Chronic kidney disease: Challenges and upcoming technologies
As March has brought another National Kidney Month, and the recognition of World Kidney Day on March 9th, it is critical to take this opportunity to highlight the impact of kidney disease and to promote awareness and research, as more effective treatments are still needed. According to the American Society of Nephrology (ASN), 850 million people in the world suffer from kidney disease. Lack of awareness is a common feature, even among those suffering from chronic kidney disease (CKD). CKD may be asymptomatic in its early stages but is progressive, with accumulating kidney damage leading to an unfortunate terminus of end-stage renal disease (ESRD), in which kidneys cease to function. In these cases, patients require kidney transplantation or dialysis for survival.
The causes of CKD are manifold, and include recurrent infection, various forms of nephritis, or other conditions, such as diabetes or high blood pressure and associated cardiovascular disease, which lead to kidney damage and a subsequent progressive, accelerating decline in kidney function. A subset of kidney disease is inherited, including polycystic kidney disease, which may be passed on in a more common autosomal dominant manner, or more rarely, as an autosomal recessive disorder. These genetic disorders lead to the formation of numerous fluid-filled cysts in the kidneys as a defining characteristic.
The pharmaceutical treatment landscape
The pharmaceutical landscape for CKD is rather barren, especially for therapeutics that directly treat the underlying mechanisms of kidney dysfunction, and options can be few depending on the type of CKD the patient is experiencing. Typical approaches may seek to control comorbidities that can lead to kidney damage, such as controlling blood sugar in diabetes using insulin or employing the SGLT2 inhibitor canagliflozin to lower blood glucose levels in the context of diabetic nephropathy. Indeed, Farxiga (dapagliflozin), approved in 2021 by the FDA to inhibit progression of CKD, was originally approved to treat type II diabetes by EU regulators, and lowers blood glucose as well as kidney blood vessel pressure. Cardiovascular complications in CKD may be addressed with antibody-based drugs to reduce atherosclerosis, or with the mineralocorticoid receptor antagonist finerenone, which reduces the risk of adverse cardiovascular events in CKD patients.
Other kidney disease etiologies, such as polycystic kidney disease, of which autosomal dominant polycystic kidney disease (ADPKD) is the most common, affecting up to 1 out of every 400 individuals in the United States per the National Institute of Diabetes and Digestive and Kidney Diseases, currently have few therapeutic options. Inhibition of angiotensin converting enzyme may help to attenuate hypertension, as well as growth of renal cysts. Tolvaptan, a drug developed to treat hyponatremia and used in congestive heart failure patients, was granted orphan drug designation by the FDA in order to reduce cyst growth and kidney volume and to slow progressive kidney function decline in ADPKD patients, but has the potential for liver damage and consequently is restricted to short-term use.
The boon of data and technology for identifying targets
However, as data accumulate and new analytical approaches are applied, our understanding of the pathways and mechanisms involved in kidney dysfunction grows. Accompanying new understanding, potential new therapeutic targets are become evident, as large pharmaceutical interests have been joined by an ecosystem of clinical stage biotechnology companies to investigate novel therapeutic approaches.
In one such pathway, the enzyme xanthine oxidase (XO) catalyzes uric acid production from xanthine and hypoxanthine as part of the metabolic breakdown of purines. Increased uric acid production and hyperuricemia are risk factors for increased kidney volume and early onset of ESRD in some ADPKD patients. At the recent ASN Kidney Week annual conference, our team, in partnership with the laboratory of Dr. Charles Edelstein of the University of Colorado, presented data demonstrating that increased uric acid resulted in a statistically significant increase in total kidney to body weight ratio and decreased kidney function in rodent models of polycystic kidney disease. Direct inhibition of XO can modulate the enzyme and subsequently lower uric acid levels, potentially retarding disease progression. Indeed, our preclinical study demonstrated that inhibition of XO, using our proprietary formulation of oxypurinol called XORLO, blocks this mechanism of injury in rodent PKD. XORTX Therapeutics expects to advance XORLO into a Phase 3 study for ADPKD this year.
Another promising therapeutic is GLPG2737, an inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, which has been hypothesized to reduce cyst growth and kidney enlargement and is currently in Phase 2 trials. Inhibition of microRNA-17 (miR-17) is a distinct approach that is aimed at de-repression of genes regulated by miR-17, including the Pkd1 and Pkd2 genes, which encode polycystin and are common mutational targets underlying ADPKD.
Given the long period over which effective and diverse treatment options have been for the most part not available, this recent activity in pharmaceutical research and patient clinical trials provides hope that novel and efficacious drugs for ADPKD and other forms of CKD may be on the horizon. This would provide clinicians with new options and would be welcome news to the many suffering from kidney disease.
About the author
Dr Allen Davidoff is the founder and CEO of XORTX. Dr Davidoff has a broad range of clinical and regulatory experience and senior management experience in pharmaceutical R&D, including two investigational new drug (“IND”) applications or supplemental IND’s, two phase I studies (four of which were multi-country), seven phase II studies, and one NDA. Prior to forming XORTX, Allen was the chief scientific officer, VP Product Development, and co-founder of Stem Cell Therapeutics Corp. (seven years), as well senior scientist and Head of Pharmacology at Cardiome Pharma Corp.