Small Molecule APOL1 Channel Inhibitor Reduces Proteinuria, Rescues Podocyte Injury, and Reverses eGFR Decline in an APOL1-Mediated Kidney Disease Mouse Model

Background: APOL1-mediated kidney disease (AMKD) is a progressive, proteinuric nephropathy caused by gain-of-function variants (G1 or G2) in APOL1. There are currently no treatments addressing the underlying cause of AMKD. We reported results from a proof-of-concept clinical study with inaxaplin (IXP, VX-147), a small molecule inhibitor of APOL1, which has potential to become the first genetically-targeted therapy for kidney disease. Our previous preclinical data demonstrated that therapeutic intervention with a small molecule APOL1 channel inhibitor with similar structure and potency to IXP (Compound 3) reduced proteinuria and podocyte injury in a chronic AMKD mouse model. Methods: To develop a chronic AMKD mouse model with glomerulopathy, we used transgenic APOL1 mice homozygous for the APOL1 G2 variant (G2SC). A plasmid encoding interferon γ (IFNγ) was hydrodynamically injected (HDI) into G2SC mice to continuously secrete IFNγ from the liver. Mice were treated for 7 days with Compound 3 or vehicle at two therapeutic timepoints after HDI. Proteinuria and eGFR were assessed throughout the study. Morphological assessment of podocyte health was evaluated using 3D-structural illumination microscopy. Results: HDI of IFNγ plasmid into G2SCmice led to a dramatic and sustained increase in proteinuria and progressive glomerulopathy. Therapeutic intervention with Compound 3 at both intervention timepoints dramatically reduced proteinuria. Morphological assessment of podocytes showed that loss of filtration slit density was present prior to treatment initiation and was reversed with Compound 3, highlighting the recovery of effaced podocytes. Furthermore, therapeutic intervention with Compound 3 preserved the eGFR when administered early, and reversed eGFR decline back to near baseline level at a later timepoint of intervention. Conclusion: Here we demonstrate that APOL1 channel inhibition by Compound 3, a close analog of the clinical candidate inaxaplin, reduces proteinuria and glomerulopathy and reverses eGFR decline after APOL1-mediated glomerular damage is well established. Funding: Commercial Support - Vertex Pharmaceuticals, inc.