Tenapanor Receives FDA Approval for Reducing Serum Phosphorous in CKD

Credit: US Food and Drug Administration

In a major win for patients with chronic kidney disease (CKD), the US Food and Drug Administration (FDA) has approved tenapanor (Xphozah) for reducing serum phosphorous levels in patients with CKD on dialysis.

Announced by Ardelyx Inc. on October 17, 2023, the decision comes 5 months after the FDA accepted Ardelyx’s resubmission of a New Drug Application (NDA) for tenapanor and indicates the agent to reduce serum phosphorus in adults with CKD on dialysis as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy.¹

"Hyperphosphatemia management has been a persistent clinical challenge, as the majority of patients receiving maintenance dialysis are unable to consistently achieve target serum phosphate concentrations despite treatment with phosphate binders. XPHOZAH is not a phosphate binder," said Glenn Chertow, MD, MPH, professor of medicine, Stanford University. "XPHOZAH is a phosphate absorption inhibitor. In patients not adequately responding to phosphate binder therapy, XPHOZAH has been shown to help increase the proportion of patients achieving target serum phosphate concentrations. I believe XPHOZAH can advance the care of patients with hyperphosphatemia, providing a new treatment option with a complementary mechanism of action.”

Already boasting a prior approval from the FDA in 2019 for the treatment of irritable bowel syndrome with constipation in adult patients, the journey to an official regulatory decision for tenapanor for hyperphosphatemia in patients with CKD has not been straightforward. The FDA accepted an NDA for tenapanor on September 15, 2020, but issued a Complete Response Letter on July 29, 2021, describing the magnitude of tenapanor’s treatment effect as "small and of unclear clinical significance" and requesting “an additional adequate and well-controlled trial demonstrating a clinically relevant treatment effect on serum phosphorus or an effect on the clinical outcome thought to be caused by hyperphosphatemia in CKD patients on dialysis." ^2,3

An appeal to the CRL for the NDA for tenapanor was granted on December 29, 2022, following a favorable outcome of a November 16, 2022, Cardiovascular and Renal Drugs Advisory Committee meeting. The Advisory Committee voted the benefits of treatment with tenapanor outweigh its risks for the control of serum phosphorus in adults with chronic kidney disease on dialysis when administered as a monotherapy, 9 to 4. An additional 10 to 2 vote, with 1 abstention, supported the benefits of treatment with tenapanor in combination with phosphate binder treatment outweigh its risks.⁴

Ardelyx announced the resubmission of their NDA to the FDA for tenapanor on April 18, 2023, with the application based on data from a trio of phase 3 clinical trials: PHREEDOM, BLOCK, and AMPLIFY.

PHREEDOM

A 26-week, open-label study with a 12-week, placebo-controlled study with a randomized withdrawal period followed by an open-label long-term safety extension, PHREEDOM launched in January 2018 and enrolled 1559 participants from 104 centers in the United States. It assessed the safety and efficacy of tenapanor for the treatment of hyperphosphatemia in end-stage renal disease on hemodialysis and peritoneal dialysis.⁵

Participants were randomized 3:1 to receive either tenapanor at a starting dose of 30 mg orally, twice daily for 26 weeks, or sevelamer carbonate for 52 weeks. At the end of the randomized treatment period, participants who completed the 26-week treatment with tenapanor were rerandomized 1:1 to either continue to receive tenapanor treatment at the same dose or switch to placebo for 12 weeks in a randomized withdrawal period.⁵

Upon analysis, results suggested the difference in estimated mean change in serum phosphate level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was −1.4 mg/dl (P < .0001) in the efficacy set and −0.7 mg/dl (P = .002) in the intention-to-treat set. During the 26-week treatment period, 77% of tenapanor-treated patients in the intent-to-treat population had a decrease in serum phosphorus, with a mean reduction from baseline of 2.0 mg/dl.⁵

BLOCK

An 8-week, double-blind, randomized trial with a 4-week placebo-controlled randomized withdrawal period, BLOCK launched in January 2017 and enrolled 219 participants to assess the efficacy, safety, and tolerability of tenapanor to treat hyperphosphatemia in patients with end-stage renal disease on hemodialysis.⁶

Participants were randomized 1:1:1 to receive 3 mg BID, 10 mg BID, or a titration regimen of tenapanor for an 8-week treatment period. At the end of the treatment period, patients were rerandomized 1:1 to either remain on their current tenapanor treatment or placebo.⁶

The responder population had a 2.56 mg/dL mean reduction in serum phosphorus from baseline to the end of the 8-week treatment period, with 33% of patients having a reduction in serum phosphorus of greater than 3 mg/dL. Results also showed a statistically significant difference in serum phosphorus levels from the end of the 8-week treatment period to the end of the 4-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% confidence interval [CI], -1.44 to -0.21; LS mean, -0.82 mg/dL; P = .01).⁶

