Ardelyx, a clinical-stage biopharmaceutical company focussed on cardio-renal, gastrointestinal and metabolic diseases, announced publication of data in the Journal of the American Society of Nephrology (JASN) showing that in a preclinical in vivo model of chronic kidney disease (CKD), tenapanor reduced phosphorus absorption and protected against vascular calcification. The article was published online at http://jasn.asnjournals.org/content/early/recent. Tenapanor, a minimally-systemic inhibitor of the intestinal sodium transporter NHE3, has demonstrated the ability to reduce the absorption of dietary sodium and phosphorus in human and animal studies.  

"Elevated levels of phosphate and sodium are key factors in the progression of kidney disease.  We have known that tenapanor administration reduces the absorption of sodium in animals and humans, so it was exciting to see such a strong effect of phosphate in these animal models of human disease," said Mike Raab Ardelyx's president and chief executive officer. "In addition, the study demonstrated the ability of tenapanor to protect against vascular calcification, one of the most common complications in end-stage renal disease (ESRD) and CKD patients.  The results further deepen our understanding of tenapanor and its potential in treating hyperphosphatemia in ESRD. We look forward to seeing the results of our ongoing phase 2b clinical trial in hyperphosphatemic ESRD patients in the first quarter of 2015."

According to the research findings reported in JASN, tenapanor decreased phosphorous absorption in rats, both in a setting of normal renal function and in a model of CKD. In the normal renal function group, tenapanor administration resulted in significantly decreased urinary phosphate excretion. In a model of CKD (5/6th nephrectomised (NPX), fed a high-salt diet), administration of tenapanor consistently lowered urinary phosphorus excretion over the course of 28 days compared with untreated controls. Additionally, in a CKD model of vascular calcification, tenapanor reduced serum phosphorus and serum creatinine as well as soft tissue calcification, as shown by significantly reduced phosphorous and calcium content of the aortic arch and stomach compared with vehicle treatment.  Tenapanor-treated animals also demonstrated significant attenuation of renal and cardiac hypertrophy, signs of a compromised kidney and heart.  Tenapanor in this model also reduced the expression of FGF-23, an important hormone suspected to aggravate vascular calcification and heart hypertrophy in CKD.

"The ability to stop vascular calcification over the long-term may be one of the most important goals in the management of kidney disease," said Orson Moe, MD, Professor of Internal Medicine, University of Texas Southwestern Medical Center.  "I am impressed with the results reported in this paper, and look forward to the results from studies in humans to determine if tenapanor can demonstrate similar effects." Dr. Moe is a leading researcher in mineral metabolism.  Dr. Moe is an advisor to Ardelyx, but was not involved in the study reported in JASN.

CKD is marked by a progressive loss in renal function, resulting in less efficient blood filtration and phosphorus elimination, ultimately leading to hyperphosphatemia.  CKD can lead to the nearly total loss of kidney function.  When this occurs, it is called end-stage renal disease (ESRD), and the patient must receive a kidney transplant, undergo frequent dialysis or risk death.  In ESRD patients on hemodialysis, buildup of excess levels of phosphorus in the blood have been shown to lead to an increase in cardiovascular disease risk, as well as increases in serum FGF-23, an important serum endocrine hormone that regulates phosphorus metabolism.  Elevated levels of FGF-23 are strongly associated with an increased risk of cardiovascular mortality. With concurrent elevated calcium levels common in these patients, particularly when calcium is used as a means of controlling phosphorus, deposits containing calcium and phosphate, called vascular calcification, develop in arteries, joints, skin, soft tissue and other organs. Increased coronary artery calcification is associated with an increased risk of heart disease, stroke and death.  Intestinal phosphate binders are currently used in this market to control phosphorus accumulation in the body.  The Company estimates, based on phosphate binder utilization, the only approved therapies for hyperphosphatemia, that there are approximately 270,000, 215,000 and 220,000 ESRD patients with hyperphosphatemia in the United States, Europe and Japan, respectively.

Tenapanor (also known as RDX5791 and AZD1722) is a minimally-systemic small molecule inhibitor of NHE3, a transporter of sodium in the gastrointestinal tract. Orally administered tenapanor has been shown in clinical trials to reduce the intestinal absorption of both dietary sodium and phosphorus. Ardelyx licensed tenapanor to AstraZeneca in October 2012.  Under this license agreement, Ardelyx and AstraZeneca are evaluating tenapanor for the treatment of hyperphosphatemia in patients with ESRD in an ongoing Phase 2b study. In October 2014, Ardelyx announced positive results from its phase 2b clinical trial evaluating tenapanor in patients with constipation-predominant irritable bowel syndrome (IBS-C). Ardelyx and AstraZeneca are also evaluating tenapanor in an ongoing phase 2a study for its effect on kidney function and fluid overload in patients with CKD with type 2 diabetes mellitus.