Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease

Stephen A Harrison, Seth J Baum, Nadege T Gunn, Ziad H Younes, Anita Kohli, Rashmee Patil, Margaret J Koziel, Harinder Chera, Jeff Zhao, Manu V Chakravarthy, Stephen A Harrison, Seth J Baum, Nadege T Gunn, Ziad H Younes, Anita Kohli, Rashmee Patil, Margaret J Koziel, Harinder Chera, Jeff Zhao, Manu V Chakravarthy

Abstract

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.

Trial registration: ClinicalTrials.gov NCT04073368.

Conflict of interest statement

Guarantor of the article: Manu V. Chakravarthy, MD, PhD.

Specific author contributions: S.A.H., M.J.K., H.C., J.Z., and M.V.C.: study design and conduct of the study. S.A.H., M.K., H.C., and M.V.C.: collection, analysis, and interpretation of data. J.Z., M.K., and M.V.C.: statistical analysis of the data. M.V.C.: drafting of the manuscript. S.A.H., S.J.B., N.T.G., Z.H.Y., A.K., R.P., M.J.K., H.C., J.Z., and M.V.C.: critical revision of the manuscript for important intellectual content.

Financial support: This study was funded by Axcella Health. Medical writing support, funded by Axcella Health, was provided by Diann Glickman of Envision Pharma Group.

Potential competing interests: S.A.H.: stock shareholder: Akero, Cirius, Galectin, Genfit, HistoIndex, Madrigal, Metacrine, NGM Bio, and NorthSea; consultant: Akero, Alentis, Altimmune, Axcella, Cirius, Chronic Liver Disease Foundation, CiVi BioPharma, CymaBay, Echosens, Fibronostics, Forsite Labs, Fortress Biotech, Galectin, Genfit, Gilead, HighTide, HistoIndex, Hepion, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, NorthSea, Novartis, Novo Nordisk, Perspectum, Poxel, Prometic, Ridgeline Therapeutics, Sagimet, Terns, and Viking; grant/research support: Akero, Axcella, Bristol Myers Squibb, Cirius, CiVi Biopharma, Conatus, CymaBay, Enyo, Galectin, Galmed, Genentech, Genfit, Gilead, Hepion, HighTide, Immuron, Intercept, Madrigal, Metacrine, NGM Bio, NorthSea, Novartis, Novo Nordisk, Pfizer, Sagimet, Second Genome, Tobira/Allergan, and Viking. S.J.B.: consultant: Akcea, Amgen, Esperion, GLG Group, Guidepoint Global, Madrigal, Novartis, Novo Nordisk, Regeneron, and Sanofi; speaking and teaching: Amgen, Boehringer Ingelheim, Eli Lilly, and Esperion; advisory committee or review panel: Akcea, Alexion, Altimmune, Amgen, AstraZeneca, Esperion, Madrigal, Novartis, Regeneron, and Sanofi. N.T.G.: grant/research support: Axcella, Bristol Myers Squibb, CymaBay, Genentech, Genfit, Gilead, HighTide, Madrigal, NGM Bio, NorthSea, and Novo Nordisk; speaking and teaching: AbbVie, Dova, Gilead, Intercept, and Salix. Z.H.Y.: consultant: Gilead; grant/research support: Allergan, AXA, Bristol Myers Squibb, Conatus, Cymabay, Gilead, HighTide, Intercept, Madrigal, NGM Bio, Novartis, and Novo Nordisk; speaking and teaching: Intercept. A.K.: consultant: Gilead, Intercept, and Novartis; grant/research support: Gilead. R.P.: speaking and teaching: Intercept. M.K., H.C., J.Z., and M.V.C.: current employees of Axcella Health and own stock options in the company.

Clinical trial registry website and trial number: US National Library of Medicine (Ethics: The protocol was approved by a central institutional review board (IntegReview) before study initiation. All subjects provided written informed consent.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.

Figures

Figure 1.
Figure 1.
Study design (a) and subject disposition (b). aCalorie-matched placebo control; breasons for exclusion are presented in Supplementary Table (see Supplemental Digital Content 2, http://links.lww.com/AJG/C100); c10 subjects were randomized but not dosed and thus were not part of the safety population; and d3 subjects who received AXA1957 high dose in error on day 1 (randomized to AXA1957 low dose) were included in the AXA1957 high-dose safety analysis, considered part of the AXA1957 low-dose completer population, and excluded from both arms of the per-protocol analysis. b.i.d., 2 times a day; BMx, biomarkers; D, day; cT1, corrected T1; MRI-PDFF, MRI-proton density fat fraction; OGTT, oral glucose tolerance test; T2D, type 2 diabetes; W, week.
Figure 2.
Figure 2.
Change from baseline in liver fat content (MRI-PDFF) (a and b) and insulin resistance (HOMA-IR) (c) in the overall safety population. *P < 0.05 vs AXA1957 high dose. b.i.d., 2 times a day; D, day; HOMA-IR, homeostatic model assessment of insulin resistance; isocal, isocaloric; isoN, isonitrogenous; MRI-PDFF, MRI-proton density fat fraction; W, week.
Figure 3.
Figure 3.
Change from baseline in ALT (a and b) and K-18 M65 (c) in the overall safety population. *P < 0.05 vs placebo. ALT, alanine aminotransferase; K-18 M65, keratin-18 measured using M65 enzyme-linked immunosorbent assay.
Figure 4.
Figure 4.
Change from baseline in biomarkers of fibroinflammation (a, b, and c) in the overall safety population. *P < 0.05 vs placebo. b.i.d., 2 times a day; cT1, corrected T1; D, day; isocal, isocaloric; isoN, isonitrogenous; Pro-C3, N-terminal type III collagen propeptide; W, week.
Figure 5.
Figure 5.
Proportion of subjects with clinically relevant thresholds of biologic activity (a, b, and c) in the overall safety population. ALT, alanine aminotransferase; cT1, corrected T1; MRI-PDFF, MRI-proton density fat fraction.

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Source: PubMed

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