A new drug, inaxaplin, targeting the APOL1 protein, has shown promising results in a clinical trial for treating kidney disease, particularly in African Americans who are disproportionately affected by APOL1-mediated kidney disease. The trial, published in March 2023, demonstrated that patients with serious kidney disease experienced, on average, a nearly 50% reduction in protein leaking into their urine after three months of treatment with inaxaplin. Some participants even saw improvements exceeding 70% in this key measure of kidney function.
Rapid Development of Targeted Therapy
Inaxaplin's development marks a rapid translation of scientific discovery into a targeted therapy. The APOL1 protein was first implicated in kidney disease only 14 years ago, and Vertex Pharmaceuticals initiated its APOL1 program in 2015. This swift progress offers hope for addressing a significant racial health disparity: the rate of kidney failure in Black Americans is more than three times higher than that of European Americans.
APOL1 Gene Variants and Kidney Disease Risk
The Vertex study exclusively recruited African American volunteers, focusing on individuals carrying specific APOL1 gene variants (G1 and G2) known to increase the risk of renal failure. Individuals with two copies of these variants face an estimated 15-20% lifetime risk of developing kidney disease. These variants are prevalent among Black Americans, with approximately 13% carrying two copies.
David Friedman, a nephrologist at Harvard University and co-discoverer of the APOL1 variants, notes the rarity of such a common and potent genetic risk factor. Research suggests that carrying one copy of the G1 or G2 variant provides protection against a deadly form of African sleeping sickness, potentially explaining the high frequency of these variants in individuals of West African descent.
Addressing Racial Disparities in Kidney Disease
The discovery of APOL1's role has reframed the understanding of racial disparities in kidney disease. Previously, the higher prevalence of kidney failure among Black Americans was often attributed to socioeconomic factors. While these factors remain important, the identification of a biological basis provides a more complete picture. Marva Moxey-Mims, a pediatric nephrologist at the Children’s National Hospital, expressed that having hard scientific data to explain the increased risk offers a sense of relief and a new avenue for targeted interventions.
Clinical Trials and Future Directions
Vertex Pharmaceuticals is currently conducting a larger, placebo-controlled Phase 2/3 trial involving over 400 participants to further evaluate inaxaplin. This study includes various kidney disease types in individuals with two APOL1 gene variants, including children as young as 10. The trial, expected to conclude in 2026, will assess kidney health markers and the time to progression to dialysis, transplant, or death. Ogo Egbuna, Vertex’s vice president of clinical development, anticipates participants will receive the drug for approximately two years.
AstraZeneca, in partnership with Ionis, is also developing a genetic therapy to reduce APOL1 protein production. Maze Therapeutics is pursuing a small molecule approach similar to Vertex, with safety trials underway.
Implications for Kidney Transplantation
APOL1 insights may also transform kidney transplantation practices. Currently, transplant centers use a 10-factor scale to assess potential transplant organs, with kidneys from African American donors often downgraded due to historically faster failure rates. However, studies indicate that APOL1 genotype is a significant factor. Kidneys from Black donors without two high-risk APOL1 alleles have shown similar longevity to those from other groups.
Moxey-Mims is leading an investigation to chart the longevity of kidneys donated by African Americans based on APOL1 genes in over 2,600 transplants. Preliminary results, expected in 2025, could lead to APOL1 genotype replacing race on the transplant checklist, potentially increasing the number of available kidneys, as approximately 87% of Black Americans do not have two copies of high-risk gene variants.
The Future of APOL1-Targeted Therapies
Neil Powe, a physician at the University of California, San Francisco, emphasizes the potential of APOL1-targeted therapies to advance “precision equity” in addressing health disparities. Effective genetic screening and regular monitoring of at-risk individuals will be crucial for ensuring that these therapies reach the right people before irreversible kidney damage occurs. The global implications are also significant, with efforts needed to ensure access to APOL1 drugs across the African diaspora and in low- and middle-income countries.
