Izicopan Shows Over 100-Fold Lower Reactive Metabolite Formation Than Avacopan
In a head-to-head in vitro glutathione trapping assay at 10 µM, InflaRx’s izicopan showed minimal reactive metabolite formation over 40 minutes, while avacopan generated thiol adduct levels over 100-fold higher at 5 and 10 minutes and approximately 10-fold higher at 20 and 40 minutes. These preclinical data indicate izicopan’s lower bioactivation risk profile.
1. In Vitro Metabolite Profiling
Izicopan and avacopan were tested in human liver microsomes at 10 µM using a standard glutathione trapping assay with 0–40-minute incubations to quantify reactive metabolite formation. Reactive thiol adducts, including glutathione and cysteine conjugates, were measured over time to assess bioactivation potential.
2. Comparative Results
Izicopan demonstrated minimal reactive metabolite formation throughout the 40-minute assay, while avacopan showed reactive conjugate peak areas exceeding izicopan by over 100-fold at 5 and 10 minutes and roughly 10-fold at 20 and 40 minutes. These differences highlight izicopan’s lower bioactivation in this preclinical model.
3. Potential Safety Implications
The reduced reactive intermediate formation for izicopan suggests a lower bioactivation-related safety risk profile compared with the marketed comparator. If clinical studies confirm these findings, izicopan’s differentiated safety characteristics could strengthen its position in the C5aR1 inhibitor class.