APOL1 Kidney Disease Discovery to Targeted Therapy in 10 Years

Advanced CKDs are more common in Black people than in other populations. Current and historical social inequities, driven by policy, economic structure, and environmental factors, are critical drivers of this disparity.1 However, pathobiology also contributes. Kidney failure incidence in Black compared with White men is significantly higher, regardless of systolic BP level and after adjustment for some social factors.2 Given the familial clustering of kidney diseases, genetic studies were one of the designs to discover the candidate, biological causes of this excess kidney disease risk in Black people. A specific locus on chromosome 22 was associated with common, nondiabetic kidney disease in Black but not non-Black people. Two genetic variants in the APOL1 gene, which changes its protein coding sequence, accounted for the association signal.3,4 This association has been replicated in studies of participants with both categorical and continuous CKD phenotypes. Importantly, APOL1 high-risk genotypes are found only in some individuals of African ancestry and are associated with hypertension-associated kidney disease, the second most common cause of kidney failure. Two copies of APOL1 genes with kidney risk variants greatly increase kidney disease risk. However, most carriers of the APOL1 high-risk genotypes do not develop kidney diseases, indicating additional stresses, most yet not all definitively established and some likely social factors, are required for disease development. Finally, APOL1 both circulates and is synthesized by kidney cells, but studies of kidney transplant recipients demonstrate that kidney injury is a result of locally produced APOL1. APOL1 is an innate immune effector molecule that confers protection against African trypanosomes in humans and some non-human primates. We now know that kidney disease–associated APOL1s cause trypanolysis of species, which cause African sleeping sickness4 by forming pores in membranes that permit movement of cations. In vitro work established that variant APOL1s also form pores in mammalian cells and caused cytotoxicity because of cation flux. Mice that expressed variant, but not reference, APOL1 transgenes under control of their human promoters develop kidney disease, providing evidence for their causality.5,6 These and other studies have identified APOL1 function as a credible target for novel therapies to reduce some of the public health burden of kidney disease borne by Black people. In a recent publication, Egbuna and colleagues report preclinical data and the results of a small, phase 2 trial that tested the effects of a small molecule blocker of APOL1 pore function, inaxaplin.7 Inaxaplin blocked ion flux in cells treated with tetracycline to stimulate APOL1 expression from a transgene and reduced albuminuria in a transgenic APOL1 mice model of proteinuric kidney disease. Sixteen participants with biopsy-proven FSGS were treated with inaxaplin in a single-group, open-label trial to test its safety and efficacy to reduce proteinuria. Thirteen participants, three with nephrotic range proteinuria, met predefined criteria for inclusion in the efficacy analysis and had a geometric mean reduction in proteinuria of −47.6% (95% confidence interval, −60.0% to −31.3%) after 13 weeks of inaxaplin treatment. Nine of these participants continued to be followed for 12 weeks off the drug and had a persistent reduction in proteinuria of approximately 30%. Adverse events were mild to moderate. No participant was discontinued from the study. On the basis of this trial, inaxaplin has been granted Breakthrough Therapy designation by the US Food and Drug Administration for FSGS in people with APOL1 kidney risk genotypes and Priority Medicines designation for APOL1-medicated CKD by the European Medicines Agency. These results are remarkably impactful. In 10 years, our community has progressed from a seminal discovery, the association of APOL1 genetic variants in Black people with some nondiabetic kidney diseases, to successful completion of an early-phase clinical trial. The speed of this process is breathtaking and should be celebrated. While optimism is justified, it must be tempered. The published study is quite small, lacks a control group, and may be subject to unrecognized confounders. The persistent decrease in proteinuria after the end of active treatment suggests some benefit may have been derived from care delivery in a clinical trial. Changes in eGFR are not reported. Only participants with FSGS were enrolled, and inaxaplin efficacy remains an open question in individuals with other APOL1 kidney diseases, especially hypertension-associated CKD. Thirteen of the 16 people enrolled in the