The US Food and Drug Administration (FDA) is asking for an additional clinical trial to demonstrate greater benefits of tenapanor before it can decide on approval of the drug for the control of serum phosphorus in adults with chronic kidney disease (CKD) who are on dialysis, the drug’s maker, Ardelyx, reports.
According to the company, the FDA said “the submitted data provide substantial evidence that tenapanor is effective in reducing serum phosphorus in CKD patients on dialysis,” but they characterize the magnitude of the treatment effect as “small and of unclear clinical significance,” in a recently issued complete response letter.
Tenapanor is an oral, first-in-class inhibitor of the sodium-proton exchanger NHE3, and the application for approval for hyperphosphatemia in patients with CKD on dialysis was supported by three phase 3 clinical trials involving more than 1000 patients that all met their primary and key secondary endpoints, the company notes. No safety or nonclinical issues were noted in the FDA’s letter.
The FDA stated that approval of the application would require Ardelyx to conduct 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.”
Ardelyx said it plans to meet with the FDA to discuss possible paths forward for the approval.
Current Therapies for Hyperphosphatemia Only “Moderately Effective”
Patients receiving dialysis for the management of CKD are highly likely to be hyperphosphatemic.
“Current strategies for the management of hyperphosphatemia include more frequent hemodialysis, dietary phosphate restriction, and phosphate binder therapy, but these are only moderately effective and difficult to implement,” writes Pablo E. Pergola, MD, PhD, Renal Associates PA, San Antonio, Texas, in the recent publication of one of the phase 3 trials of tenapanor, AMPLIFY, in the Journal of the American Society of Nephrology.
In that study, 236 patients who were on dialysis and had hyperphosphatemia despite treatment with phosphate binder therapy were randomized to 4 weeks of treatment with either the twice-daily oral tenapanor or placebo.
The results showed that the tenapanor treatment group had a significantly greater mean change in serum phosphorus concentration versus placebo (P < .001).
“Tenapanor would enable a substantially larger fraction of patients to reach target serum phosphorus concentrations and would yield significant clinical benefit to this vulnerable population,” senior author of the AMPLIFY study, Glenn Chertow, MD, MPH, division chief of nephrology and professor of medicine at Stanford University, California, said in the Ardelyx press release.
Untreated, hyperphosphatemia can lead to “dystrophic calcification, accelerated arteriosclerotic vascular disease, fractures, and other complications that profoundly affect patients’ lives,” Chertow said.
He disagrees with the FDA’s conclusion, stating that “the effect of tenapanor on serum phosphorus observed in the Phase 3 trials is clinically meaningful.”
“Tenapanor would enable a substantially larger fraction of patients to reach target serum phosphorus concentrations and would yield significant clinical benefit to this vulnerable population,” he added.
Tenapanor previously received FDA approval in 2019 for the treatment of irritable bowel syndrome with constipation in adults.
Chertow has been an investigator for several of the tenapanor trials for hyperphosphatemia.
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