A group of FDA advisors 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 9-4, the Cardiovascular and Renal Drugs Advisory Committee on Wednesday said 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 do not tolerate currently approved agents for this indication.
And by a 10-2 vote (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 don't achieve adequate control of phosphorus levels on their current therapies.
The somewhat surprising recommendation comes a little more than a year after the FDA , citing uncertainty over the clinical significance of the treatment effect.
"Usually more choice is better," said C. Noel Bairey Merz, MD, from Cedars-Sinai Medical Center in Los Angeles, who voted "yes" on both questions and called for the use of shared decision-making when data are not ironclad. "I would favor this as an add-on therapy and as an alternative for folks who just cannot take existing therapy."
Patrick Nachman, MD, of the University of Minnesota in Minneapolis, voted "no" for tenapanor's use as monotherapy but "yes" as an add-on therapy.
"Recognizing all the limitations of our data, if there is a patient population that is likely to benefit from substantial reduction in serum phosphorus, it would be those who have very severe hyperphosphatemia or complications thereof," said Nachman. "Those patients are not likely to get control with monotherapy; they are likely to require multiple agents and if tenapanor can get them to the finish line, in addition to other agents, I think it's worth having that option on the table."
In its complete 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 unclear clinical significance." Wednesday's advisory committee meeting was convened in response to an appeal by Ardelyx, the manufacturer 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 FDA's assessment and voted "no" to both questions.
"I believe there are insufficient data to support the clinical benefits of this intervention," said de Boer. "I certainly understand the need and the desire for new tools, but I think we need tools that work for outcomes that matter."
A lower pill burden is an advantage of tenapanor over phosphate binders, and taking fewer, smaller pills "matters to almost all of our patients," said committee chair Julia Lewis, MD, of Vanderbilt Medical Center in Nashville, who voted in support of the drug.
She noted, however, that monotherapy treatment with tenapanor is problematic because of an effect size that is smaller than that with existing therapies.
"I agree that there's a small subset that will respond to monotherapy, but let's make that available to them," said Lewis.
Intent-to-treat analyses of the randomized trials supporting the drug's application for approval showed an average reduction in serum phosphorus level of approximately 0.7 mg/dL with monotherapy treatment, as compared with about 1.5-2.2 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 for those who did not tolerate phosphate binders, which unfortunately is a fair number. I see its usefulness more as add-on therapy, reflecting the difficulty in getting phosphorus down."
The difference in efficacy would translate to a 15% greater rate of morbidity and mortality in tenapanor recipients, based on observational data assessing the relationship between serum phosphorus levels and outcomes in adults with CKD on dialysis, said Scott Emerson, MD, PhD, of the University of Washington Seattle, though he cautioned about relying on observational data in the absence of clinical trial data linking therapeutic reductions in phosphorus levels with improvement in outcomes. Emerson voted to recommend approval of tenapanor as both monotherapy and combination therapy.
Is a 0.7 mg/dL reduction "enough when we're talking about a surrogate endpoint that has not been validated?" asked Christopher O'Connor, MD, from Inova Heart and Vascular Institute in Falls Church, Virginia, who ultimately voted "no" on both questions. "We're looking at an effect size that is, at best, 40% less than current therapies."
As add-on therapy, Emerson cited data showing that with tenapanor titration, an additional 20% of patients could achieve a target phosphorus level of <5.5 mg/dL. "I think this is the way it should be used, [and] is an important tool to have," he said.
At the meeting, Ardelyx showed data that responders can be identified early in the treatment course and that 79% who achieve an early response remain responsive at later time points.
"Given that I don't see a compelling safety problem, I would argue ... that approval of this would allow treating physicians the ability to put this in their arsenal, [and] identify people who seem to be responding," said Thomas Cook, PhD, of the University of Wisconsin-Madison, who voted in favor of tenapanor for both questions.
The risk imposed by diarrhea with tenapanor is minimal in a carefully 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, reminded Bairey Merz.
While the FDA is not required to follow the recommendations of its advisory committees, it usually does.