Inaxaplin reduces proteinuria in patients with focal segmental glomerulosclerosis (FSGS) and 2 risk variants of the gene encoding apolipoprotein L1 (APOL1), investigators reported in the New England Journal of Medicine.

Inaxaplin is an investigational selective small-molecule inhibitor of APOL1 ion channel function, Ogo Egbuna, MD, of Vertex Pharmaceuticals in Boston, Massachusetts, and colleagues explained.

In a phase 2a clinical study ( number: NCT04340362), the investigators administered inaxaplin (15 mg orally once daily for 2 weeks, followed by 45 mg once daily for 11 weeks) to 16 adults with an APOL1 genotype of G1/G1, G2/G2, or G1/G2 and biopsy-proven FSGS. At baseline, patients had nephrotic- or subnephrotic-range proteinuria, defined as a urinary protein-to-creatinine ratio (UPCR) of at least 0.7 but less than 10 g/g.

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Mean UPCR decreased 47.6%, from 2.21 g/g at baseline to 1.27 g/g at 13 weeks, among 13 patients who had at least 80% adherence to inaxaplin, Dr Egbuna and colleagues reported. In the nephrotic and subnephrotic-range groups, proteinuria decreased 47.7% and 47.5%, respectively. For unknown reasons, 1 treatment-adherent patient had no response.

Inaxaplin was taken with standard of care medications such as glucocorticoids, immunosuppressants, and renin-angiotensin-aldosterone inhibitors. These background medications did not account for the change in UPCR.

According to Dr Egbuna’s team, “these data provide a rationale to test the hypothesis that with a longer treatment period, inaxaplin therapy may prevent or slow progression to end-stage kidney disease.”

Patients had an estimated glomerular filtration rate (eGFR) of 27 mL/min/1.73 m2 or higher at baseline. Neither eGFR nor blood pressure changed during treatment.

A total of 94% of patients had at least 1 mild to moderate adverse event, most commonly headache, back pain, and nausea. No serious treatment-related adverse events occurred, and no one discontinued inaxaplin.

According to Neil R. Powe, MD, MPH, of Harvard School of Public Health in Boston, Massachusetts, “This research appears to be a major scientific breakthrough with enormous implications, especially for persons of African ancestry.” Comparative effectiveness research on inaxaplin is now needed, he suggested in an accompanying editorial, including in patients with hypertensive kidney disease and with a clinical endpoint of change in eGFR and/or end-stage kidney disease. APOL1 testing is uncommon, but may increase if future studies continue to show promise results.

Disclosure: This research was supported by Vertex Pharmaceuticals. Please see the original reference for a full list of disclosures.


Egbuna O, Zimmerman B, Manos G, et al. Inaxaplin for proteinuric kidney disease in persons with two APOL1 variants. N Engl J Med 388:969-79. Published online March 15, 2023. doi:10.1056/NEJMoa2202396

Powe NR. A step forward for precision equity in kidney disease. N Engl J Med 388:1043-1044. Published online March 15, 2023. doi:10.1056/NEJMe2301003