The small-molecule compound inaxaplin (VX-147) reduced proteinuria in a small phase 2a study of patients with 2 apolipoprotein L1 (APOL1) variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria, researchers report. Administered orally, the drug is a selective inhibitor of APOL1 channel function, which is thought to be enhanced by the mutations and directly damage podocytes in the renal glomerulus.
The study included both a preclinical analysis of the effects of inaxaplin in a mouse model and an open-label clinical trial. Daily inaxaplin for 13 weeks with standard care produced these outcomes: “In preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was −47.6% (95% confidence interval, −60.0 to −31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation.”
Editorial 1: “The results of these investigations … constitute a step forward in making the promise of precision medicine a reality by means of industry–academia collaboration and the targeting of the large excess risk of end-stage kidney failure among Black persons in the United States for which the two prevalent APOL1 risk variants (occurring in one in eight Black adults) contribute to health inequity,” writes an editorialist. “Precision equity is the use of innovative approaches for disease prevention and treatment that takes into consideration differences among persons’ genes, environments, and lifestyles to address health disparities and achieve health equity. Small bites at the multifactorial causes of racial disparities, taken together with other interventions, can be epic disrupters of the inexorable progression of kidney disease and lead to long, healthy, and productive lives.”
A science-behind-the-study editorial explains how APOL1 produces damage in patients with focal segmental glomerulosclerosis (FSGS): “APOL1 is secreted by cells into the blood, where it forms a complex either with high-density lipoprotein, to form trypanosome lytic factor 1 (TLF1), or with IgM, to form trypanosome lytic factor 2 (TLF2). TLF1 and TLF2 undergo uptake into the trypanosome by means of endocytosis. The acidic environment of endosomes and lysosomes catalyzes a change in the conformation of TLF1 to a porelike structure, which then inserts into the plasma and lysosomal membranes. This porelike structure has been considered to be selective for anions, particularly chloride ions, by some investigators and selective for cation channels by others. Transmembrane chloride flux, osmotic swelling, and possibly rupture of the lysosome are thought to lead to death of the trypanosome, but the precise means by which TLF1 and TLF2 kill the trypanosome are incompletely elucidated.”