Scale-up Supply of a Major Human Metabolite of a Dermal Drug Candidate for Unambiguous Structure Determination, Biological Quantification and in vitro Biological Tests for MIST Compliance
Presented at: 1st RSC Anglo Nordic meeting, 2017, Denmark
Ingenol disoxate is a chemically-stable drug developed by LEO Pharma, effective at treating actinic keratosis topically and currently in Phase 3 clinical trials. Profiling of ingenol disoxate against multiple species of hepatocytes revealed M27 as a predominant metabolite, particularly in human hepatocytes. Although accurate mass spectrometry indicated the metabolite was monohydroxylated in the ingenol moiety, the precise location of the hydroxyl group could not be identified. Consequently, chemical synthesis was not feasible, nor biological quantification and further biological testing possible.
Screening ingenol disoxate against Hypha’s Phase I microbial panel highlighted several strains that produced oxidized metabolites, with one strain selected for scale-up to provide 100s of milligrams of M27 at >99% purity for unambiguous MetID and further biological studies. This poster illustrates the process undertaken at Hypha to obtain M27, together with information on the studies performed with the material by LEO Pharma for compliance with metabolite safety testing (MIST) and drug-drug interaction (DDI) guidelines.