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American Association for the study of liver disease (AASLD) | November 8-12, 2019

Authors: Manu Chakravarthy, Stephen A Harrison, Scharmen Confer, Joel Neutel, Rizwana Mohseni, Peng Zhao, Nadine Daou, Michael Hamill, Tony Tramontin, Ranjit Randhawa, Tripti Kulkarni, Svetlana Marukian

Background: Convergent dysregulation of metabolism, inflammation, and fibrosis appears to be central to NASH pathogenesis. Previously [Hepatology 68(1) Suppl, pg 67A: #106], we showed AXA1125, a unique composition of amino acids (LIVRQNac), positively impacted lipotoxicity, insulin resistance, inflammation and fibrosis markers in T2D subjects with NAFLD as evidenced by reductions in liver fat, HOMA‐IR, ALT, CK‐18, MCP‐1, and ProC3. We conducted comprehensive assessments to enumerate the key biochemical pathways and mechanisms underlying these clinical findings.

Methods: 32 subjects with T2D and NAFLD were enrolled in an open‐label pilot study and administered AXA1125 24g TID over 12 wks. Plasma from d1, wk6, and wk12 were subjected to targeted secretomic, metabolomic, and lipidomic analyses coupled with assessments in primary human hepatocytes and adipocytes. Key molecular mediators and biochemical pathways were characterized and verified using two independent metabolomics platforms (OWL and Duke) and multiplexed functional assays.

Results: Despite 12 wks of AXA1125 dosing (which contains 24g BCAAs) and 3‐5X Cmax above endogenous levels following each dose, fasted plasma BCAA concentrations were unchanged and C5‐OH/C3‐DC levels increased 30% (p = 0.047), suggestive of increased BCAA catabolism. Cell autonomous experiments showed a 55% increase (p=0.0002) in insulin‐dependent glucose uptake into hepatocytes and 40% decrease (p=0.0052) in free‐fatty acid release from adipocytes, corroborating the observation of improved HOMA‐IR in humans. After 12 wks, plasma levels of proinflammatory mediators, tryptophan and its metabolite, kynurenine were decreased by 7.3% (p=0.0021) and 11.8% (p=0.05), respectively vs. baseline. Consistent with these changes, plasma levels of YKL40, a marker of fibroinflammation and a component of an in vitro NASH diagnostic panel, was reduced 20% (p=0.0034) on w12 vs. d1. Plasma levels of proline, associated with fibrosis, decreased 16.5% (p <0.0001) consistent with the antifibrogenic effects of AXA1125 suggested by plasma proC3 reduction at 12 wks. Conclusion: Together, these findings provide a wider view of pathways and mechanisms contributing to the multimodal effects of AXA1125 across metabolic, inflammatory, fibrotic markers observed in T2D subjects with NAFLD. Given these results, studies are currently underway to examine AXA1125's effects on safety, tolerability, liver structure and function over 16 wks in NAFLD subjects with or without T2D.