Patients with non-alcoholic steatohepatitis (NASH) and fibrosis do not currently have options for pharmaceutical treatment. Numerous compounds have been in development including pegbelfermin, a polyethylene glycol-conjugated recombinant analogue of the metabolic hormone FGF21¹. The
recent completion of the FALCON 1 study² showed modest clinical benefit for NASH or fibrosis improvement in patients with fibrosis stage 3. A quantitative systems pharmacology (QSP) model, NAFLDsym3 (Figure 1), was subsequently employed to simulate and better understand the mechanistic underpinnings contributing to the observed top-line clinical responses.
Exposure of pegbelfermin in NASH patients was reproduced from FALCON 1 pharmacokinetic data and combined with a mechanistic representation of the actions of the pegbelfermin on adipose. The subsequent simulated effects of increased
adiponectin on the liver elicited a decrease in de novo lipogenesis and mono-acyl glycerol transferase activity along with an increase in hepatic fatty acid oxidation⁵-⁸ (Figure 2). All are consistent with AMP kinase activation. These effects act to reduce hepatic lipid burden and relieve lipotoxicity. Phase IIa clinical data were used to help validate these quantitative effects¹. Subcutaneous administration of 10 mg QW, 20 mg
QW, and 40 mg QW over 24 weeks was simulated in a cohort of F3 NASH patients (n=55) with similar clinical characteristics as the clinical cohorts (Table 1). Changes in liver fat, plasma ALT, NAFLD activity score, and fibrosis stage were simulated and compared with clinical data for each dose. Some parameter adjustments were made to provide better alignment with clinical data.
NAFLDsym recapitulated the observed modest efficacy in NASH patients with F3 fibrosis scores treated with pegbelfermin over 24 weeks (FALCON 1). Of note was an attenuation in the adiponectin increase over time (Figure 3). Liver fat and plasma ALT were reduced 5-20% for all doses, and the simulated change for each attenuated over time (Figure 3). The fraction of patients predicted to show improvement in both fibrosis and NASH ranged from 8-33% across the doses (Table 2); the simulation results in the
treatment groups were generally in agreement with the clinical data. Note that NAFLDsym was unable to predict improvements in simulated patients treated with placebo.
Simulations in NAFLDsym helped substantiate the hypothesis that pegbelfermin-driven increases in adiponectin mediate the observed effects on liver outputs in NASH patients. However, the attenuated increase in adiponectin over time may be associated with loss of durability over time.
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Scott Q. Siler, Vinal Lakhani, Grant Generaux, Giridhar Tirucherai
American Association for the Study of Liver Diseases (AASLD) Liver Meeting, November 4-8, 2022, Washington, DC