 降低≥80-ms。研究产品安全且耐受性良好，血脂和体重状况稳定。讨论 两种组合物均显示出对相关 NAFLD 途径的多靶点活性。AXA1125 在 16 周内表现出最大的活性，值得在非酒精性脂肪性肝炎受试者中继续进行临床研究。