Ardelyx has developed drug candidates in several therapeutic areas including fluid overload, hypertension in kidney and cardiovascular diseases, constipation-related disorders, hyperphosphatemia and hyperkalemia in chronic kidney and end-stage renal disease, and diabetes. These different therapeutic areas have one thing in common: the regulation of minerals and imbalance of nutrients by affecting processes in the gastrointestinal tract.
Ardelyx molecules are designed to provide therapeutic benefits by targeting proteins in the gut that affect systemic functions of the body. One of the ways we achieve systemic effects by targeting only the gut is to restore the proper balance of nutrients and minerals in the body. These nutrients and minerals include:
A major consequence of excess sodium consumption is hypertension and fluid overload. This can be particularly harmful for people with chronic kidney disease (CKD) and cardiovascular disease (CVD). In patients with CKD, the kidneys are damaged, thus are inefficient at eliminating excess sodium and fluid from the body. Excess sodium can exacerbate damage to the kidneys, leading to further reductions in kidney function and additional build-up of fluid and uremic toxins in the body tissues and bloodstream. In patients with CVD and heart failure, retention of sodium can also result in significant elevation of blood pressure that can accelerate the course of disease as well as edema and shortness of breath as fluid accumulates in the lungs.
The pharmacological modulation of sodium absorption in the gut also can be used to correct bowel disorders. By retaining sodium in the gastrointestinal tract, osmotic pressure will cause water to enter the GI tract to equalize the osmotic pressure. This water can normalize bowel form and frequency in patients with constipation-related disorders.
In patients with chronic kidney disease (CKD), the kidneys are less efficient at removing phosphate from the blood. This leads to a cascade of hormonal disorders with untoward effects on:
Hyperkalemia is characterized by high levels of serum potassium and can be an acute life-threatening condition if not quickly resolved. Hyperkalemia is common in CKD patients as their urinary potassium excretion is impaired. The risk is notably increased with the use of renin-angiotensin-aldosterone-system (RAAS) blockade drugs (such as ACE inhibitors and mineralocorticoid receptor antagonists) to treat hypertension and/or heart failure. Current treatments for hyperkalemia include potassium binding resins (Kayexalate®). The main shortcomings of these resins include their modest capacity and selectivity to bind potassium ions, as well as introduction of other ions in the body (e.g. Na+ Ca++ or H+) since these resins act as ion-exchangers. The patient is therefore required to take dozens of grams of these agents each day, often causing many GI side effects for a modest benefit.
Glucose regulation is critical for the normal function of the human body. The inability to regulate glucose appropriately, such as in patients with diabetes, can result in obesity, blindness, kidney and heart disease, organ failure and death. Secretion of insulin and the hormones that regulate insulin (e.g., incretins) are critical for maintaining glucose control.
Ardelyx is developing a series of molecules to stimulate an incretin response in patients with diabetes resulting in an increase in the amount of insulin released from the pancreatic beta cells after a meal, while also increasing the sensitivity of insulin to its receptors. These effects have the potential to improve the metabolic dysfunction present in diabetes (elevated fasting plasma glucose, elevated postprandial plasma glucose and decreased insulin sensitivity).