After the FDA rejected and questioned Ardelyx’s potential to control blood phosphorus levels in adults with chronic kidney disease on dialysis, the FDA’s Cardiovascular and Kidney Drugs Advisory Committee voted Wednesday 9-4 in favor of the drug. as monotherapy, and 10-2 (with one abstinence) in favor of the drug when administered with phosphate combination therapy.
The drug, known as tenapanor, offers smaller tablets, and while it may see lower efficacy than the current standard of care, there is a small subset of CKD patients who will respond to monotherapy, said Julia Lewis, MD, chair of the Adcomm Committee of Vanderbilt Medical Center. and “Let’s make that available to them.”
Committee member Edward Kasper, MD, a professor of cardiology at Johns Hopkins University, also voted in favor of it as the only treatment, called the safety questions about acute diarrhea acceptable given how closely these populations were monitored, and said there was clearly a role for this drug. Others who voted against tenabanor as a monotherapy have raised questions about the size of the drug’s effect.
Wednesday morning’s discussion focused on questions from the Food and Drug Administration about how useful the drug is in pivotal trials.
But Ardelyx explained that tenapanur, which is already approved for irritable bowel syndrome with constipation in adults, could help with what is a huge unmet need for new options for controlling blood phosphorus levels. Even the FDA’s initial rejection letter in 2021 said the data provided “provides substantial evidence that tinabanor is effective in reducing serum phosphorus in chronic kidney disease patients on dialysis,” Ardlex’s presentation read.
However, the FDA noted that the median treatment effect of Tinapanor in this population was 0.7 mg/dL in both monotherapy studies, which “appeared to be lower than that observed with approved agents (~1.5 to 2.2 mg/dL). deciliter).” For the use of tenapanur in combination with a phosphate binder treatment, the FDA said the effect size of the treatment was similar to what was observed in monotherapy trials.
Even still, in the panel discussion, panelists reiterated that there would be a subset of patients who would benefit from Ardelyx pills, particularly those who could not tolerate large, hard-to-swallow phosphate binders (although there was no pill burden on the schedule). And it should be taken in the middle of a meal, according to some general comments.
Susan Mindley, MD, a member of the Adcomm Committee in the Division of Kidney, Urology, and Hematology at the National Institutes of Health, who voted for tinabanor as monotherapy, noted that while oral phosphate binders have shown a greater effect size, many patients do not tolerate them, and they are not of good to take. As the only treatment for the right patient, “I think they achieved their results,” she said.
But panelist Christopher O’Connor of the Inova Cardiovascular Institute in Virginia, who voted against tenabanor, questioned whether 0.7 mg/dL was “sufficient” when you’re talking about an alternative endpoint that hasn’t been validated. We have to talk about the clinical significance we have, And I worry that he might not be there.”
Adcomm’s Linda Fried, of the University of Pittsburgh, who also voted for it as a monotherapy, said she only sees tinabane or monotherapy in those who are intolerant of phosphate bonds.
Safety concerns were sharpened by the FDA about irritating and sometimes severe diarrhea, with the majority of cases lasting more than 30 days and, severely, the trial participant being unable to work or carry out usual activities. Nearly half of the arm of Tinapanor in one of the pivotal trials required a dose change or discontinuation because of diarrhea, Selena Deconte, an FDA safety analyst, told the panel.
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