AMPLIFY

A double-blind, placebo-controlled, randomized study, AMPLIFY launched in February 2019 and enrolled 236 participants to assess the effect of tenapanor on changes in serum phosphorus levels as adjunctive therapy to patients with end-stage renal disease and hyperphosphatemia on stable phosphate binder therapy.⁷

Participants were randomized in a 1:1 ratio to receive tenapanor or placebo while continuing their existing phosphate binder treatment.⁷

Upon analysis, patients treated in the tenapanor arm had a statistically significant (P = .0004) mean reduction in serum phosphorus from baseline to the end of the 4-week treatment period of 0.84 mg/dL, while those treated in the binder arm had a mean reduction of 0.19 mg/dL. Patients in the tenapanor arm also had statistically significant decreases in serum phosphorus during all 4 weeks ranging from 0.84 to 1.21 mg/dL (P-values < .0004). During the treatment period, 49.1% of patients in the tenapanor arm achieved a serum phosphorus of <5.5 mg/dL which was statistically significant compared to 23.5% in the binder arm (P-values ≤ .0097). There was a statistically significant 22% to 24% reduction (P-values ≤ .0027) in FGF23 levels in the tenapanor arm as compared to the binder arm.⁷

““The approval of XPHOZAH is an important milestone for patients on dialysis, their families and the nephrology care community, as it represents a new mechanism and new option for patients who, despite treatment with phosphate binders, continue to have elevated phosphorus. It is also a significant accomplishment for everyone at Ardelyx,” said Mike Raab, president and chief executive officer of Ardelyx.¹

In a release on October 13, 2023, Ardelyx noted plans to present data updates on tenapanor for hyperphosphatemia and expects the agent to be available by the end of 2023.^8,9

References:

1. FDA approves XPHOZAH® (Tenapanor), a first-in-class phosphate absorption inhibitor. Ardelyx, Inc. October 17, 2023. Accessed October 17, 2023. https://ir.ardelyx.com/news-releases/news-release-details/fda-approves-xphozahr-tenapanor-first-class-phosphate-absorption.
2. Ardelyx. Ardelyx Announces FDA Acceptance for Filing of its New Drug Application of Tenapanor for the Control of Serum Phosphorus in Adult Patients with CKD on Dialysis. September 15, 2020. Accessed October 17, 2023. https://ir.ardelyx.com/news-releases/news-release-details/ardelyx-announces-fda-acceptance-filing-its-new-drug-0
3. Ardelyx. Ardelyx Receives Complete Response Letter from U.S. FDA for New Drug Application for Tenapanor for the Control of Serum Phosphorus in Adult Patients with CKD on Dialysis. July 29, 2021. Accessed October 17, 2023. https://ir.ardelyx.com/news-releases/news-release-details/ardelyx-receives-complete-response-letter-us-fda-new-drug
4. Ardelyx. FDA Grants Appeal for Ardelyx's XPHOZAH® (tenapanor). December 29, 2022. Accessed October 17, 2023. https://ir.ardelyx.com/news-releases/news-release-details/fda-grants-appeal-ardelyxs-xphozahr-tenapanor
5. Clinicaltrials.gov. A Phase 3 Study of Tenapanor to Treat Hyperphosphatemia in ESRD Patients on Dialysis. June 29, 2023. Accessed October 17, 2023. https://clinicaltrials.gov/study/NCT03427125
6. Clinicaltrials.gov. An 8-Week Study to Evaluate Tenapanor in the Treatment of Hyperphosphatemia in End-Stage Renal Disease Patients on Hemodialysis (ESRD-HD). August 10, 2020. Accessed October 17, 2023. https://clinicaltrials.gov/study/NCT02675998
7. Clinicaltrials.gov. Study to Evaluate the Efficacy of Tenapanor as Adjunctive Therapy to Phosphate Binder Therapy. March 6, 2023. Accessed October 17, 2023. https://clinicaltrials.gov/study/NCT03824587
8. Ardelyx to present data updates for XPHOZAH (Tenapanor) for hyperphosphatemia at Kidney Week 2023 november 1-5 in Philadelphia, PA. Ardelyx, Inc. October 13, 2023. Accessed October 17, 2023. https://ir.ardelyx.com/news-releases/news-release-details/ardelyx-present-data-updates-xphozah-tenapanor-hyperphosphatemia.
9. Ardelyx announces FDA acceptance and six-month review for resubmission of its New Drug Application of XPHOZAH® (Tenapanor). Ardelyx, Inc. May 17, 2023. Accessed October 17, 2023. https://ir.ardelyx.com/news-releases/news-release-details/ardelyx-announces-fda-acceptance-and-six-month-review.