Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants.
In a phase 2a open-label study, the oral APOL1 inhibitor inaxaplin reduced proteinuria by a mean of 47.6% at 13 weeks in patients with two APOL1 variants and focal segmental glomerulosclerosis, providing the first targeted therapy for this genetically defined nephropathy.
Background
Toxic gain-of-function variants (G1 or G2) in the APOL1 gene place persons of recent African ancestry at high risk for rapidly progressive, proteinuric nephropathy. Despite this known genetic cause, no therapies specifically targeting proteinuric kidney disease in persons carrying two APOL1 variants existed, and standard care does not halt progression to kidney failure.
Study design
After preclinical work showing inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in a G2-homologous transgenic mouse model, investigators conducted a single-group, open-label phase 2a study. Sixteen participants with two APOL1 variants, biopsy-proven FSGS, a urinary protein-to-creatinine ratio of at least 0.7, and an eGFR of at least 27 received inaxaplin daily for 13 weeks (15 mg for 2 weeks, then 45 mg for 11 weeks) plus standard care.
Key findings
Among the 13 participants who met the 80% adherence threshold, the mean change from baseline urinary protein-to-creatinine ratio at week 13 was -47.6% (95% confidence interval, -60.0 to -31.3). Similar reductions were observed in an analysis of all participants regardless of adherence, except in one participant. Adverse events were mild or moderate, and none led to study discontinuation.
Clinical implications
Targeted inhibition of APOL1 channel function represents a precision-medicine approach for APOL1-mediated kidney disease, reinforcing the value of APOL1 genotyping in proteinuric CKD. These proof-of-concept findings supported advancement to a larger phase 2/3 pivotal trial powered on kidney-function endpoints.
Category
Research
Source
N Engl J Med
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