Dados do Trabalho

Título

APOL1 GENOTYPING AND DESIGN OF A PHASE 2/3 ADAPTIVE TRIAL EVALUATING INAXAPLIN IN APOL1-MEDIATED KIDNEY DISEASE

Introdução

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. These variants are common in persons of recent African ancestry; however, identifying persons with AMKD is uniquely challenging in Brazil due to the high degree admixture of the population. In a Ph2a study, inaxaplin (IXP), an inhibitor of APOL1 function, reduced proteinuria by 47.6% in participants with 2 APOL1 variants and FSGS. We report interim data from a global APOL1 genotyping study and describe the design of a Ph2/3 trial of IXP in a broad AMKD population.

Material e Método

The APOL1 genotyping study is enrolling up to 2500 participants of recent African ancestry with focal segmental glomerulosclerosis (FSGS) or proteinuric nondiabetic kidney disease (NDKD) to determine the percent of participants with 2 APOL1 variants and identify potential participants for the Ph2/3 trial of IXP. A blood sample is collected during a single visit to determine APOL1 genotype using a validated PCR assay.

The randomized, double-blind, placebo-controlled, Ph2/3 adaptive trial is enrolling persons with 2 APOL1 variants, UPCR ≥0.7 to <10 g/g, eGFR ≥25 to <75 mL/min/1.73m2, who are on stable standard-of-care therapy. In Ph2, ~66 participants will be randomized to receive 1 of 2 daily doses of IXP or placebo for 12 weeks to select a dose for Ph3. Ph3 (~400 participants) will evaluate the efficacy and safety of the selected IXP dose and will begin after Ph2 enrollment is complete.

Resultados

Interim analysis of the APOL1 genotyping study included 1463 participants. Among 392 participants with FSGS and 1071 with NDKD, 184 (46.9%) and 248 (23.2%) have 2 APOL1 variants, respectively.

In the Ph2/3 adaptive trial of IXP, the primary endpoint for the final analysis is reduction in rate of decline of kidney function as measured by eGFR slope in participants receiving IXP vs placebo with at least 2 years of data.

Discussão e Conclusões

The high prevalence of 2 APOL1 variants in participants with recent African ancestry and proteinuric chronic kidney disease emphasizes the importance of APOL1 genotyping in kidney disease care to optimize disease management and identify patients who may be eligible for clinical trials of APOL1-targeted therapies. The Ph2/3 adaptive trial will determine the efficacy and safety of IXP in preserving kidney function and reducing proteinuria in AMKD.

Palavras Chave

Apolipoprotein L1, APOL1-mediated kidney disease, nondiabetic kidney disease, focal segmental glomerulosclerosis, proteinuric chronic kidney disease, proteinuria, inaxaplin, APOL1 genotyping, APOL1-targeted therapies, adaptive clinical trial design