On Nov.16, the FDA’s Cardiovascular and Renal Drug Advisory Committee will meet to assess the data supporting Ardelyx's New Drug Application for tenapanor in chronic kidney disease.
Tenapanor, a sodium hydrogen exchanger 3 inhibitor, is being evaluated for the control of serum phosphorus in adult patients with CKD who are on dialysis.
Specifically, the Committee will determine whether the size of the treatment effect on serum phosphorus is clinically meaningful and if the drug’s benefits outweigh its risks.
The FDA is giving disease experts, health care providers and patients until Nov. 1 to weigh in on tenapanor. Comments received will be considered during the adcomm.
The central question is, how is ‘clinical meaningfulness’ defined in this patient population?
At the American Society of Nephrology’s Kidney Week 2022, Nov. 3-6, there are multiple panels focused on this very topic.
People who have been diagnosed with CKD are unable to remove excess levels of phosphorous from the body. Phosphorous levels that are too high, an indication called hyperphosphatemia, lead to a loss of calcium in the bones, which causes them to weaken. Beyond that, the calcium that is leached from the bones is deposited in other parts of the body, particularly blood vessels and organs.
Those calcium buildups cause the blood vessels to lose flexibility, which increases cardiovascular events, said Dr. Kamyar Kalantar-Zadeh, M.D., Ph.D., a nephrologist and professor of public health at UCLA’s Fielding School of Public Health, in an interview with BioSpace.
Studies have consistently shown a correlation of high phosphorous levels and mortality in CKD patients, Kalantar- Zadeh said. While this is well known, managing phosphorous levels is not easy.
Tenapanor is designed to control serum phosphorus by inhibiting the sodium hydrogen exchanger 3.
A Rough Regulatory Path
Last year, the FDA issued a Complete Response Letter for tenapanor despite the drug hitting its primary endpoint in late-stage studies.
Ardelyx conducted three Phase III tenapanor studies. The PHREEDOM study looked at tenapanor as a monotherapy, while the AMPLIFY trial assessed the drug in combination with phosphate binders. As BioSpace previously reported, each study hit its primary and secondary endpoints.
While the clinical data showed tenapanor reduces serum phosphorus in CKD patients on dialysis, the regulator called the results “small and of unclear clinical significance.”
Undeterred by the CRL, Ardelyx has continued to push for potential approval in this indication.
When the adcomm meets, experts in the field will provide their input into the clinical meaningfulness of the phosphate-lowering effect the company reported in Phase III.
While the merits of tenapanor may be at issue for regulators, the high unmet need in this indication is not.
An Urgent Patient Need
To control phosphorous levels, CKD patients are required to maintain a strict diet and take phosphorous-binding drugs with their food. A nurse dietician, Rory Pace is quite familiar with this limited diet.
Pace is senior director of nutrition services at Satellite Healthcare. There, she guides practice for over 100 nephrology dietitians across the United States.
Not only is phosphorous naturally found within the majority of foods we consume, but Pace told BioSpace it can also be added into foods along with other preservatives.
“Patients are just bombarded by phosphorous in their food,” she said. “Then they come to dialysis and we try to give them the best treatment we can. But dialysis won’t remove phosphorous levels.”
As a dietician, Pace tries to help patients understand what foods are better to eat and the importance of reading labels. Still, it remains a challenge for these patients to control their levels – even when phosphorous-binding drugs are added into the equation.
“Phosphorous control is not just done through dietary restrictions. Phosphorous binders bind it in the gut so less phosphorous is absorbed,” Kalantar-Zadeh noted.
The dietary restrictions aimed at lowering serum phosphorous levels deprive patients of important nutritional requirements, he added. Foods that must be avoided are often high-protein foods, including meat, fish, cheese and other dairy products. Not only that, Kalantar-Zadeh, who provides direct care to more than 60 dialysis patients at any given time, said their quality of life is significantly reduced.
“Enjoying food and diet is an important quality of life and we are impacting that through these strict controls,” he said. “If you tell patients their phosphorous is high, they can no longer go and enjoy pizza with their children.”
A Pill Burden
Beyond the controlled diet, patients often rely on phosphorous binders that must be taken with each meal. Each meal typically requires multiple pills. That means that throughout the day, depending on how much they eat, patients will take 10 or more pills. This creates a pill burden.
Despite the numerous binder options, it’s estimated that 77% of patients who take these medications are unable to maintain target phosphorus levels despite active treatment.
Beyond the pill burden, other side effects of phosphorous binders can include bloating and constipation, said Dr. Jay Wish, M.D., professor of clinical medicine at Indiana University School of Medicine and chief medical officer for outpatient dialysis at Indiana University Health. Wish was not involved in the clinical development of tenapanor.
While phosphate binders can remove levels of phosphate associated with a meal that a patient will consume, they do not reduce current levels of serum phosphate in the body. That’s where a drug like tenapanor can come into play, Wish said, adding that the drug shows a robust effect on reducing those levels.
Tenapanor has already been approved by the FDA as a treatment for irritable bowel disease with constipation. It’s known to cause diarrhea in patients, and Wish said CKD patients who suffer from constipation due to the binders might welcome that side effect.
“Diarrhea is in the eye of the beholder. It’s the combination of the diarrhea effect of the tenapanor and binders that may make Goldilocks’ porridge just right,” he quipped.
The treatment regimen for tenapanor, should it be approved in this indication, would likely be one or two pills per day. Both Wish and Kalantar- Zadeh said the twice-per-day regimen would be more patient-friendly, given the reduction in the number of required pills. Noting there will be no “magic bullet treatment,” Wish said that binders may continue to be prescribed alongside tenapanor, particularly in the more serious cases.
Like Wish, Kalantar- Zadeh has not been involved with the evaluation of tenapanor. But, the literature shows the potential, he said.
“Any innovative intervention for pharmacological therapy that can improve phosphorous management that can give patients back their quality of life… and allow them the freedom to enjoy protein, healthy foods - that would be the solution,” he continued. “Tenapanor has shown its potential. One or two pills per day that could help with the lowering of phosphorous, this could be a paradigm shift.”
https://www.biospace.com/article/ardelyx-s-ckd-drug-to-face-adcomm-following-asn/
