After 2 rejections, FDA panel rallies around Ardelyx's kidney disease prospect

Upon weathering a pair of surprise kidney disease snubs this year and last, Ardelyx managed to wrangle a high-stakes FDA hearing to present its case for NHE3 inhibitor tenapanor. Wednesday, the medicine’s judgment day arrived. And, after roughly eight hours of deliberation, tenapanor seems to have gained some regulatory ground.

After hearing the case for—and against—the drug's application to control serum phosphorous in adults with chronic kidney disease (CKD) on dialysis, nine members of the FDA’s Cardiovascular and Renal Drug Advisory Committee voted in favor of Ardelyx’s drug. The remaining four panelists voted against tenapanor’s use as a monotherapy.

When the prospect of combining tenapanor with the current standard of care for hyperphosphatemia—phosphate binders—was raised, the panel of experts was even more optimistic: 10 members of the advisory committee voted yes, with only two nos and one abstention.

In CKD patients, hyperphosphatemia refers to a buildup of serum phosphorous, which can cause blood calcium levels to drop, potentially leading to muscle cramps or spasms, rashes, bone and joint pain and more.

Following the positive vote, the FDA’s Office of New Drugs is expected to respond to Ardelyx’s approval appeal by mid-December, the company said in a release.The agency first rejected Ardelyx's drug last summer and did so again in February. Tenapanor is already approved as Ibsrela in irritable bowel syndrome (IBS), though it would carry a different name if cleared to control phosphate levels in CKD patients.

One panelist, C. Noel Bairey Merz, M.D., of Cedars-Sinai Medical Center in Los Angeles, endorsed tenapanor alone and in tandem with phosphate binders. She reasoned there’s a large number of patients who are "unable or unwilling to take the standard of care right now.”

CKD patients trying to manage their phosphorous levels with phosphate binders must take a surfeit of meds. Ardelyx estimates those patients take a median of 19 pills each day.

Aside from the inconvenience of current status quo therapy, some 42% of patients on phosphate binders fail to adequately control their condition in any given month, the company estimates. Over a six-month stretch, that proportion of patients rises to 77%.

“The current status quo is not tenable,” added another voting member, Paul Conway of the American Association of Kidney Patients.

Overall, the yay-sayers on the advisory committee generally agreed tenapanor would provide doctors and patients with another useful tool to control serum phosphorous. While the med’s benefit may not be huge, it carries a convenience edge over phosphate binders and is largely safe enough not to raise concerns.

A tenepanor approval as either a monotherapy or in combination with binders "would be a win for patients," Ardelyx CEO Mike Raab said over email. He added that the company will "continue to seek the broadest label we can for Xphozah," referring to the candidate by its proposed commercial name. 

Some experts still harbor doubts, however. Take Javed Butler, M.D., of the University of Mississippi and the Baylor Scott and White Research Institute, who issued a “reluctant” yes in response to both voting questions. Citing an “acceptable” safety profile, Butler said the bigger issue at play is “this field probably deserves a higher bar for efficacy.” At the same time, he noted that the data on tenapanor “[meet] the precedent of what has been done previously in this area.”

He agreed with other panelists that only a “small subset” of CKD patients would benefit from a tenapanor monotherapy, but he figures patients deserve another option regardless.

On the flip side, tenapanor’s “modest” efficacy informed the monotherapy no vote from the Inova Heart and Vascular Institute’s Christopher O’Connor, M.D. The expert took issue with Ardelyx’s trial design and suggested the company run another study.

Still, it now looks "highly unlikely" that Ardelyx will need to run additional studies before it can reapply at the FDA, the company's CEO Raab added. He caveated that Ardelyx "won't have complete certainty until after we receive a response from the Office of New Drugs."

Ardelyx has been working hard to redeem its drug after an initial rejection last summer, which came as a shock to both analysts and the company. Ardelyx’s therapy received another rejection in February after the company appealed its complete response letter from the FDA.

Undiscouraged, the fledgling commercial player moved to summon an advisory committee, and its request was granted in April. As recently as Monday, the FDA seemed to be telegraphing yet another dismissal of the med.

Now, in light of Wednesday’s decision, Ardelyx is more determined than ever to see tenapanor through to the serum phosphorous finish line. "We are really pleased," Raab said. "Our mission was to clearly communicate our data, and we believe we succeeded with that."

Tenapanor's next test will come in December, where Raab foresees at least two "potential favorable" outcomes on its regulatory appeal. 

"First, if the appeal is granted, the NDA resubmission would likely take us directly to labeling discussions with the FDA," he explained. The second scenario would see the appeal denied but "with a clear path forward articulated in the letter" from the Office of New Drugs, Raab said. 

“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,” the CEO noted.

Editor's note: This story was updated with comments from Ardelyx CEO Mike Raab.