What We Do
Our pipeline of gut-restricted therapies is concentrated on providing better medicines in two therapeutic areas: cardiorenal & GI diseases.
TENAPANOR FOR HYPERPHOSPHATEMIA
Tenapanor, invented and developed internally by scientists at Ardelyx, is a first-in-class, proprietary, 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 hyperphosphatemia, acts by inhibiting, or blocking, the NHE3 transporter in the GI tract to reduce the absorption of dietary sodium, which in turn, increases the number of protons in a cell. These increased protons cause specific tight junction resistance between cells, which then limits the amount of dietary phosphate that can pass from the gut into the blood. Importantly, the effects appear to be selective to phosphate with no apparent impact on other ions, nutrients or macromolecules.
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.

- Tenapanor blocks NHE3, increasing sodium in the gut; NHE3 transports sodium in exchange for protons
- Elevated proton levels in cells selectively increase tight junction resistance to phosphate transport
- Increased tight junction resistance reduces gut phosphate absorption
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.
LEARN MORE ABOUT HYPERPHOSPHATEMIAEliminating the Pill Burden
Conventional dialysis and dietary restriction of foods and drinks high in phosphorus are the first step in controlling hyperphosphatemia, but this is often not enough in the majority of ESRD patients. Historically, the only other way to manage elevated phosphorus has been to require ESRD patients to take large amounts of oral phosphate binders. This requires patients to take multiple tablets, or single large chewable tablets with every meal and snack. This added pill burden is a significant challenge for dialysis patients as the amount of fluid they are allowed to drink each day is severely restricted. As a result of these challenges, a large proportion of patients have uncontrolled blood phosphorus levels, significantly increasing their risk of poor health outcomes and even death. With tenapanor, which we are evaluating to be a twice-daily dose of a small pill similar to the size of a baby aspirin, we are aiming to significantly reduce that pill burden for these patients.

1. Investigational small molecule currently in phase 3 development-target dose 10-30 mg BID. (10 mg BID shown here)
2. 800mg of Renvela (sevelamer carbonate) up to three times per day with meals per package insert
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.
LEARN MORE ABOUT HYPERKALEMIATenapanor 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.

- Tenapanor blocks NHE3, which transports sodium in exchange for protons
- Blocking NHE3 increases sodium outside cells/in the gut
- Increased sodium increases water in the gut, which loosens stool, alleviating constipation
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.
1. Doshi, 20142. Lovell, 2012 LEARN MORE ABOUT IBS-CPARTNERING
OUR STRATEGIC PARTNERS
In November 2017, we executed a license agreement with Kyowa Hakko Kirin for the development and commercialization of tenapanor for cardiorenal diseases and conditions associated with them, including hyperphosphatemia, in Japan.
Learn more about the collaboration.
In December 2017, we executed a license agreement with Shangai Fosun Pharmaceutical Industrial Development Company Limited for the development and commercialization of tenapanor for IBS-C and hyperphosphatemia related to chronic kidney disease in China.
Learn more about the collaboration.
In March 2018, we executed a license agreement with Knight Therapeutics, Inc. which provides Knight with exclusive rights to commercialize tenapanor in Canada for the treatment of IBS-C and hyperphosphatemia.

