Kidney Week

Abstract: TH-PO1203

AMPLITUDE: A Phase 2/3 Adaptive Trial of Inaxaplin in APOL1-Mediated Kidney Disease

Session Information

• Late-Breaking Science Posters
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics

Authors

• Chertow, Glenn M., Stanford University School of Medicine, Palo Alto, California, United States

Glenn M. Chertow, MD, MPH, FASN

• Manos, George, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

George Manos, PhD

• Egbuna, Ogo I., Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, United States

Ogo I. Egbuna, MD, MSc, FASN

Background

Two variants in APOL1 drive progressive, proteinuric nephropathies called APOL1-mediated kidney disease (AMKD). Inaxaplin (IXP), an oral inhibitor of APOL1, reduced proteinuria by 47.6% in persons with 2 APOL1 variants and FSGS in a Ph2 study. We report interim data from an APOL1 genotyping study, describe the Ph2/3 IXP trial (AMPLITUDE) design in a broader AMKD population, and provide interim baseline data from the Ph2 portion of AMPLITUDE.

Methods

Our genotyping study is enrolling up to 4000 participants of recent African ancestry with FSGS or nondiabetic kidney disease and UPCR≥0.5g/g. One blood sample is collected to verify APOL1 genotype by PCR to optimize care and inform eligibility for clinical trials.
Our Ph2/3, randomized, double-blind, placebo-controlled, adaptive trial is enrolling persons (Ph2:18-65yrs; Ph3:10-65yrs) with 2 APOL1 variants, UPCR≥0.7 to <10g/g, and eGFR≥25 to <75mL/min/1.73m². In the Ph2 portion, participants received IXP (different doses) or placebo for 12wks to select a dose for evaluation of IXP efficacy/safety in ~400 participants in the Ph3 portion. For the final analysis, the primary endpoint is reduction in rate of decline of kidney function (eGFR slope) by IXP vs placebo; secondary endpoint is time to composite clinical outcome (sustained decline of ≥30% from baseline in eGFR, onset of ESKD, or death). Final analysis will occur when ≥2yrs of eGFR data and ~187 composite clinical outcomes are obtained.

Results

The genotyping study interim analysis included 2866 participants of whom 674(23.5%) have 2 APOL1 variants; 36 of these participants enrolled in the completed Ph2 portion of AMPLITUDE. A 45mg IXP once daily dose was selected for Ph3 after review of Ph2 efficacy/safety data by an independent data monitoring committee.
Among 64 participants dosed, 34(53.1%), 24(37.5%), and 6(9.4%) have G1/G1, G1/G2, or G2/G2 genotypes. The mean (SD) age was 42.7 (11.0) yrs and mean (SD) baseline eGFR was 42.8 (14.0) mL/min/1.73m². Ph3 is ongoing in 9 countries.

Conclusion

The high prevalence of 2 APOL1 variants in participants with recent African ancestry and proteinuric CKD reinforces the importance of APOL1 genotyping to optimize kidney disease management and enable referral to clinical trials of APOL1-targeted therapies. Our Ph2/3 trial will evaluate the effects of IXP on preserving kidney function and reducing proteinuria in a broad AMKD population.

Funding

• Commercial Support – Vertex Pharmaceuticals