FDA panel approves kidney disease drug for serum phosphorus control

A group of FDA advisors has recommended approval of tenapanor (Ibsrela) for the control of serum phosphorus levels in adults with chronic kidney disease (CKD) on dialysis, both as a single agent and in combination with phosphate binder treatment.

By a vote of 9 to 4, the Cardiovascular and Kidney Drugs Advisory Committee said on Wednesday that the benefits of monotherapy treatment with the sodium/hydrogen exchanger 3 (NHE3) inhibitor outweigh its risks, primarily diarrhea, with panelists emphasizing the importance of having another option for patients who cannot tolerate agents currently approved for this indication.

And by a vote of 10 to 2 (with one abstention), the committee determined that the positive risk-benefit profile extended to its use in combination with phosphate binders, as a significant proportion of patients do not get adequate control of phosphorus levels on their skin. current therapies.

The somewhat surprising recommendation comes just over a year after the FDA tenapanor rejected for this indicationciting uncertainty about the clinical significance of the treatment effect.

“Usually more choice is better,” said C. Noel Bairey Merz, MD, of Cedars-Sinai Medical Center in Los Angeles, who voted “yes” on both questions and called for the use shared decision-making when the data is not ironclad. . “I would favor this as a complementary therapy and as an alternative for people who just can’t keep up with existing therapy.”

Patrick Nachman, MD, of the University of Minnesota in Minneapolis, voted “no” for using tenapanor as monotherapy but “yes” as an add-on therapy.

“Acknowledging all the limitations of our data, if there is one patient population that could benefit from a substantial reduction in serum phosphorus, it would be those with very severe hyperphosphatemia or complications thereof,” said Nachman. “These patients are not likely to achieve control with monotherapy; they will likely need multiple agents and if tenapanor can get them to the finish line, in addition to other agents, I think it is worth it. to have that option on the table.”

In its full response letter, the FDA had stated that although tenapanor reduces serum phosphorus in CKD patients on dialysis, “the magnitude of the treatment effect is small and of uncertain clinical significance.” . Wednesday’s advisory board meeting was called in response to a call from Ardelyx, the maker of tenapanor. (Tenapanor is currently approved for irritable bowel syndrome with constipation.)

Panelist Ian de Boer, MD, of the University of Washington in Seattle, sided with the FDA’s assessment and voted “no” to both questions.

“I think there is not enough data to support the clinical benefit of this intervention,” de Boer said. “I certainly understand the need and desire for new tools, but I think we need tools that work for results that matter.”

A lower pill burden is an advantage of tenapanor over phosphate binders, and taking fewer smaller pills “is important for almost all of our patients,” said committee chair Julia Lewis, MD, of Vanderbilt Medical Center. in Nashville, which voted in favor of the drug.

She noted, however, that monotherapy treatment with tenapanor is problematic due to an effect size that is smaller than that of existing therapies.

“I agree that there is a small subset that will respond to monotherapy, but let’s make this available to them,” Lewis said.

Intent-to-treat analyzes of randomized trials supporting the drug’s application for approval showed a mean reduction in serum phosphorus of approximately 0.7 mg/dL with treatment as monotherapy compared to approximately 1. 5 to 2.2 mg/dL with existing approved therapies.

Linda Fried, MD, MPH, of the University of Pittsburgh, said, “I see this drug [as monotherapy] would only be reserved for those who are intolerant of phosphate binders, which is unfortunately a reasonable number. I see its usefulness more as a complementary therapy, reflecting the difficulty in lowering phosphorus.”

According to Scott Emerson, MD, PhD, of the University of Washington Seattle, although he cautioned against relying on observational data in the absence of clinical trial data linking therapeutic reductions in phosphorus levels to the improved results. Emerson voted to recommend approval of tenapanor as both monotherapy and combination therapy.

Is a reduction of 0.7 mg/dL “enough when talking about a surrogate endpoint that has not been validated?” asked Christopher O’Connor, MD, of the Inova Heart and Vascular Institute in Falls Church, Va., who ultimately voted “no” on both questions. “We envision an effect size that is, at best, 40% lower than current therapies.”

As an add-on therapy, Emerson cited data showing that with tenapanor titration, an additional 20% of patients could achieve a target phosphorus level of

At the meeting, Ardelyx showed data that responders can be identified early in treatment and that 79% who achieve an early response remain responsive at later times.

“Given that I don’t see a compelling safety issue, I would say…approving this would allow treating physicians to put this in their arsenal, [and] identify people who seem to respond,” said Thomas Cook, PhD, of the University of Wisconsin-Madison, who voted tenapanor for both questions.

The risk imposed by diarrhea with tenapanor is minimal in a closely monitored population such as those with CKD on dialysis, several committee members said. Diarrhea is a known side effect of tenapanor since the agent is already approved for the treatment of irritable bowel syndrome with constipation, Bairey Merz recalled.

Although the FDA is not required to follow the recommendations of its advisory committees, it generally does.

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