FDA: Ardelyx phosphorus control drug tenapanor lacks ‘clinical significance’
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While acknowledging the “substantial evidence” presented by Ardelyx Inc. in its new drug application for tenapanor, the FDA said in a letter to the pharmaceutical company that the phosphorus control drug lacked “clinical significance.”
According to the complete response letter, Ardelyx Inc. said that while the FDA agrees "the submitted data provide substantial evidence that tenapanor is effective in reducing serum phosphorus in [chronic kidney disease] CKD patients on dialysis," the agency characterized the magnitude of the treatment effect as "small and of unclear clinical significance," the company said in a press release.
Additionally, Ardelyx said the FDA is requiring the company to “conduct an additional adequate and well-controlled trial demonstrating a clinically relevant treatment effect on serum phosphorus or an effect on the clinical outcome thought to be caused by hyperphosphatemia in CKD patients on dialysis."
Ardelyx saw a 70% drop in its stock value on July 19 after announcing the FDA had “identified deficiencies” in the company’s NDA for tenapanor.
"We are saddened by this communication from the FDA and what it means for the patients and the physicians who treat them," Mike Raab, president and CEO of Ardelyx, said in the release. "We continue to believe tenapanor represents an important, first-in-class treatment option for patients with elevated phosphorus.”
Ardelyx submitted an NDA for tenapanor in June 2020. In April 2021, the company said the FDA extended the Prescription Drug User Fee Act date to July 29, following the submission of additional analyses.
“We do not agree with the FDA's subjective assessment on the clinical relevance of the treatment effect of tenapanor in our studies which met all clinical endpoints agreed upon by the FDA,” Raab said in response to the FDA letter. “In our view, the serum phosphorus lowering data generated with tenapanor in all of our clinical studies is meaningful and clinically significant. We will work with the agency to address the issues raised and, to the extent possible, find an expeditious path forward."
There were no safety, clinical pharmacology/biopharmaceutics or non-clinical issues identified in the complete response letter, Raab said. Clinical trials for tenapanor included 1,000 patients and three phase 3 clinical trials, all of which met primary and key secondary endpoints, according to the release.
Raab said the FDA indicated in the letter it is willing to meet with Ardelyx to discuss the application.
Arnold Silva, MD, PhD, director of clinical research at Boise Kidney and Hypertension Institute, said in the release, “I've seen the clinical benefits of tenapanor first-hand in my patients and I'm stunned that the FDA is not granting approval of this novel mechanism drug, despite extensive clinical data demonstrating its safety and efficacy."
Perspective
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Chris Gisler, MD
On July 10, 2019, the White House and HHS introduced the Advancing American Kidney Health Initiative with the goal of preventing kidney failure through better diagnosis, treatment and preventative care.
Regardless of one’s political preference, this was a landmark movement, calling attention to the importance of caring for kidney patients prior to dialysis and to explore opportunities to increase home modality utilization, to expand opportunities for transplantation and even further research on artificial kidneys.
For many nephrologists, this initiative represented a renaissance in the care of kidney patients. With more enthusiasm came additional therapeutic research from new pharmaceutical companies.
Unfortunately, recent decisions by the FDA seem to be in discord with the spirit of the Advancing American Kidney Health Initiative (AAKH) and have hampered the nephrologist’s access to new medications.
Most recently, the FDA failed to approve veverimer (TRC101, Tricida) and tenapanor (ibsrela, Ardelyx).
Metabolic acidosis
The treatment of metabolic acidosis has been shown to slow the progression of kidney disease, decrease muscle degradation and decrease osteoclast activity. A therapeutic that can treat metabolic acidosis has the potential to slow progression of chronic kidney disease and to improve the functional status of patients.
Veverimer is a first in class drug that represented a significant advance over the current practice of using sodium bicarbonate, a therapy that was not particularly effective and that provided the patient with an excessive sodium load. Despite having strong efficacy data and a favorable side effect profile, veverimer was not approved by the FDA in August 2020 and turned down again after an appeal by Triceda in February. As a result, nephrologists are forced to balance bicarbonate levels with hypertension and volume management.
Hyperphosphatemia
Hyperphosphatemia remains a difficult disease to treat in patients with end-stage renal disease. Data from the Dialysis Outcomes and Practice Patterns Study demonstrate that management of hyperphosphatemia has worsened in recent years with fewer patients at goal for phosphorus levels.
Like ESRD, hyperphosphatemia is a socioeconomic disease, striking hardest at the underserved given the relative affordability of foods which use phosphorus as a preservative when compared to healthier options.
The FDA’s failure to approve tenapanor, which targets the paracellular pathway of phosphorus absorption, was even more perplexing than veverimer. The studies performed by the developing company, Ardelyx, were co-designed by the FDA and met all specified primary endpoints.
Depending on the study, phosphorus levels improved by 0.82-1.37 mg/dL when compared to placebo. No significant safety issues were identified; in fact, the medication has already been approved by the FDA for treatment of irritable bowel syndrome
The FDA determined these results not to be significant, but the majority of practicing nephrologists would consider lowering phosphorus by 1 mg/dL to be a success. While tenapanor is unlikely to completely replace phosphorus binders, it represents an excellent option in the management of metabolic bone disease, particularly for patients who are intolerant of binders or not at goal on maximum doses of binders.
Failure to approve appropriate medications not only affects the current kidney disease population but also impacts future generations of patients. The FDA has sent a clear message to pharmaceutical companies and investors that accepting the challenge of the AAKH initiative may be a fruitless endeavor. Small start-up companies will not have the opportunity to innovate.
As patient advocates, nephrologists need to question the FDA’s credibility and decisions in not making these medications available to improve the care of kidney disease.
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