What is CKD?

Chronic kidney disease (CKD) is the progressive deterioration of kidney function that can occur over time. The kidneys’ main job is to filter excess water and waste out of blood via urine. To keep the body working properly, the kidneys balance salts and minerals—such as calcium, phosphorus, sodium, and potassium—that circulate in the blood. Kidneys also make hormones that help control blood pressure, make red blood cells, and keep bones strong.

If deterioration of the kidneys continues, the disease will likely cause significant cardiovascular morbidity, and can progress to kidney failure.

Current management of kidney failure includes hemodialysis and peritoneal dialysis as a means to filter toxins from the blood once the kidneys have failed. Without dialysis or transplant, kidney failure results in the accumulation of waste products that may ultimately cause death. Hemodialysis, the most common form of dialysis, generally requires a patient to visit a dialysis center at least three times per week for a minimum three-hour session, significantly impacting quality of life.

There are currently estimated to be more than 35 million people in the U.S. suffering from chronic kidney disease, more than 550,000 of whom are treated with dialysis.

What is Hyperphosphatemia?

Hyperphosphatemia, a nearly universal condition among patients with CKD on dialysis, is an electrolyte disorder in which there is an elevated level of phosphate in the blood. Hyperphosphatemia is a major independent risk factor for cardiovascular morbidity and mortality in patients on dialysis.  In fact, cardiovascular disease is the leading cause of death in this patient population and traditional risk factors alone do not explain the high rates of cardiovascular disease. Hyperphosphatemia has emerged as a predominant and modifiable risk factor for cardiovascular morbidity and mortality, and as such, effective management of serum phosphorus is critical for patients with CKD on dialysis.

While dialysis is the basis for homeostatic electrolyte management, dialysis regimens are unable to successfully remove excess phosphate in order to achieve a neutral phosphate balance. As a result, approximately 80% of patients with CKD on dialysis require phosphate-lowering therapy on top of restrictive, low phosphorus diets.

Despite widespread treatment with currently available therapies, a significant proportion of patients are unable to achieve and maintain target phosphorus levels. While the 2017 KDIGO clinical practice guidelines recommend lowering elevated phosphate levels toward the normal range (2.5-4.5 mg/dL or 0.81-1.45mmol/L), due to the difficulties in managing phosphorus, most clinicians target phosphorus levels between 3.5-5.5 mg/dL (1.13-1.78 mmol/L), based on the 2003 KDOQI clinical practice guidelines. Even the less aggressive targets are often unachievable today with approximately 40% of patients having phosphorus levels >5.5 mg/dL (1.78 mmol/L)  in any given month, and approximately 80% of patients unable to consistently maintain phosphorus levels  ≤5.5 mg/dL (1.78 mmol/L) over a 6-month period.

Currently available treatments all belong to the class of drugs referred to as phosphate binder therapies. Achieving and maintaining effective phosphate control with phosphate binders is extremely challenging. Phosphate binders act by binding dietary phosphorus in the gut. The binding mechanism requires frequent dosing and often, many large pills in order to bind enough phosphorus, making phosphate binders the largest contributor to excessive pill burden for patients on dialysis. Phosphate binders also tend to be associated with a number of GI side effects including nausea, vomiting, abdominal pain, diarrhea, and constipation.

Here at Ardelyx, we have discovered that the paracellular pathway is the primary mechanism by which dietary phosphorus is absorbed. By developing first-in-class therapeutics to specifically target and block phosphorus absorption through the paracellular pathway, we hope to address what continues to be a significant unmet medical need in patients on dialysis.

What is Hyperkalemia?

Hyperkalemia is a potentially life-threatening condition in which blood levels of potassium are elevated above normal. Potassium is a nutrient that is critical to the normal function of nerve and muscle cells, including those in the heart. Normal potassium blood levels are tightly balanced and maintained primarily by the kidneys. For people with chronic kidney disease (CKD), heart failure, and diabetes, and particularly those also taking highly beneficial renin-angiotensin-aldosterone system (RAAS) inhibitors, there is a greater risk of developing hyperkalemia due to side effects and the kidney’s limited ability to keep potassium in balance.

Because of the risk of hyperkalemia, several published guidelines have suggested that physicians should reduce and possibly discontinue RAAS inhibitors in order to manage the risk of hyperkalemia in CKD and heart failure patients. The alternative medications used to control hypertension, including diuretics and calcium channel blockers, are less effective than RAAS inhibitors, particularly in patients with failing kidneys and severe hypertension.

According to the 2015 publication Market Dynamix: Hyperkalemia, released by Spherix Global Insights, U.S. cardiologists reported that of the patients who would benefit from RAAS inhibition, up to 38% of patients with heart failure and up to 55% of patients with both heart failure and CKD are being administered a sub-optimal dose or none at all. Nephrologists reported that at least one-third of patients who would benefit from RAAS inhibition receive a sub-optimal dose or none at all. We believe there is clearly a strong medical need for new medications that control hyperkalemia in order to allow for optimal use of RAAS inhibitors to control hypertension in these patient populations.

It is estimated that 2.1 million people in the U.S. with CKD and/or heart failure have hyperkalemia, which remains an emerging and unaddressed market with today’s treatments.