What could be the first precision medicine for APOL1-mediated kidney disease (AKMD) has successfully completed a Phase I trial. People of African ancestry are at greater risk of this disease. The drug, AstraZeneca’s AZD2373, is an antisense oligonucleotide that targets APOL1 mRNA to reduce its protein synthesis and is in development in collaboration with Ionis Pharmaceuticals.
“Based on the promising results of Phase I studies, we are anticipating a decision to enter Phase II in 2025, and AZD2373, if approved, will be the first precision medicine for the treatment of AMKD,” said Regina Fritsche Danielson, Senior Vice President at AstraZeneca and Head of Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D.
AMKD is associated with toxic gain of function variants in people of African ancestry carrying the high-risk APOL1 genotypes (G1 and G2). APOL1 protein is part of the innate immune system but not considered essential.
In the U.S. alone, an estimated 13% of people of African descent have mutations in both copies of APOL1. These people have a one in five chance of developing AKMD, which can lead to a rapid decline in kidney function, typically progressing to end-stage kidney disease within a decade. No specific treatments exist for AMKD, and patients do not respond to the current standard of care for chronic kidney disease.
“Our ambition and what we really want to achieve is to design a molecule that has the potential to be first-in-class and with disease modifying characteristics. Alongside that, we want to ensure we are planning a clinical development programme that identifies and reaches the patients most likely to benefit from this treatment,” said Danielson.
In genomic APOL1-transgenic mice, AZD2373 reduced APOL1 expression in kidney and liver, reduced plasma APOL1 protein concentration, and prevented development of IFN-γ induced proteinuria in high-risk genotype mice. The drug has also shown promise in people. In a single ascending dose study (NCT04269031), AZD2373 was well tolerated. Its safety and tolerability was also assessed in a multiple ascending dose study including pharmacokinetics, and pharmacodynamic effect on APOL1 plasma protein levels.
This most recent phase I study (NCT05351047) was in healthy male volunteers of West African ancestry. Participants were enrolled after a pre-screening study where they were genotyped for APOL1 prospectively and 18 participants had either one copy or two copies of the G1/G2 APOL1 high-risk allele.
Low, medium, and high dose cohorts each with eight participants each receiving six weekly subcutaneous injections of either AZD2373 (n = 6) or placebo (n = 2) and were subsequently followed up for nine-weeks post-last dose. The primary objective was safety and tolerability; secondary objectives included assessment of pharmacokinetics and pharmacodynamics of AZD2373. In total, 24 participants were randomized and completed the study. No major safety and tolerability concerns were reported up to the highest dose of AZD2373 administered.
After dosing, AZD2373 had a rapid distribution phase (hours) and prolonged elimination phase (days to weeks). Clearance was similar across dose levels after single and repeated dosing, and the renal contribution to overall clearance was minimal. Exposure generally increased in a dose proportional manner. Repeated doses of AZD2373 reduced plasma APOL1 concentrations in a dose- and time-dependent manner in healthy males of West African ancestry.
The American Kidney Fund reports that, “Black people with kidney disease are more likely to develop kidney failure than any other racial/ethnic group. Research of the APOL1 genetic mutation and the substantially increased risk for kidney disease among impacted Black people has helped to improve understanding of the kidney disease disparities in this population.”
