Updated: In surprise turn, FDA adcomm votes in favor of Ardelyx CKD drug despite agency questions
After the FDA rejected and questioned Ardelyx’s potential drug for the control of serum phosphorus levels in adults with chronic kidney disease on dialysis, the FDA’s Cardiovascular and Renal Drugs advisory committee on Wednesday voted 9-4 in favor of the drug as a monotherapy, and 10-2 (with one abstention) in favor of the drug when administered in combo with phosphate binder treatment.
Adcomm committee chair Julia Lewis of Vanderbilt Medical Center said the drug, known as tenapanor, offers smaller pills, and although it may see less efficacy than the current standard of care, there’s a small subset of CKD patients who will respond to monotherapy and “let’s make that available to them.”
Panelist Edward Kasper, professor in cardiology at Johns Hopkins, also voted in favor of it as a monotherapy, calling the safety questions around severe diarrhea acceptable given how closely this population will be monitored, and he said there’s clearly a role for this drug. Others who voted against tenapanor as a monotherapy raised questions about the magnitude of the effect of the drug.
In after-hours trading yesterday evening, Ardelyx’s stock price rose by as much as 75%. The FDA’s Office of New Drugs is expected to provide a response to Ardelyx’s appeal to its earlier CRL within 30 days, the company said.
“Today’s vote by the CRDAC is a promising development for the chronic kidney disease community, as patients continue to struggle to control serum phosphorus levels despite use of currently available therapies, which are all limited to the phosphate binder class,” Mike Raab, president and CEO of Ardelyx, said in a statement. “We are confident that the data from three Phase 3 clinical trials involving more than 1,200 patients support the approval of XPHOZAH in the U.S. for the control of serum phosphorus in adult patients with CKD on dialysis.”
Debate during the morning Wednesday centered on FDA’s questions around the magnitude of benefit of the drug in the pivotal trials.
But Ardelyx made the case that tenapanor, which is already approved for irritable bowel syndrome with constipation in adults, can help what is a significant unmet need for new options to control serum phosphorus levels. Even the FDA’s initial rejection letter in 2021 said that the submitted data “provide substantial evidence that tenapanor is effective in reducing serum phosphorus in CKD patients on dialysis,” Ardelyx’s presentation said.
FDA, however, pointed to a mean treatment effect for tenapanor in this population of −0.7 mg/dL in both monotherapy studies, which “appeared to be less than that observed with approved agents (~1.5 to 2.2 mg/dL).” And for tenapanor use in combination with phosphate binder treatment, the FDA said the magnitude of the treatment effect was similar to that observed in the monotherapy trials.
Even still, in the committee’s discussion, panelists reiterated that there would be a subset of patients who will benefit from Ardelyx’s pill, particularly those who can’t tolerate phosphate binders that are large and difficult to swallow (although pill burden wasn’t tabulated) and have to be taken mid-meal, according to some of the public comments.
Adcomm panelist Susan Mendley of the NIH’s Division of Kidney, Urologic and Hematologic Diseases, who voted in favor of tenapanor as monotherapy, noted that while oral phosphate binders have shown a larger effect size, many patients don’t tolerate them, and they’re not pleasant to take. As a monotherapy in the right patient, “I think they have met their outcome,” 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 has not been validated. We have to talk about the clinical meaningfulness we have, and I’m concerned it may not be there.” FDA briefing documents raised similar questions about the magnitude of the treatment effect.
Adcomm member Linda Fried of the University of Pittsburgh, who voted in favor of the drug’s risk-benefit profile, said she doesn’t see tenapanor much as a monotherapy except in those who don’t tolerate the phosphate binders.
Safety concerns from FDA honed in on bothersome and sometimes severe diarrhea, with the majority of cases lasting more than 30 days, and with severe meaning the trial participant was unable to work or conduct usual activities. Almost half of the tenapanor arm in one of the pivotal trials required a change of dose or discontinued because of diarrhea, FDA’s safety analyst Selena DeConti told the committee.
Editor’s note: Article updated with comment from Ardelyx and the change in stock price.