PUBLICATIONS
2018 10. World Congress of Gastroenterology at ACG 2018. An Open-label, Long-term Safety Trial of Tenapanor in Patients with Irritable Bowel Syndrome with Constipation (IBS-C): T3MPO-3.
2017 10. World Congress of Gastroenterology at ACG 2017. Tenapanor Reduces IBS Pain Through Inhibition of TRPV1-dependent Neuronal Hyperexcitability In Vivo.
2017 10. World Congress of Gastroenterology at ACG 2017. Efficacy and Safety of Tenapanor in Patients with Constipation-Predominant Irritable Bowel Syndrome: A 12-Week, Double-Blind, Placebo-Controlled, Randomized Phase 3 Trial.
2017 02. American Journal of Gastroenterology. Tenapanor Treatment of Patients With Constipation-Predominant Irritable Bowel Syndrome: A Phase 2, Randomized, Placebo-Controlled Efficacy and Safety Trial.
2016 10. American College of Gastroenterology Annual Meeting 2016. Effect of Tenapanor on Global Endpoints in Patients with IBS-C: Results from a 12-Week, Double-Blind, Placebo-Controlled, Randomized Phase 2b Trial.
2015 05. Digestive Disease Week 2015. Efficacy and Safety of Tenapanor in Patients with Constipation-predominant Irritable Bowel Syndrome: a 12-week, Double-blind, Placebo-controlled, Randomized Phase 2b Trial.
2018. Nephrology Dialysis Transplant. The Effects of Tenapanor on Serum Fibroblast Growth Factor 23 in Patients Receiving Hemodialysis with Hyperphosphatemia.
2017 11. American Society of Nephrology Kidney Week 2017. Gastrointestinal Tolerability of Tenapanor to Treat Hyperphosphatemia in Patients on Hemodialysis.
2017 11. American Society of Nephrology Kidney Week 2017. Efficacy of Tenapanor to Treat Hyperphosphatemia in Patients on Hemodialysis.
2017. Journal of the American Society of Nephrology. Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis.
2016 09. Clinical Pharmacology in Drug Development. Preclinical and Healthy Volunteer Studies of Potential Drug–Drug Interactions Between Tenapanor and Phosphate Binders.
2015 11. American Society of Nephrology Kidney Week 2015. A Phase 2 Study on the Effect of Tenapanor on Albuminuria in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.
2015 11. American Society of Nephrology Kidney Week 2015. Tenapanor, a Gastrointestinal NHE3 Inhibitor, Reduces Serum Phosphate in Patients with Chronic Kidney Disease Stage 5D and Hyperphosphatemia.
2014 11. American Society of Nephrology Kidney Week 2014. Tenapanor, a Minimally Absorbed NHE3 Inhibitor, Reduces Dietary Phosphorus Absorption in Healthy Volunteers.
2014 11. American Society of Nephrology Kidney Week 2014. Tenapanor Inhibits Phosphorous Absorption and Protects Against Vascular Calcification in Nephrectomized Rats.
2012 05. 49th ERA-EDTA Congress. RDX5791, a Non-systemic NHE3 Inhibitor for the Treatment of Fluid and Sodium Overload, Shifts Sodium Excretion from Urine to Feces in Healthy Subjects.
2018 01. Clinical Drug Investigation. Pharmacodynamics, Safety, and Tolerability of the NHE3 Inhibitor Tenapanor: Two Trials in Healthy Volunteers.
2017 04. British Journal of Clinical Pharmacology. Tenapanor Administration and the Activity of the H+-coupled Transporter PepT1 in Healthy Volunteers.
2017 01. Clinical Pharmacology in Drug Development. Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study.
2017 01. Clinical Pharmacology in Drug Development. Effects of Tenapanor on Cytochrome P450-Mediated Drug-Drug Interactions.
2016 06. Clinical and Experimental Nephrology. A Phase 1 Study of the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Tenapanor in Healthy Japanese Volunteers.
2018 06. Digestive Disease Week 2018. RDX023-2, a Minimally Systemic, Non-bile Acid FXR Agonist, Reduces Steatosis, Inflammation and Fibrosis in Three Mouse Models of NASH.
2018 06. Digestive Disease Week 2018. Inhibition of Gastrointestinal (GI) NHE3 Normalizes GI Transit in Models of Opioid-induced Constipation, Multiple Sclerosis and Cystic Fibrosis.
2018 06. Digestive Disease Week 2018. Tenapanor Attenuates Increased Macromolecule Permeability in Human Colon Monolayer Cultures Induced by Inflammatory Cytokines and Human Fecal Supernatants.
2015. Current Opinion – Nephrology Hypertension. Pharmacologic Inhibition of Intestinal Sodium Uptake: A Gut Centric Approach to Sodium Management.
2015 11. American Society of Nephrology Kidney Week 2015. Prophylactic and Therapeutic Tenapanor are Vascular Protective in a Rat Model of Chronic Kidney Disease.
2014 03. Science Translational Medicine. Intestinal Inhibition of the Na+/H+ Exchanger 3 Prevents Cardiorenal Damage in Rats and Inhibits Na+ Uptake in Humans.
2014. Journal of the American Society of Nephrology. Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.