trial had mild-to-moderate interstitial fibrosis. Early biopsy and diagnosis may be critical to optimize inaxaplin efficacy, although encouragingly, the three individuals with severe fibrosis still had significant proteinuria reduction. On the basis of these outcomes, a blinded, randomized trial, with an adaptive design, has been initiated to definitively test the efficacy of inaxaplin in APOL1 kidney diseases (NCT05312879). Nondiabetic Black people with proteinuric kidney diseases and APOL1 risk genotypes are eligible to enroll. Primary outcomes are change in proteinuria and eGFR slopes at specified times. A composite secondary outcome of sustained loss of eGFR >30%, kidney failure, or death is being ascertained. The trial results just reported have significant implications but represent an early step in the evaluation of inaxaplin. Further testing of its efficacy and safety will occur in the ongoing definitive trial. As a community, we must help ensure its successful execution by educating our patients about APOL1 kidney disease, an effort supported by the patient community, and encouraging those who meet inclusion to consider enrolling. Other therapies for APOL1 kidney diseases are in the pipeline. The weight of the data demonstrates that variant APOL1s have a toxic gain of function, which causes tissue injury. Given this, reducing APOL1 synthesis should have benefit. The coronavirus disease 2019 vaccine highlighted the efficacy of RNA-based therapeutics. A RNA medicine, which blocks APOL1 synthesis by degrading it messenger RNA, reduced albuminuria in a mouse model of APOL1 kidney disease.6 A trial of this type of RNA medicine has been concluded in 30 healthy men, but no results have been released (NCT04269031). Cytokines stimulate APOL1 synthesis, and another trial will test the safety and efficacy of blocking cytokine-activated signaling pathways with the JAK/STAT inhibitor baricitinib8 (NCT05237388). As basic and translational research progresses, other targets for APOL1 kidney diseases may emerge. A small molecule suppressor screen is ongoing to identify small molecules that block APOL1 protein synthesis.9 Interesting preclinical data demonstrate that variant APOL1 activates the cytosolic stimulator of interferon genes and NOD-like receptor family pyrin domain-containing 3 pathway.10 Agents that block specific components of the NLR family pyrin domain-containing 3 pathway are in clinical trials as treatments of other diseases and could be repurposed for the treatment of APOL1 kidney diseases if additional evidence justifies targeting this pathway. In anticipation of successful trials, we need to prepare ourselves and our trainees to make culturally sensitive, shared decisions with our patients about proceeding with APOL1 genetic testing to guide their CKD treatments. This is time for our community to celebrate. After years mired by limited therapeutic innovation, a pipeline of clinical trials is testing drugs targeting molecular mechanisms, revealed by years of bench and translational research. As a community, we have to step up. First, we must get the word out to our internal medicine trainees that kidney medicine is alive and well and is using cutting-edge approaches to bring new diagnostic and therapeutic approaches to the clinic. We need the best and brightest to join these efforts. In addition to the new inaxaplin trial, we must also support other clinical and translational research initiatives using patient cohorts to identify targeted therapies and test their efficacy for kidney disease treatments. For example, the NEPTUNE Match Trial (NCT04571658) will identify the molecular mechanisms in patients with nephrotic syndrome by measuring urinary biomarkers of pathway activity and determine whether these participants can be matched to ongoing trials of drugs that target those pathways. The inaxaplin trial is a remarkable milestone that tests a targeted therapeutic, on the basis of molecular mechanisms, for common kidney diseases, specifically affecting people of African ancestry. However, successful clinical trials of novel treatments of kidney diseases will only address part of the root cause of the kidney disease burden. The edifice of structural racism must be challenged and dismantled to ultimately reduce the excess burden of kidney and other common chronic diseases in communities of color. The intensive efforts invested in translational sciences, which have bought a targeted therapy for APOL kidney disease in 10 years, must also be directed to reducing the social factors that perpetuate health disparities. With people with kidney disease as our partners, we have the scientific momentum and shared purpose to meaningfully affect kidney health. Now is the time; delay is not an option.