Background

The FGFR1/beta-klotho receptor (FGFR1/KLB) in adipose has been demonstrated to be a promising target for treating NASH, primarily due to enhanced adiponectin secretion. Several agonists for this receptor are analogues of the
endogenous hormone, FGF21. The resultant actions of increased adiponectin on the liver have been reported to lead to improvements in steatosis, NASH, and fibrosis. A quantitative systems pharmacology (QSP) model, NAFLDsym (Fig 1), was employed to aid in the understanding of the role that adiponectin increases play in improving NASH. Efficacy was predicted for multiple agonists of FGFR1/KLB, including pegbelfermin², efruxifermin³, Bio89-100⁴, and BFKB8488A⁵.

Methods

Compartmental pharmacokinetic models (Fig 2) were developed for each compound and combined with a mechanistic representation of the effects of the pegbelfermin, efruxifermin, Bio89-100, and BFKB8488A interactions with
the FGFR1/KLB in adipose. The subsequent simulated effects to increased adiponectin were validated by comparisons with reported clinical data for each compound (Fig 3-4). The
simulated adiponectin effects on the liver elicited a decrease in hepatic de novo lipogenesis and mono-acyl glycerol transferase
activity and an increase in hepatic fatty acid oxidation, consistent with the activation of AMP kinase6-9. These effects acted in concert to reduce hepatic lipid burden and relieve
lipotoxicity. The effects on liver fat, plasma ALT, NAFLD activity score (NAS), and fibrosis stage were predicted for 48 weeks of treatment with each compound in SimCohorts of F1 (n=32), F2 (n=35), F3 (n=55), or F4 (n=35) NASH patients
(Figure 4).

The simulated patients in the SimCohorts included pathophysiologic and clinical characteristics of NASH patients (Table 1); inter-patient variability was also included to ensure reported diversity.

Results

The simulated increases in serum adiponectin and reductions of liver fat align well with reported clinical data (Fig 4). Of note is the trend towards greater relief of steatosis with compounds and doses that elicit higher adiponectin increases. Greater improvements in plasma ALT, NAS, and fibrosis stage were
also predicted for compounds that caused the substantial increases in serum adiponectin (Fig 5).

Conclusion

Greater treatment-induced adiponectin production likely mediates enhanced simulated efficacy with FGFR1/KLB agonists. Compounds and doses that achieve ≥60% increases in serum adiponectin are predicted to have greatest benefits in clinical metrics such as fibrosis stage, collagen area, and NAS.

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Vinal Lakhani, Giridhar Tirucherai, Grant Generaux, Scott Q. Siler

American Association for the Study of Liver Diseases (AASLD) Liver Meeting, November 4-8, 2022, Washington, DC