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If approved, Xphozah will be the first phosphate absorption inhibitor for adults with chronic kidney disease who are on dialysis. An FDA decision is expected within 30 days.
An FDA advisory committee has voted in favor of Ardelyx’s Xphozah (tenapanor) in the control of serum phosphorus in adult patients with chronic kidney disease (CKD) on dialysis. The Cardiovascular and Renal Drugs Advisory Committee voted 9 to 4 in favor of Xphozah as a monotherapy and 10 to 2 in favor of Xphozah in combination with phosphate binders.
“Xphozah is a novel treatment that provides a clinically meaningful effect on serum phosphate. I am encouraged by the committee's vote. The nephrology community is enthusiastic to have access to this therapy with its novel mechanism of action to help our patients, Sharon Moe, M.D., chief of the division of nephrology and hypertension, Indiana University School of Medicine, said in a press release.
Hyperphosphatemia is a serious condition resulting in an abnormally elevated level of phosphorus in the blood that is estimated to affect the vast majority of the 550,000 patients in the United States with chronic kidney disease on dialysis. When kidney function is impaired, phosphorus is not adequately eliminated from the body. Hyperphosphatemia is a major cause of morbidity and mortality in patients with chronic kidney disease.
The committee review was based on findings from a clinical trial program of more than 1,200 patients in three phase 3 trials, all of which met their primary and key secondary endpoints (PHREEDOM, BLOCK and AMPLIFY).
FDA officials had issued a complete response letter in July 2021, which the company appealed twice. Regulators at that time noted that data submitted indicate the treatment effect is small and of unclear clinical significance. They had requested an additional study to demonstrate that Xphozah lowers serum phosphorus. Ardelyx filed the first appeal in November 2021, which was denied. The second appeal was filed in February 2022.
At issue for agency officials was the magnitude of effect was small and may not be clinically relevant. The agency had accepted serum phosphorus as a surrogate endpoint, but said there is no evidence that the treatment’s effect on serum phosphorus predicts its effect on clinical outcomes.
Committee member Christopher M. O’Connor, M.D., who voted no on the use of Xphozah both as a monotherapy and in combination with phosphate binders, said the surrogate endpoint used hasn’t been validated and said the degree of efficacy was modest. O’Connor is professor of Medicine, Duke University President and Executive Director at Inova Heart and Vascular Institute.
“Millions of patients sadly with this condition, 200+ patient trials, 116 on active therapy, modest efficacy on surrogate endpoint; as a community, we must do better for our patients,” he said.
One committee member who voted yes for Xphozah both as monotherapy and in combination was C. Noel Bairey Merz, M.D., mentioned the patients who are unable to take the standard of care. “While I do support this as an add-on therapy primarily, it should be made available for those patients who would otherwise be untreated.” Merz is director of Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center.
Committee member Edward K. Kasper, M.D., also voted in support Xphozah and noted doctors have no other choice but to assess a surrogate endpoint. “The whole point is to drive phosphorus as low as you can get. I think this drug can help do that.” Kasper director of Outpatient Cardiology at E. Cowles Andrus Professor in Cardiology Johns Hopkins School of Medicine.
The company released additional data on Xphozah at the National Kidney Foundation 2022 Spring Clinical Meetings early in April. Ardelyx has completed three phase 3 pivotal trials, and two phase 4 clinical trials (OPTIMIZE and NORMALIZE) for Xphozah, a first-in-class, phosphate absorption inhibitor.
In the OPTIMIZE phase 4 trial, Xphoza as monotherapy helped 63% of patients with uncontrolled hyperphosphatemia who were naïve to phosphate binder therapy to achieve target serum phosphate levels. For those with uncontrolled hyperphosphatemia despite being on treatment with phosphate binders, switching to Xphozah or adding Xphozah to a reduced binder dose enabled 34% to 38% of these patients to achieve target levels.
In the NORMALIZE phase 4 trial, up to 49.4% of patients treated with Xphozah monotherapy or in combination with sevelamer achieved a serum phosphate level within the normal range during the 18-month treatment period, which is 66.3% better than standard of care.