Pinnacle Clinical Research, San Antonio, Texas, USA.
Excel Medical Clinical Trials, Boca Raton, Florida, USA.
Am J Gastroenterol. 2021 Dec 1;116(12):2399-2409. doi: 10.14309/ajg.0000000000001375.
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.
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.
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.
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.
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性肝病（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、耐受性和生物学活性。
在这项多中心、16 周、安慰剂对照、单盲、随机临床试验中，根据 2 型糖尿病对患有 NAFLD 的受试者进行分层，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（磁共振质子密度脂肪分数[MRI-PDFF]和稳态模型评估的胰岛素抵抗[HOMA-IR]）和纤维炎症标志物（丙氨酸氨基转移酶[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。安全性结果包括不良事件和标准实验室评估。
102 名入组受试者的基线特征，包括 40 名 2 型糖尿病患者，与非酒精性脂肪性肝炎相符。AXA1125 显示出比 AXA1957 或安慰剂更一致的生物学活性。与安慰剂相比，AXA1125 在第 16 周时从基线的变化：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）和 Pro-C3 -13.6% vs -3.6%。AXA1957 20.3 g 从基线的第 16 周变化：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%。接受 AXA1125 治疗的受试者中有更大比例达到了临床相关阈值：≥30%的 MRI-PDFF、≥17-IU/L 的 ALT 和≥80-ms 的 cT1 降低。研究产品安全且耐受良好，血脂和体重状况稳定。
两种组合物均显示出对相关 NAFLD 途径的多靶向活性。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。
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