Ardelyx Announces FDA Approval of Xphozah (tenapanor) as First-in-Class Phosphate Absorption Inhibitor for Hyperphosphatemia in Adult CKD Patients on Dialysis

On October 17, 2023, local time, Ardelyx, Inc. (NASDAQ: ARDX) announced that the U.S. Food and Drug Administration (FDA) has approved Xphozah (tenapanor) as an add-on treatment to reduce serum phosphorus levels in adult patients with chronic kidney disease (CKD) on dialysis who have had an inadequate response to phosphate binders or who are intolerant to any dose of phosphate binder therapy.

Ardelyx will hold a conference call at 8:00 a.m. Eastern Time on October 18, 2023, to discuss the announcement.

Xphozah is a twice-daily tablet that inhibits paracellular phosphate absorption in the intestinal epithelium, thereby reducing serum phosphate levels. Ardelyx is an innovative pharmaceutical company focused on the research and development of novel therapies for cardiorenal and gastrointestinal diseases. Founded in 2007 as Nteryx, Inc., the company adopted its current name in June 2008 and is headquartered in Fremont, California, USA.

Dr. Glenn Chertow, Professor of Medicine at Stanford University, stated: “The management of hyperphosphatemia has remained a persistent clinical challenge, as most patients on maintenance dialysis fail to consistently achieve target serum phosphate levels despite treatment with phosphate binders. Xphozah is not a phosphate binder but rather a phosphate absorption inhibitor. In patients who have an inadequate response to phosphate binder therapy, Xphozah has been shown to increase the proportion of patients achieving target serum phosphate concentrations. I believe that Xphozah can advance the care of patients with hyperphosphatemia by providing a new therapeutic option with a complementary mechanism of action.”

“The approval of Xphozah represents a significant milestone for dialysis patients, their families, and the nephrology care community, as it offers a novel mechanism of action and a new treatment option for patients whose phosphorus levels remain elevated despite therapy with phosphate binders,” said Mike Raab, President and Chief Executive Officer of Ardelyx. “Since its founding in 2007, Ardelyx has been dedicated to the field of kidney disease. Xphozah originated within the company in 2008, and we look forward to our world-class team delivering more best-in-class products in the future.”

The development and approval journey of Xphozah has been anything but smooth.

In 2008, Xphozah was born at Ardelyx.

In October 2012, AstraZeneca entered into an agreement with Ardelyx, securing global rights to the product through a licensing deal valued at $273 million.

Dramatically, in 2015, Ardelyx decided to repurchase Xphozah from AstraZeneca.To reclaim the rights to this project, Ardelyx also returned $25 million to AstraZeneca (AZ). A major reason for AstraZeneca’s willingness to abandon this drug was its failure to meet the primary endpoint of proteinuria in a Phase 2a trial conducted that year among patients with diabetic kidney disease. After the data were disclosed that year, Raab, CEO of Ardelyx, discussed the possibility of AZ withdrawing from the project and took the initiative to buy back the drug.

Notably, in September 2019, Xphozah was approved for marketing in the United States under the brand name Ibsrela for the treatment of irritable bowel syndrome with constipation.

However, in the following years, misfortune successively befell Xphozah and Ardelyx.

On September 15, 2020, Ardelyx submitted to the FDA and gained acceptance for a new indication application for Xphozah, intended for the control of serum phosphorus in adult patients with chronic kidney disease (CKD) on dialysis, with a PDUFA date of April 29, 2021. However, in early April 2021, the FDA requested that Ardelyx submit additional analyses to help the agency better understand the clinical data regarding the novel mechanism of action of Xphozah compared to approved therapies.

In response, Ardelyx promptly submitted the analyses requested by the FDA, and the PDUFA date was subsequently extended to July 29, 2021.

However, in July 2021, the FDA issued a Complete Response Letter stating that while Xphozah effectively reduced serum phosphorus levels in patients, the magnitude of reduction was small and its clinical significance remained unclear. The FDA required Ardelyx to conduct additional clinical trials to demonstrate the efficacy of Xphozah in lowering serum phosphorus levels or treating hyperphosphatemia caused by chronic kidney disease (CKD).

