Background
Patients with non-alcoholic steatohepatitis (NASH) do not currently have options for pharmaceutical treatment. AXA1125 is an endogenous metabolic modulator (EMM) composition of LIVRQNac, which has shown efficacious potential when administered to patients in early clinical studies. In vitro studies and literature review have enumerated several contributing mechanisms of action (MoA’s) by which AXA1125 dosing may be reducing levels of ALT, liver fat, Pro-C3, and HbA1c in patients. To further advance and quantitate the differential multi-targeted mechanisms driving improvements seen in in the clinic, a quantitative systems pharmacology (QSP) model, NAFLDsym¹, was employed to simulate AXA1125 under many combinations of candidate MoA’s and further substantiate the MoA underlying the clinical benefit observed to date in patients.
Methods
Clinical trial NCT04073368 was simulated by several software packages. Exposure of AXA1125 was modeled in Monolix® using a 1-compartment model based on data from a single 22.6 g dose (Fig 1A). This model was then used to predict the exposure of multiple doses (24 g BID) for 16 weeks using Simulx® (Fig 1B). Separately, various candidate MoA’s of AXA1125 were mechanistically represented in NAFLDsym (Fig 2 & Fig 3), including the secretion of incretins (GLP-1 and GIP) and relevant downstream effects, direct reduction of oxidative stress, increased AMPK-responsive enzyme expression, inhibition of hepatic stellate cell activation and proliferation, and decreased TNFα production. Each of these MoA’s has the potential to reduce the hepatic lipid burden, lipotoxicity, inflammation and/or fibrosis. NAFLDsym simulations combined the predicted exposure of 24 g BID dosing with various combinations and strengths of candidate MoA’s. Simulation results were evaluated against clinical data from a Phase IIa Study².
Results
Simulations with NAFLDsym implicate multiple mechanisms that may be playing a role in the efficacy of AXA1125. The clinical data² were recapitulated in simulations invoking combinations of incretin secretion, and increased AMPK-responsive enzyme expressions (Figure 3). Additional simulations which further invoked direct antioxidant activity, or antioxidant activity and decreased TNFα production, increased fatty acid oxidation, also recapitulated clinical observations.
Conclusion
NAFLDsym, a QSP model of NAFLD/NASH, was used to investigate the combination of mechanisms playing a role in AXA1125, a NASH therapeutic candidate. NAFLDsym simulations support the following mechanisms contributing to the clinical response of AXA1125: incretin effects, AMPK-responsive enzyme expression, antioxidant-mediated reduction of lipotoxicity, and inhibition of TNFα production. This work independently recapitulates previously published MoA findings, including AXA1125 as a mitochondrial activator, and predicts novel contributions which require additional work to be validated and expanded upon.
References
- Siler, S. Q. (2022). Applications of Quantitative Systems Pharmacology (QSP) in Drug Development for NAFLD and NASH and Its Regulatory Application. Pharmaceutical Research, 0123456789.
- A 16-Week, Single-Blind Randomized, Placebo- Controlled Food Study of the Safety and Tolerability of AXA1125 and AXA1957 in Subjects With Non-Alcoholic Fatty Liver Disease (NAFLD) – Clinical Trials ID: NCT04073368, AXA1125-003
- Daou, N., Viader, A., Cokol, M., Nitzel, A., Chakravarthy, M. v., Afeyan, R., Tramontin, T., Marukian, S., & Hamill, M. J. (2021). A novel, multitargeted endogenous metabolic modulator composition impacts metabolism, inflammation, and fibrosis in nonalcoholic steatohepatitis-relevant primary human cell models. Scientific Reports, 11(1), 11861.
By Vinal V Lakhani, Ming Gao, Paul Hinderliter, Matthew Russel, Karim Azer, Scott Q Siler
American Association for the Study of Liver Diseases (AASLD) Liver Meeting 2023, Boston, Massachusetts, November 10-14, 2023