What We Do

PROGRAM
INDICATION
RESEARCH
PHASE 1
PHASE 2
PHASE 3
MARKETED
Cardiorenal Programs
Tenapanor
ESRD Hyperphosphatemia
(NHE3 Inhibitor)
RDX011
Cardiorenal Indications
(NHE3 Inhibitor)
RDX013
Hyperkalemia
(Potassium Secretagogue)
GI Programs
Tenapanor
IBS-C
(NHE3 Inhibitor)
RDX011
GI Indications
(NHE3 Inhibitor)

TENAPANOR FOR HYPERPHOSPHATEMIA

Tenapanor, discovered and developed by Ardelyx, is a first-in-class, proprietary, oral, medicine in late-stage clinical development for the control of serum phosphorus in patients with CKD on dialysis. Tenapanor has a unique mechanism of action and acts locally in the gut to inhibit the sodium hydrogen exchanger 3 (NHE3). This results in the tightening of the epithelial cell junctions, thereby significantly reducing paracellular uptake of phosphate, the primary pathway of phosphate absorption.

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.

 

  1. Tenapanor blocks NHE3, increasing sodium in the gut; NHE3 transports sodium in exchange for protons
  2. Elevated proton levels in cells selectively increase tight junction resistance to phosphate transport
  3. Increased tight junction resistance reduces gut phosphate absorption
Tenapanor selectively blocks paracellular transport of phosphate – a major pathway for regulation of phosphate absorption into blood
Tight junctions utilize different combinations of claudin proteins to facilitate paracellular transport of other ions
Clinical and preclinical data suggest no adverse effect on absorption of nutrients or other ions

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 chronic kidney disease (CKD) who require dialysis.  Tenapanor has completed two Phase 3 trials, demonstrating the ability of tenapanor as a monotherapy and in combination with phosphate binders, to statistically, significantly reduce serum phosphorus in dialysis patients.  The company is conducting an additional Phase 3 trial, PHREEDOM, a long-term Phase 3 monotherapy study.

In September 2019, we reported results from the AMPLIFY trial, a pivotal Phase 3 study of tenapanor in combination with phosphate binders in patients with chronic kidney disease (CKD) on dialysis whose hyperphosphatemia was not previously controlled with binders alone. The AMPLIFY study met the primary endpoint and all key secondary endpoints.  For the primary endpoint, patients treated in the tenapanor arm (tenapanor in combination with phosphate binders, n=116) had a statistically significant (p=0.0004) mean reduction in serum phosphorus from baseline to the end of the four-week treatment period of 0.84 mg/dL, as compared to those treated in the binder arm (placebo in combination with phosphate binders, n=119) who had a mean reduction of 0.19 mg/dL. Patients in the tenapanor arm had statistically significant decreases in serum phosphorus during all 4 weeks ranging from 0.84 to 1.21 mg/dL (p-values<0.0004). During the treatment period, up to 49.1% of patients in the tenapanor arm achieved a serum phosphorus of <5.5 mg/dL which was statistically significant compared with up to 23.5% in the binder arm (p-values≤0.0097). There was a statistically significant reduction (p-values≤0.0027) in FGF23 levels in the tenapanor arm as compared to the binder arm. Elevated levels of FGF23 are associated with an increased risk of major cardiovascular events.

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.

The ongoing PHREEDOM trial, is expected to be completed 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 the successful Phase 3 clinical trial completed in 2017, which achieved statistical significance for the primary endpoint.

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.

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 HYPERPHOSPHATEMIA

Eliminating 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 HYPERKALEMIA

IBSRELA® (tenapanor) for Irritable Bowel Syndrome with Constipation (IBS-C)

FDA Approved on September 12, 2019

On September 12, 2019, Ardelyx received approval of IBSRELA (tenapanor) for the treatment of irritable bowel syndrome with constipation (IBS-C). To efficiently bring its treatments to market, Ardelyx is pursuing strategic collaborations for IBSRELA for IBS-C and tenapanor for hyperphosphatemia in certain territories. Ardelyx has established agreements with Kyowa Kirin Company Limited in Japan, Fosun Pharma in China and Knight Therapeutics in Canada.

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.

IBSRELA (tenapanor) is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for the absorption of dietary sodium. In vitro and animal studies indicate its major metabolite, M1, is not active against NHE3. By inhibiting NHE3 on the apical surface of the enterocytes, tenapanor reduces absorption of sodium from the small intestine and colon, resulting in an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and results in a softer stool consistency.

Tenapanor has also been shown to reduce abdominal pain by decreasing visceral hypersensitivity and by decreasing intestinal permeability in animal models. In rat model of colonic hypersensitivity, tenapanor reduced visceral hyperalgesia and normalized colonic sensory neuronal excitability.

What is IBSRELA?

IBSRELA® (tenapanor) 50 mg tablets is a prescription medicine used in adults to treat Irritable Bowel Syndrome with Constipation (IBS-C). It is not known if IBSRELA is safe and effective in children less than 18 years of age.

IMPORTANT SAFETY INFORMATION

  • Do not give IBSRELA to children who are less than 6 years of age. It may harm them.
  • You should not give IBSRELA to patients 6 years to less than 18 years of age. It may harm them. IBSRELA can cause severe diarrhea and your child could get severe dehydration (loss of a large amount of body water and salt).
  • Do not take IBSRELA if a doctor has told you that you have a bowel blockage (intestinal obstruction).

Before you take IBSRELA, tell your doctor:

  • If you have any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if IBSRELA will harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if IBSRELA passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take IBSRELA.
  • Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Side Effects

  • Diarrhea is the most common side effect of IBSRELA, and it can sometimes be severe. Stop taking IBSRELA and call your doctor if you develop severe diarrhea.

The other most common side effects of IBSRELA include:

  • swelling, or a feeling of fullness or pressure in your abdomen (distension).
  • gas (flatulence).
  • dizziness

These are not all the possible side effects of IBSRELA. Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to www.fda.gov/medwatch or you can report side effects to Ardelyx at 1-844-427-7352.

Please also see Medication Guide within the full Prescribing Information.

Tenapanor has been specifically designed to work within the GI tract, thereby significantly reducing the amount of drug that is absorbed into the bloodstream.

 

  1. Tenapanor blocks NHE3, which transports sodium in exchange for protons
  2. Blocking NHE3 increases sodium outside cells/in the gut
  3. Increased sodium increases water in the gut, which loosens stool, alleviating constipation
Data from preclinical studies have shown that tenapanor works to reduce abdominal pain caused by IBS-C by decreasing visceral hypersensitivity and by decreasing intestinal permeability.

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-C

PARTNERING

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. 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.