As a result, Ardelyx’s stock price plummeted by 74% at the time, and the company laid off approximately 60% of its workforce.

Perhaps the blow was so severe that Ardelyx decided to take a gamble, battling the FDA by refusing its request for additional clinical trials and filing an appeal.

A year later, the situation took a turn for the better.FDA Invites Ardelyx to Attend Cardiovascular and Renal Drugs Advisory Committee (CRDAC) Meeting to Discuss the Clinical Significance of Xphozah’s Phosphate-Lowering Effects. During this meeting, the CRDAC voted 9:4 in favor that the benefits of Xphozah monotherapy for hyperphosphatemia in adult patients with chronic kidney disease (CKD) on dialysis outweigh the risks, and voted 10:2 in favor that the therapeutic benefits of Xphozah in combination with phosphate binders outweigh the risks.

On April 19 this year, Ardelyx announced that it had resubmitted to the FDA a new drug application for Xphozah, for the treatment of hyperphosphatemia in adult patients with chronic kidney disease (CKD) on dialysis who have an inadequate response to or are intolerant of phosphate binder therapy.

Just yesterday, this drug, which has weathered many storms, finally received FDA approval for market launch.

Despite the twists and turns in the development and commercialization of Xphozah, Ardelyx has remained steadfast in its commitment to never give up on or abandon the drug.

As the only approved phosphate absorption inhibitor currently on the market, Ardelyx is poised to seize a first-mover advantage, thereby offsetting the setbacks it has faced over the past few years in its regulatory approval journey.

It is reported that hyperphosphatemia is a serious condition closely linked to renal function. Healthy kidneys are responsible for eliminating excess phosphate; however, as renal function declines, phosphate cannot be adequately cleared from the body, leading to elevated serum phosphate levels. Consequently, hyperphosphatemia is nearly ubiquitous among patients with chronic kidney disease (CKD) undergoing maintenance dialysis. Although the condition typically presents with no specific clinical symptoms in its early stages, prolonged hyperphosphatemia can lead to hypocalcemia, manifesting as tetany, and subsequently cause secondary hyperparathyroidism and renal osteodystrophy.

Xphozah is an NHE3 sodium transporter inhibitor. NHE3 is an antiporter expressed on the apical surface of the small intestine and colon. By inhibiting NHE3, it tightens the junctions between cells, thereby reducing phosphate absorption via the paracellular pathway (the primary route for phosphate absorption) and lowering serum phosphate levels.

Xphozah features a unique mechanism of action, selectively inhibiting sodium and phosphate absorption without affecting the intestinal uptake of other ions, molecules, and nutrients. The drug itself is not absorbed by the gastrointestinal tract but is excreted in feces, thereby reducing the likelihood of adverse effects.

The FDA’s approval of Xphozah is based on a comprehensive development program that included three Phase 3 clinical trials enrolling more than 1,000 diverse patients, which evaluated the efficacy and safety of XPHOZAH as monotherapy and in combination with phosphate binders. All trials met their primary and key secondary endpoints. Data from the three clinical trials demonstrated that XPHOZAH significantly reduces elevated serum phosphorus levels in patients undergoing maintenance hemodialysis.

According to Ardelyx’s announcement, diarrhea occurred in 43% to 53% of patients, making it the only adverse reaction reported during dialysis in more than 5% of CKD patients treated with Xphozah across various trials. It was reported that diarrhea in patients receiving Xphozah was mostly mild to moderate in severity; only 5% of treated patients experienced severe diarrhea, which resolved with dose reduction and over time.

Furthermore, Ardelyx has completed two open-label clinical trials (OPTIMIZE and NORMALIZE) to evaluate various options for integrating Xphozah into clinical practice. We look forward to Ardelyx entering a harvest season after weathering successive setbacks.

References:

https://ir.ardelyx.com/news-releases/news-release-details/fda-approves-xphozahr-tenapanor-first-class-phosphate-absorption