Unique nonclinical safety profile of PF-06835919, a ketohexokinase inhibitor, highlights a species-dependent mechanism.

PF-06835919 is a ketohexokinase inhibitor developed for the treatment of non-alcoholic fatty liver disease and type 2 diabetes. To support its clinical development, nonclinical safety studies in rats up to 6 months and in dogs up to 9 months were conducted. In rat repeat-dose studies, findings consistent with hepatic microsomal enzyme induction (hepatocyte hypertrophy/hyperplasia, with secondary hypertrophy/hyperplasia of thyroid follicular cells and vacuolation of cells in the pars distalis of the pituitary gland) were observed and, in the 6-month study, foci of hepatocellular alteration and thyroid follicular cell adenoma were also noted at higher doses. Other findings included heart weight increase, changes in white and brown fat and serum lipids, decreased/absent corpora lutea in the ovary, and seminiferous tubular degeneration in the testis. None of these findings, except for lower cholesterol and higher heart weight, were present in dog studies. In vitro, PF-06835919 showed little effect on PPAR α, β/δ or γ activities at therapeutic concentrations. It is concluded that PF-06835919 does not directly activate PPARs at exposures achieved at planned clinical doses and most of these rat findings reflect species-specific adaptive changes to liver enzyme induction in addition to the pharmacology of the compound.