Abstract

The agonist anti-FGFR1/KLB bispecific antibody, BFKB8488A, has been shown to be effective at reducing liver fat in NAFLD patients in a Ph1b study [1]. However, FGFR1/KLB receptors are primarily expressed in adipose rather than liver, suggesting a role for adipokine mediators such as adiponectin (Adpn). Adpn levels have been shown to increase with BFKB8488A treatment. NAFLDsym, a QSP mechanistic, mathematical model of NAFLD and NASH, was employed to evaluate the plausibility of Adpn increases mediating the reduction in liver fat observed with BFKB8488A treatment. Exposure of BFKB8488A was predicted from PopPK modeling and combined with a mechanistic representation of the effects of BFKB8488A interaction with the FGFR1/KLB complex in adipose. The mechanistic model incorporated the effects of increased Adpn to elicit changes in several hepatic pathways that can act in concert to reduce the hepatic lipid burden. This included decreases in hepatic de novo lipogenesis and mono-acyl glycerol transferase activity along with an increase in hepatic fatty acid oxidation. Subcutaneous administration of 50 mg Q2W, 75 mg Q2W, 100 Q2W or 250 Q4W BFKB8488A was simulated for 12 weeks in a virtual cohort of NAFLD patients with steatosis (n=42). Generally, simulations of BFKB8488A-mediated increases in Adpn were able to predict comparable reduction in liver fat as those observed in the Ph1b study. Simulated BFKB8488A administration was predicted to increase serum Adpn 40-80% over 12 weeks of dosing in an exposure-related manner (Figure 1), which was within range of the clinical data (except for 100 mg Q2W). Liver fat reductions were predicted to increase in magnitude with increasing dose within the simulated patient population, ranging from 0% to >90% relative to baseline. The inter-patient variability in the liver fat reduction was reasonably predicted. Alternative simulations without Adpn increase did not predict any effects on liver fat The hypothesis that BFKB8488A-induced increases in Adpn mediate the observed effects on liver fat in NAFLD patients is consistent with NAFLDsym simulations. The similarity between the clinical observations and model predictions utilizing the simulated mechanistic effects of Adpn on hepatic lipid pathways suggests that Adpn participates in mediating the potentially beneficial response to BFKB8488A.

By Zackary R. Kenz, Brett A. Howell, Ajit Dash, Chin Wong, Felix L. Yeh, Leslie W. Chinn, Puneet Arora, Kenta Yoshida, and Scott Q. Siler

(AASLD) The Liver Meeting, Nov. 13-16, 2020