After the FDA rejected and questioned Ardelyx’s potential drug for controlling serum phosphorus levels in adults with chronic kidney disease on dialysis, the FDA’s Cardiovascular and Kidney Drug Advisory Committee voted Wednesday 9-4 in favor of the drug as monotherapy, and 10-2 (with one abstention) in favor of the drug when given in combination with phosphate binder therapy.
Adcomm committee chair Julia Lewis of Vanderbilt Medical Center said the drug, known as tenapanor, offers smaller pills, and while it may be less effective than the current standard of care, there are a small subset of CKD patients who will respond to monotherapy and “will make this available to them.
Panelist Edward Kasper, professor of cardiology at Johns Hopkins, also voted for it as a monotherapy, calling the safety issues around severe diarrhea acceptable given the close monitoring of this population, and he said that this drug clearly had a role to play. Others who voted against tenapanor as a monotherapy raised questions about the magnitude of the drug’s effect.
Wednesday’s morning debate focused on questions from the FDA about the extent of the drug’s benefits in pivotal trials.
But Ardelyx argued that tenapanor, which is already approved for irritable bowel syndrome with constipation in adults, may help what is a significant unmet need for new options to control serum phosphorus levels. Even the initial FDA rejection letter in 2021 stated that the submitted data “provides substantial evidence that tenapanor is effective in reducing serum phosphorus in CKD patients on dialysis,” Ardelyx’s presentation said.
The FDA, however, pointed to a mean treatment effect for tenapanor in this population of -0.7 mg/dL in the two monotherapy studies, which “appeared to be lower than that seen with the approved agents (~1.5 at 2.2 mg/dL)”. And for the use of tenapanor in combination with phosphate-binding therapy, the FDA said the magnitude of treatment effect was similar to that seen in monotherapy trials.
Even still, during the committee discussion, panelists reiterated that there would be a subset of patients who would benefit from the Ardelyx pill, particularly those who cannot tolerate phosphate binders which are large and difficult to swallow (although the pill burden has not been tabulated) and should be taken between meals, according to some public comments.
Adcomm panelist Susan Mendley of the NIH Division of Kidney, Urology, and Hematology, who voted in favor of tenapanor monotherapy, noted that while oral phosphate binders showed greater effect size, many patients do not tolerate them, and they are not pleasant to take. As monotherapy in the right patient, “I think they hit their mark,” she said.
But panelist Christopher O’Connor of Virginia’s Inova Heart and Vascular Institute, who voted against tenapanor, questioned whether 0.7 mg/dL “is enough when you’re talking about a surrogate endpoint that doesn’t has not been validated. We need to talk about the clinical significance that we have, and I’m afraid it’s not there.
University of Pittsburgh Adcomm member Linda Fried, who also voted for it as a monotherapy, said she does not consider tenapanor a monotherapy except in those intolerant of binders. of phosphate.
FDA safety concerns focused on bothersome and sometimes severe diarrhea, the majority of cases lasting longer than 30 days, and with severe significance the trial participant was unable to work or carry out usual activities . Nearly half of the tenapanor arm in one of the pivotal trials required a dose change or was discontinued due to diarrhea, FDA safety analyst Selena DeConti told the committee.
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