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Abstract: TH-PO480

Design of a Phase 2/3 Adaptive Trial Evaluating Inaxaplin in APOL1-Mediated Kidney Disease

Session Information

Category: Glomerular Diseases

  • 1303 Glomerular Diseases: Clinical‚ Outcomes‚ and Trials

Authors

  • Falk, Ronald, UNC, Chapel Hill, North Carolina, United States
  • Barisoni, Laura, Duke University, Durham, North Carolina, United States
  • Friedman, David, BIDMC, Harvard Medical School, Boston, Massachusetts, United States
  • Gipson, Debbie, University of Michigan, Ann Arbor, Michigan, United States
  • Lipkowitz, Michael, Georgetown University Hospital, Washington DC, District of Columbia, United States
  • Ojo, Akinlolu, University of Kansas School of Medicine, Kansas City, Kansas, United States
  • Pollak, Martin, BIDMC, Harvard Medical School, Boston, Massachusetts, United States
  • Chirieac, Madalina, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Faria-Urbina, Mariana, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Song, Yang, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Manos, George, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Ferreira, Anna, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Egbuna, Ogo I., Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States
  • Chertow, Glenn, Stanford University School of Medicine, Stanford, California, United States
Background

There is a critical need for therapies targeting the underlying cause of APOL1-mediated kidney disease (AMKD), a proteinuric nephropathy caused by 2 APOL1 variants (G1 or G2) that affects about 100,000 people in US and Europe. Inaxaplin (IXP; VX-147) is a small molecule inhibitor of APOL1 pore function. In a Ph2a trial, IXP significantly reduced proteinuria by 47.6% in participants with 2 APOL1 variants, proteinuria, and focal segmental glomerulosclerosis (FSGS). We describe the design of a Ph2/3 trial evaluating IXP in adults with AMKD.

Methods

This randomized, double-blind, placebo-controlled, Ph2/3 adaptive trial in adults with AMKD will first evaluate different doses of IXP to select a dose for Ph3 and subsequently evaluate the efficacy and safety of the selected IXP dose in the Ph3 portion of the trial. Participants aged 18 to 60 years, with 2 APOL1 variants, urine protein to creatinine ratio (UPCR) of ≥0.7g/g to <10g/g, estimated glomerular filtration rate (eGFR) of ≥25 to <75mL/min/1.73m2, and on stable standard-of-care medications may be eligible to enroll. In Ph2, ~66 participants will be randomized to receive 1 of 2 daily doses of IXP or placebo for 12wks. Ph3 (~400 participants) will begin after Ph2 enrollment is complete.

Results

The primary endpoint for the final analysis is reduction in the rate of decline of kidney function as measured by eGFR slope in participants receiving IXP versus placebo at ~2 years. The secondary efficacy endpoint for the final analysis is time to composite clinical outcome, which is defined as a sustained decline of ≥30% from baseline in eGFR, the onset of end-stage kidney disease (i.e., maintenance dialysis for ≥28 days, kidney transplantation, or a sustained eGFR of <15mL/min/1.73m2), or death. The final trial analysis will occur when participants have ≥2 years of eGFR data and when ~187 composite clinical outcomes have occurred. The trial has a pre-planned interim analysis at Week 48 evaluating proteinuria, as measured by the percent change from baseline in UPCR, and eGFR slope.

Conclusion

This Ph2/3 adaptive trial will determine the efficacy and safety of IXP in preserving kidney function and reducing proteinuria in a broad population with AMKD.

Funding

  • Commercial Support