Ardelyx does 'not agree' with FDA's view after agency rejects blockbuster prospect—and one analyst is 'flummoxed'

Ardelyx has suffered a setback in its quest to advance chronic kidney disease (CKD) candidate tenapanor.

The FDA bounced back Ardelyx’s application for tenapanor to control serum phosphorus in CKD patients on dialysis, the company said Thursday. Already approved as Ibsrela, the NHE3 inhibitor scored its first green light to treat irritable bowel syndrome (IBS) with constipation back in September 2019.

After a positive phase 3 trial in CKD back in 2019, analysts had thought the drug might reach blockbuster heights. Now, Ardelyx will have to work through the FDA's concerns to try and realize that goal. The decision comes as a shock, and Ardelyx isn't the only one feeling "flummoxed" by the regulator's view. 

There’s a little bit of phosphorous in everyone’s blood, but patients with kidney disease often have trouble clearing the mineral, which can lead to an excess known as hyperphosphatemia. In some CKD patients, high phosphate levels can cause blood calcium levels to drop, potentially leading to muscle cramps or spasms, rash, bone and joint pain, and more. 

RELATED: AstraZeneca, FibroGen hit another roxadustat setback as FDA panel calls for more safety data

Ardelyx’s data offered “substantial evidence” that tenapanor reduces serum phosphorous in those patients, the FDA acknowledged. But in a complete response letter, the agency characterized the treatment effect as “small and of unclear clinical significance,” according to the biotech.

Before Ardelyx can reapply for approval, the company needs to run another study to confirm the drug's “clinically relevant treatment effect," the FDA said in its CRL. To right the ship, Ardelyx says it will request a meeting with the FDA “as soon as possible” to discuss the letter and hash out next steps.

Despite the setback, Ardelyx still believes its drug candidate is an important first-in-class prospect for CKD patients with high phosphorous levels, Mike Raab, president and CEO at Ardelyx, said in a statement.

“We do not agree with the FDA's subjective assessment on the clinical relevance of the treatment effect of tenapanor,” the CEO said. Ardelyx’s studies “met all clinical endpoints agreed upon by the FDA," he added.

RELATED: AstraZeneca's diabetes drug Farxiga nabs coveted kidney disease nod, way ahead of rival Jardiance

The letter didn’t raise any issues related to clinical pharmacology or biopharmaceutics, manufacturing or nonclinical problems, Ardelyx said.

Some analysts share the company's confusion. A Piper Sandler team led by Christopher Raymond said it was "flummoxed" by the FDA's "conflicting messaging" around tenapanor's application. Given the drug's success in the clinic and the fact that Ardelyx entered labelling negotiations with the FDA earlier this year, the analysts were "shocked to see such capriciousness from what we’ve heretofore seen as a shining example of regulatory excellence." 

The Piper Sandler team complemented Ardelyx's "perseverance" in continuing to work with the FDA on its application, noting that few renal pipeline prospects are "more highly anticipated among nephrologists" than tenapanor. The FDA's "nonsensical" decision may add to "a growing mistrust" of the FDA and a "feeling that the agency is not prioritizing physicians or patients," the analysts said. 

The case for tenapanor in CKD looked good back in December 2019, when Ardelyx posted its second phase 3 trial win for the drug. Topline data showed that 77% of tenapanor patients experienced a mean 2.0 mg/dL drop in serum phosphorus from baseline. 

At the time, Raymond suggested the new indication could lift the med to blockbuster heights. 

The drug was up for an FDA decision on July 29, three months later than the company and FDA had originally planned. Ardelyx in late April said the FDA had extended its review and asked the company for additional analyses to help it get a sense of the clinical data "in light of tenapanor's novel mechanism of action as compared to approved therapies."

Editor's note: This story was updated to clarify that the FDA approved Ibsrela in 2019, but Ardelyx has not launched it as a commercial product.