Evobrutinib pathway to its major metabolite M463-2 and insights from a biotransformation and DDI perspective

1. Evobrutinib is a highly selective, covalent, central nervous system-penetrant Bruton's tyrosine kinase (BTK) inhibitor, currently in Phase III trials for the treatment of relapsing multiple sclerosis. One major circulating metabolite of evobrutinib has been previously identified as the racemic dihydrodiol M463-2 (MSC2430422) in a Phase I human mass balance study. 2. Phenotyping experiments were conducted to confirm the metabolic pathway of evobrutinib to M463-2. Ratio of the enantiomers was determined by enantioselective liquid chromatography with tandem mass spectrometry analysis of plasma samples from humans and preclinical species. Drug-drug interaction (DDI) characterisation, evaluation of pharmacological activity on BTK, and off-target screening experiments followed assessing safety of the metabolite. 3. The biotransformation of evobrutinib to M463-2 was determined to be a two-step process with a CYP-mediated oxidation acting to form an epoxide intermediate, which was further hydrolysed by soluble and mitochondrial epoxide hydrolase. Only the (S)-enantiomer was determined to be a major metabolite, the (R)-enantiomer was minor. In vitro studies demonstrated the (S)-enantiomer lacked clinically relevant pharmacological activity, off-target effects and DDIs. 4. The biotransformation of evobrutinib to its major metabolite has been elucidated, with the major (S)-enantiomer being shown to pose no on/off target or DDI risks.

Automated summary

Evobrutinib is a BTK inhibitor currently in Phase III trials for the treatment of relapsing multiple sclerosis. In this study, the metabolic pathway of evobrutinib to its major metabolite M463-2 was confirmed through phenotyping experiments. The (S)-enantiomer was determined to be the major metabolite with no relevant pharmacological activity, off-target effects or DDIs.