APOL1 channel blocker reduces proteinuria in FSGS

Kidney disease is not an equal opportunity offender. Individuals of recent African ancestry, including African Americans, have a higher risk of focal segmental glomerulosclerosis (FSGS) and advanced stage kidney disease, compared to individuals of European ancestry.¹ African Americans develop end-stage kidney disease at 4 times the rate of White Americans, explaining why Black people, who represent only 13% of the US population, account for more than 35% of people with end-stage kidney disease (ESKD).² Although multiple factors contribute to this racial disparity, the observation that African Americans with FSGS and ESKD tend to have relatives with kidney disease suggest that genetic factors are involved. In 2008, 2 independent groups reported that a specific locus on chromosome 22 was associated with FSGS and ESKD in African Americans.^3,4 Further investigations of this locus identified 2 coding variants of the APOL1 gene (named G1 and G2) as drivers of the association with kidney disease.^5,6

Although the association of APOL1 CKD risk variants with FSGS, hypertension-associated kidney disease, and other forms of CKD is now well established, the mechanism by which APOL1 risk variants cause kidney disease remains unclear. Several disease mechanisms have been proposed, but no consensus has emerged. Compared to the reference APOL1 (named G0), as we previously reported, APOL1 G1 and G2 proteins form cation channels that aberrantly transport sodium into the cell and cause potassium efflux from the cell. According to this model, the aberrant cation transport by G1 and G2 but not G0 triggers cytotoxicity, including podocyte injury that underlies FSGS.⁷ Therefore, this variant APOL1-specific gain-of-function represents an ideal therapeutic target.

What did the study show?

Vertex Pharmaceuticals developed Inaxaplin—an oral, small molecule inhibitor of APOL1 cation channel function. In a recent report published in the New England Journal of Medicine, Egbuna et.al. reported that Inaxaplin specifically inhibits APOL1 channel function in vitro and reduces proteinuria in transgenic mice expressing human APOL1 kidney risk variants and treated with interferon gamma to induce kidney disease. The authors then conducted a phase 2, single-group, open-label study to test the efficacy and safety of Inaxaplin use in humans.⁸

The phase 2 study enrolled 16 Black patients with APOL1-associated, biopsy-proven nondiabetic FSGS and proteinuria, ranging from 0.7 to <10 g/d. The primary efficacy outcome was percent change from baseline urinary protein-to-creatinine ratio (UPCR) at week 13. The investigators reported that 13 evaluable participants (fully compliant with the study drug) with idiopathic FSGS and 2 APOL1 kidney risk variants had a mean reduction in UPCR of 47.6%. The treatment effect was rapid—evident within 2 weeks—and sustained. Mild to moderate adverse events were reported in 15 of 16 participants but did not lead to treatment discontinuation.⁸

Why is the study important?

Inaxaplin is the first experimental therapy shown to reduce proteinuria in APOL1-associated FSGS. Achievement of this progress within 13 years of the initial discovery of the association between APOL1 kidney risk variants and increased risk of kidney failure is a major scientific advance. These early positive results reinforce the potential of a drug-discovery strategy that prioritizes diseases with well-defined genetic causes. Furthermore, the reported efficacy of Inaxaplin not only provides hope for patients with APOL1-mediated FSGS, but also supports the hypothesis that APOL1-mediated cation transport is the key mechanism underlying APOL1-mediated kidney disease.⁷

Important to note is that this is a small, uncontrolled study focused on an intermediate measure, proteinuria. The short duration of the study precluded measurement of changes in estimated glomerular filtration rate. Given these limitations, unrestrained celebration may be deferred until the efficacy and safety of Inaxaplin is confirmed in a larger, placebo-controlled phase 3 study that has already been launched by the manufacturer (ClinicalTrials.gov identifier: NCT05312879). An important point to determine is whether the benefit of Inaxaplin extends to other forms of APOL1-mediated, proteinuric CKD, including hypertension-associated CKD, which affects many more people than FSGS. How early could Inaxaplin be initiated as a treatment for APOL1-mediated kidney disease, and would early initiation of Inaxaplin in patients with mild proteinuria confer prolonged kidney protection? Does Inaxaplin delay the incidence of ESKD in patients with advanced-stage APOL1-mediated CKD with moderate to severe proteinuria? The hope is that future investigations will address these questions.

A further point to note is that the majority of individuals with APOL1-mediated kidney disease are in sub-Saharan West Africa, Brazil, and the Caribbean. Will future clinical trials of Inaxaplin and other experimental therapies for APOL1-mediated kidney disease be extended to these regions to maximize the benefits of Inaxaplin and other investigational therapies?

Finally, by demonstrating that inhibition of APOL1 function reduces proteinuria, the outcome of this study also supports ongoing investigation of alternative therapeutic strategies that inhibit the production of APOL1 protein, either by blocking JAK-STAT signaling, the upstream regulator of APOL1 transcription⁹ (ClinicalTrials.gov identifier: NCT05237388), or by using APOL1 antisense oligonucleotide, which perturbs APOL1 translation (Figure 1). A reasonable hope is that Inaxaplin, a first-in-class oral, small molecule blocker of APOL1 pore function, has opened a new therapeutic window into a future in which effective treatment of APOL1-mediated kidney disease could reduce racial disparities in kidney health.

Figure 1 |. Kidney disease–associated APOL1 variants (G1 and G2) proteins form cation pores at the plasma membrane (PM) that transport Na+ and K+ down their concentration gradients across the PM, thereby causing podocyte injury.

Inaxaplin specifically blocks the aberrant cation channel function of G1 and G2 and thereby prevents podocyte injury. Egbuna et al.⁸ reported that Inaxaplin reduced proteinuria in APOL1-associated FSGS. Inhibition of APOL1 production either by blocking JAK-STAT signaling or by APOL1 antisense oligonucleotide is an alternative therapeutic strategy that is under investigation.