Kidney Week

Abstract: SA-PO701

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

Session Information

• Glomerular Diseases: Therapeutic Strategies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Blasio, Angelo, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Angelo Blasio, PhD

• Mccarthy, Gizelle, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Gizelle Mccarthy, PhD

• Kumar, Shyamesh, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Shyamesh Kumar, PhD, DVM

• Stavropoulos, Kathy, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Kathy Stavropoulos, MS, MPH

• Senter, Timothy J., Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Timothy J. Senter, PhD

• Dakin, Leslie, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Leslie Dakin, PhD

• Proctor, Jennifer, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Jennifer Proctor

• Furey, Brinley, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Brinley Furey

• Zimmerman, Brandon, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Brandon Zimmerman, PhD

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 (G2_SC). A plasmid encoding interferon γ (IFNγ) was hydrodynamically injected (HDI) into G2_SC 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 G2_SC mice 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.