Our pipeline of gut-restricted therapies is concentrated on providing better medicines in two therapeutic areas: cardiorenal & GI diseases.

Elevated levels of phosphorus in the blood, a metabolic disorder known as hyperphosphatemia, is a very common and difficult-to-treat condition in patients with end-stage renal disease (ESRD) who require dialysis.

Tenapanor is being evaluated in a second Phase 3 trial, the PHREEDOM trial, for the treatment of hyperphosphatemia in patients with ESRD who are on dialysis, with topline results expected in the fourth quarter of 2019. This clinical trial includes a 26-week open-label treatment period, with a 12-week placebo-controlled randomized withdrawal period followed by an additional 14-week open-label safety extension period for a total of up to 52 weeks. An active control group, for safety analysis only and consistent with other Phase 3 registration studies for hyperphosphatemia, will receive sevelamer, open-label, for the entire 52-week study period. This trial follows a successful Phase 3 clinical trial completed in 2017, which achieved statistical significance for the primary endpoint.

In February 2017, we reported positive data from the first Phase 3 clinical trial in hyperphosphatemia patients with ESRD who on dialysis. The responder population (n=80 out of 164) had a mean reduction in serum phosphorus from baseline to the end of the eight-week treatment period of 2.56 mg/dL, with a reduction of up to 5.7 mg/dL. Notably, in this group, 33 percent of patients had a reduction in serum phosphorus of greater than 3 mg/dL. The study demonstrated a statistically significant difference in change of serum phosphorus levels from the end of the eight-week treatment period to the end of the four-week randomized withdrawal period between the tenapanor-treated group and the placebo-treated group in the responder patient population (mean -1.01 mg/dL, median of -1.3 mg/dL) and met its primary endpoint (95% CI -1.44, -0.21; LSmean -0.82mg/dL; p=0.01). Only 7.8 percent of patients discontinued treatment due to GI side effects.

Tenapanor, if successfully developed and approved, would be the first therapy for phosphate management that is not a phosphate binder. As tenapanor is a novel, potent, small molecule there would be significantly less pill burden than the phosphate binders with simple twice daily dosing which we believe could greatly improve patient adherence and compliance and free patients from having to take pills before every meal.

We also plan to evaluate tenapanor in combination with phosphate binders in a Phase 3 clinical trial, the Amplify trial,  expected to begin in early 2019. With successful results from Amplify, tenapanor would be the first and only phosphate lowering therapy to be indicated as adjunctive therapy for use in combination with binders.

Hyperphosphatemia

Hyperphosphatemia is commonly seen in patients with end-stage renal disease (ESRD), the most advanced stage of chronic kidney disease, who are on dialysis. Hyperphosphatemia is characterized by a build-up of excess phosphorus, a vital element that is normally kept in balance by the kidneys, with excess phosphorus removed and excreted in urine. In patients with kidney failure, phosphorus that comes from the food we eat builds up to abnormal levels and leads to bone disease, heart disease and is correlated with a higher risk of death in those patients.

RDX013 for HYPERKALEMIA

RDX013 is our novel, small molecule program for the potential treatment of hyperkalemia. Our RDX013 approach works by tapping into the GI tract’s natural ability to secrete potassium into the lumen of the gut to reduce serum potassium levels. This mechanism differs significantly from the potassium binders currently on or approaching the market. For a potassium binder to work, it must be present when dietary potassium is ingested so that the agent can bind the potassium and prevent its absorption in the gut. This results in the need for large quantities of binder in order to bind the large amounts of potassium in the diets of most individuals. In contrast, we observed in our preclinical models that a small amount of RDX013 could cause potassium to be secreted into the lumen of the gut. In this way, we believe that RDX013 may have the potential to lower serum potassium whether or not potassium is present in the diet and could result in a very low pill burden, potentially allowing better patient compliance, longer-term use and potentially better efficacy than potassium binders. As described below, certain medications commonly administered to patients with CKD and/or heart failure can also cause hyperkalemia. With the successful development of an effective potassium secretagogue to treat hyperkalemia in a small, convenient pill format, we believe our RDX013 approach may allow nephrologists and cardiologists with an opportunity to treat hyperkalemia chronically without reducing the dose of these medications

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 heart failure, chronic kidney disease and diabetes, and particularly those also taking highly beneficial renin-angiotensin-aldosterone system inhibitors (RAASi), there is a greater risk of developing hyperkalemia due to the side effects of those drugs and the kidney’s limited ability to keep potassium in balance.

Tenapanor for Irritable Bowel Syndrome with Constipation (IBS-C)

NDA accepted for review with PDUFA date September 12, 2019

Tenapanor, discovered and developed by Ardelyx, is a first-in-class, oral, experimental medication that works exclusively in the gut and is in late-stage clinical development. It has a unique mechanism of action that, in IBS-C, relieves both constipation and abdominal pain. By inhibiting, or blocking, the NHE3 transporter in the GI tract, tenapanor reduces the absorption of dietary sodium into the blood stream. Blocking NHE3 results in an increase in the amount of sodium in the gut. This increased sodium leads to an increase of fluid in the gut, which loosens stool, helping to relieve constipation. Based upon preclinical findings, we believe that tenapanor works to reduce abdominal pain caused by IBS-C through the inhibition of TRPV-1 dependent signaling. TRPV-1, better known as the “hot chili pepper receptor,” is a well-established pain target known for transmitting painful stimuli from a variety of sources including heat, protons and inflammatory molecules. We presented preclinical findings on this mechanism at the 2017 American Society of Gastroenterology Annual Meeting.

Tenapanor has been specifically designed to work exclusively within the GI tract, thereby significantly reducing the amount of drug that is absorbed into the bloodstream and the potential side effects that could occur.

IBS-C is a burdensome GI disorder affecting a significant number of people. It is characterized by significant abdominal pain, constipation, straining during bowel movements, bloating and/or gas.

On September 13, 2018, we submitted a new drug application, or NDA, to the U.S. Food and Drug Administration, or FDA, for the treatment of patients with IBS-C and have been granted a target action date under the Prescription Drug User Fee Act (PDUFA) of September 12, 2019. The NDA submission was supported by a clinical package encompassing more than 3,100 patients and healthy volunteers who have participated in Ardelyx clinical trials and extensive clinical and preclinical data supporting the excellent safety profile. The data include results from the completed IBS-C registration T3MPO program, which consisted of two Phase 3 trials, T3MPO-1 and T3MPO-2, and a long-term safety extension trial, T3MPO-3. Both the T3MPO-1 and T3MPO-2 trials achieved statistical significance for their primary endpoint and demonstrated that tenapanor had a durable effect on reducing constipation and abdominal pain that patients with IBS-C experience. The favorable safety profile of tenapanor, which has been shown across all clinical trials, was further supported by the completed T3MPO-3 study.

IBS-C

IBS-C presents a significant burden on patients, the healthcare system and the U.S. economy. While estimates vary, it is projected that approximately 11 million people in the U.S. suffer from IBS-C.