Scaled-up Production of Human Glucuronidated, Oxidative and Gut Metabolites of Epacadostat, an Investigational New Drug Targeting the Enzyme Indoleamine-2,3-dioxygenase 1

Scaled-up Production of human glucuronidated, oxidative and gut metabolites of epacadostat, an investigational new drug targeting the enzyme indoleamine-2,3-dioxygenase 1

Presented at: RSC DMPK meeting, 2018, London UK

Metabolism of drugs often results in the formation of major circulating metabolites derived from mixed clearance pathways, and can include both primary and secondary metabolites. Human metabolism of Incyte’s investigational new drug epacadostat (EPA) forms 3 major circulating plasma metabolites (Boer et al., 2016). Glucuronidation of EPA to form M9 is the dominant metabolic pathway, in conjunction with formation of an amidine M11 and an N-dealkylated metabolite, M12. Boer and co-workers showed that reductive metabolism by gut microbiota results in M11, which is then absorbed and further modified by CYP enzymes to form the secondary metabolite M12.

Hypha’s microbial biotransformation panel, comprising wild-type bacteria and fungi, provided a route to achieve formation of all three human metabolites, with several strains found able to effectively biotransform EPA. Different strains and dosing regimes were found to be optimal for production of each metabolite. Scale-up of the most productive biotransforming strains enabled the supply of high mg amounts of M9 and M11 at 95% purity to Incyte Corporation for further studies. M12 was synthesised in parallel by Incyte Corporation.

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