Targeted inhibition of APOL1 channel function with Inaxaplin may effectively reduce proteinuria in individuals with two APOL1 variants and focal segmental glomerulosclerosis.

Individuals carrying toxic gain-of-function variants in the gene responsible for producing apolipoprotein L1 (APOL1) are at an increased risk of developing rapidly progressive, proteinuric nephropathy. However, there is a lack of effective therapies targeting proteinuric kidney disease in those carrying two APOL1 variants (G1 or G2). To address this, the researchers conducted preclinical and clinical studies to investigate the effectiveness of a small-molecule compound, Inaxaplin, in inhibiting APOL1 channel function and reducing proteinuria in such individuals.

Using APOL1 human embryonic kidney (HEK293) cells and a transgenic mouse model of proteinuric kidney disease, the researchers showed that Inaxaplin selectively inhibited APOL1 channel function and reduced proteinuria. Furthermore, in a single-group, open-label, phase 2a clinical study, involving 13 participants (with two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria), who completed the study and consumed Inaxaplin daily along with standard care, showed a marked decline in urinary protein-to-creatinine ratio at week 13. Side events were mild or moderate in severity and did not cause study discontinuation.

REFERENCE-

Egbuna O, et al. Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants. N Engl J Med 2023; 388:969-979. DOI: 10.1056/NEJMoa2202396