PF-05175157: A Comprehensive Profile of a Dual ACC Inhibitor from Preclinical Promise to Clinical Discontinuation

Executive Summary

PF-05175157 is an investigational, orally bioavailable small molecule developed as a potent, dual inhibitor of Acetyl-CoA Carboxylase isoforms 1 and 2 (ACC1 and ACC2). The therapeutic rationale for this mechanism was ambitious and scientifically robust: by simultaneously inhibiting both isoforms, the compound was designed to deliver a powerful, two-pronged attack on disordered lipid metabolism. Inhibition of the cytosolic ACC1 isoform was intended to block de novo lipogenesis (DNL), the synthesis of new fatty acids, a key pathway in diseases like nonalcoholic steatohepatitis (NASH) and acne vulgaris. Concurrently, inhibition of the mitochondrial ACC2 isoform was expected to relieve the suppression of carnitine palmitoyltransferase I (CPT-1), thereby promoting fatty acid β-oxidation (FAO) and increasing the utilization of existing lipids, a highly desirable effect for treating Type 2 Diabetes Mellitus (T2DM).

This elegant mechanism of action translated successfully from preclinical models into early-phase human trials. Clinical studies demonstrated robust target engagement, evidenced by a significant and dose-dependent reduction in DNL in healthy volunteers. This provided clear proof of mechanism and validated the therapeutic hypothesis in humans, marking a significant scientific achievement. However, the program's trajectory was abruptly halted by the emergence of a critical safety signal during multi-dose studies. An asymptomatic, dose-dependent, and reversible thrombocytopenia (reduction in platelet count) was identified as the dose-limiting toxicity.