Devimistat (CPI-613): A Comprehensive Monograph on a First-in-Class Mitochondrial Metabolism Inhibitor

Executive Summary

Devimistat (CPI-613) is a first-in-class, investigational small molecule drug designed to exploit the unique metabolic vulnerabilities of cancer cells. As a synthetic lipoic acid analogue, its novel mechanism of action involves the simultaneous inhibition of two critical enzymes in the mitochondrial tricarboxylic acid (TCA) cycle: the pyruvate dehydrogenase complex (PDH) and the α-ketoglutarate dehydrogenase complex (KGDH). This dual blockade was engineered to cut off the primary energy and biosynthetic pathways fueled by both glucose and glutamine, leading to catastrophic metabolic stress and selective death of tumor cells. The compelling scientific rationale, coupled with impressive preclinical data and exceptionally promising early-phase clinical results—including a 61% objective response rate in metastatic pancreatic cancer and a 52% complete remission rate in older patients with acute myeloid leukemia (AML)—generated significant optimism within the oncology community and garnered extensive regulatory support, including multiple Fast Track and Orphan Drug designations from the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).