Year: 2025
Type: article
Abstract: Background and Aims Two variants in APOL1 drive progressive, proteinuric nephropathies called APOL1-mediated kidney disease (AMKD). Inaxaplin, an oral inhibitor of APOL1, reduced proteinuria by 47.6% in persons with 2 APOL1 variants and focal segmental glomerulosclerosis (FSGS) in a Phase 2 study. We report interim data from an APOL1 genotyping study, describe the Phase 2/3 inaxaplin trial (AMPLITUDE) design in a broader AMKD population, and provide interim baseline data from the Phase 2 component of AMPLITUDE. Methods Our genotyping study is enrolling up to 4000 participants of recent African ancestry with FSGS or nondiabetic kidney disease and UPCR ≥0.5 g/g. One blood sample is collected to verify APOL1 genotype by polymerase chain reaction to describe the genetic prevalence of AMKD and inform eligibility for clinical trials. Our Phase 2/3, randomized, double-blind, placebo-controlled, adaptive trial is enrolling persons without diabetes (Phase 2: 18 to 65 years; Phase 3: 10 to 65 years) with 2 APOL1 variants, UPCR ≥0.7 to <10 g/g, and eGFR ≥25 to <75 mL/min/1.73 m2. In the Phase 2 component, participants received inaxaplin (different doses) or placebo for 12 weeks to select a dose for evaluation of inaxaplin efficacy/safety in ∼400 participants in Phase 3. For the final analysis, the primary endpoint will be reduction in rate of decline of kidney function (eGFR slope) by inaxaplin versus 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 ≥2 years 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; 164 of the 674 (24.3%) participants are from Europe. Of the 674 participants with 2 APOL1 variants in this study, 36 enrolled in the completed Phase 2 component of AMPLITUDE. In the AMPLITUDE trial, we selected a 45 mg inaxaplin once daily dose for Phase 3 after the Phase 2 efficacy/safety data had been reviewed 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, respectively. The mean (SD) age was 42.7 (11.0) years and mean (SD) baseline eGFR was 42.8 (14.0) mL/min/1.73 m2. Phase 3 is ongoing in nine countries, including Belgium and France in Europe. Conclusions The high prevalence of two 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 Phase 2/3 trial will evaluate the effects of inaxaplin on preserving kidney function and reducing proteinuria in a broad AMKD population.
Authors: Glenn Chertow, George Manos, Ogo Egbuna
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4415426347