Potential Breakthrough for a Race-Linked Kidney Disease?

Inaxaplin is an investigational oral small molecule designed to counter the pathological effect of two variants of a gene on chromosome 22 linked with kidney damage that occur exclusively in people of sub-Saharan African ancestry. The drug has shown promise in a small proof-of-concept study.

The agent substantially reduced proteinuria in people with focal segmental glomerulosclerosis (FSGS) and the right genotype in an uncontrolled phase 2a study.

The study included only patients with biopsy-proven FSGS and proteinuria, defined as a urinary protein-to-creatinine ratio (UPCR) of ≥ 0.7 to < 10 (with protein and creatinine both measured in grams). All 16 patients also had two variant apolipoprotein L1 (APOL1) alleles — G1, G2, or one of each — and all were Black. Participants were from one of 12 sites in France, the United Kingdom, or the United States.

The results showed a significant average reduction in proteinuria (based on UPCR) of about 48% compared with baseline after 13 weeks of inaxaplin treatment, with 15 of 16 patients having a decline in UPCR. Adverse events were mild or moderate in severity and none led to study discontinuation.

The primary outcome results provide "initial evidence" that targeting a mechanistic pathway by which the two APOL1 gene variants, G1 and G2, cause disease may be a promising approach, write the authors of the report, which was published online March 15 in the New England Journal of Medicine.

Although the study used the surrogate marker of reduced UPCR as an indicator of renal protection, the results "appear to be a major scientific breakthrough with enormous implications, especially for patients of African ancestry," commented Neil R. Powe, MD, in an accompanying editorial.

However, Powe qualified this as "cautious enthusiasm," given the study's inherent limitations.

APOL1 G1 and G2 Variants Linked to Several Kidney Disorders

The implications are huge for at least the select group of people who carry two copies of either of the two pathologic APOL1 variants, G1 or G2, in part because of the wide-ranging impact of the genotype.

In addition to the link with FSGS, having a pair of variant APOL1 alleles has also been linked with a significantly increased susceptibility to several other kidney disorders including hypertensive kidney disease, HIV-associated nephropathy, COVID-associated nephropathy, and membranous nephropathy, as well as sepsis and hypertension.

These renal disorders are collectively called APOL1-mediated proteinuric kidney disease, and some experts have said "it may be more useful to think of these diseases as part of an APOL1 nephropathy spectrum rather than as separate disease states."

However, the development or severity of diabetic kidney disease appears completely unrelated to whether a person has two copies of the G1 and G2 APOL1 variants, noted Powe, of the University of California, San Francisco School of Medicine.

"The presence of the high-risk APOL1 genotype is associated with a 2-100 times higher risk of kidney failure," writes Katalin Susztak, MD, a professor at the University of Pennsylvania, Philadelphia, in a recent editorial.

But she also notes that the lifetime risk for developing kidney failure in a person with two copies of the G1 or G2 variants "is only around 20%," which has led experts to hypothesize that a dual-variant genotype only supplies a first hit, with an unknown second hit required to trigger disease onset.

People with just one copy of the G1 or G2 variant, as well as those with two copies of the wild-type G0 allele, show no evidence of an elevated risk for kidney disease.

Protection Against African Sleeping Sickness Comes at a Price

Another facet to the APOL1 story is that the apparent genetic origin of the pathological variants occurred thousands of years ago among people living in sub-Sharan Africa who were more resistant to African trypanosomiasis, also known as African sleeping sickness, caused by an endemic parasite, the blood-feeding tsetse fly.

The proteins produced by the G1 and G2 variants of the APOL1 gene are thought to be able to kill the parasite, which means natural selection favored carriers, explain the authors of a second editorial published with the inaxaplin study.

According to these authors, renal podocytes appear to be particularly vulnerable to the damaging effects of the G1 and G2 variants, which can cause large-scale changes in podocyte morphology, function, and viability in kidneys and result in several types of kidney disease with heavy proteinuria.

And because this natural selection for the G1 and G2 variants happened in sub-Saharan Africa, people who carry these problematic dual-variant alleles today are most commonly African American or other Black individuals.

**Will Inaxaplin Become a Reason to Genotype for APOL1?**

APOL1 genotyping is not part of routine practice in the United States, but the early promise seen for inaxaplin raises the possibility that this might change if further studies confirm the drug is safe and effective for blunting the risk of having two G1 or G2 variants.

"Until now, there's been no reason to genotype because there was nothing to do about it," said Powe in an interview.

But now the possibility of eventually treating high-risk people with inaxaplin — if further evidence confirms its safety and efficacy — starts to raise the question of whether Black race as a marker for sub-Saharan ancestry will become a reason to perform routine APOL1 genotyping.

Powe cautioned that just finding two G1 or G2 variants does not guarantee impending kidney disease. However, inaxaplin's development "raises a dilemma for those who say we shouldn't use race as a way to identify people for medical testing," Powe acknowledged.

Powe was co-chair of a panel assembled by the American Society of Nephrology and the National Kidney Foundation that recommended in 2021 a shift in US practice toward a formula for eGFR that does not use a race-based modifier. These two sponsoring organizations accepted and endorsed that recommendation, and adoption of the race-free eGFR equation has quickly transformed much of US practice.

The APOL1 story "is a case where the genetics and race as a social construct are almost inextricably entwined" because the high-risk genotype is so strongly associated with race, said Powe. "Hopefully, the medical community can come together on how to proceed. It's not premature to think about."

Inaxaplin is currently being studied in a randomized, phase 2/3 "adaptive" study at more than 100 sites in the United States, Canada, and Europe, with a planned enrollment of about 470 patients who have a high-risk genotype and proteinuric kidney disease. The study began in 2022 and has a planned completion date of 2026.

Inaxaplin has received breakthrough therapy designation from the US Food and Drug Administration for APOL1-mediated FSGS, and orphan drug and PRIME designations from the European Medicines Agency for APOL1-mediated kidney disease.

The inaxaplin study was sponsored by Vertex, the company developing the agent. Powe has reported no relevant financial relationships. Susztak has reported financial relationships with numerous companies but not with Vertex.

N Engl J Med. March 15, 2023. Abstract, Editorial 1, Editorial 2

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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