Considerations for small molecule NLRP3 inhibitors developed for intra - ocular delivery • Across both series, we have multiple examples achieving single - digit nM IC50 in the THP - 1 cell IL - 1 β release assay. • Conjugation handle: ‒ Substitutions on the scaffold end provide a versatile handle for conjugation to ABCD. • Intravitreal (IVT) delivery vs. systemic NLRP3 inhibitors — focus shifts to ocular ‒ Compared with systemically dosed NLRP3 inhibitors, IVT dosing yields low systemic exposure and a wider systemic safety margin. ‒ Oral availabilities and BBB properties are no longer major constraints 22