Tenapanor significantly reduced elevations in serum phosphate levels of patients undergoing maintenance dialysis for end-stage renal disease (ESRD) and was associated with infrequent adverse events in a phase 3 clinical trial.
"I am extremely excited about the therapeutic potential of tenapanor in patients with advanced chronic kidney disease. Tenapanor is not a phosphate binder but rather a novel agent that inhibits the intestinal absorption of phosphorus," senior author Glenn Chertow, MD, MPH, from the Department of Medicine at Stanford University, California, said in a news release.
The study, by first author Geoffrey A. Block, MD, vice president, Reata Pharmaceuticals, Inc, Golden, Colorado, and colleagues, was published online March 7 in the Journal of the American Society of Nephrology.
The researchers conducted a double-blind trial in which they randomly assigned patients to receive one of three doses of tenapanor or placebo twice daily for 8 weeks (randomized treatment period; RTP). Patients in the tenapanor groups received 3 mg (n = 74), 10 mg (n = 73), or 30 mg; doses were down-titrated if necessary (n = 71). To be eligible for the trial, patients had to have been receiving maintenance dialysis for at least 3 months, and their serum phosphate concentrations had to be from 4.0 to 7.0 mg/dL despite regular treatment with a phosphate binding medication.
The study's primary endpoint — as revised by the US Food and Drug Administration (FDA) before the analysis of any efficacy data — was mean change in serum phosphate during the 4-week withdrawal period for those who received tenapanor (using pooled data) compared with those in the placebo group.
A secondary efficacy outcome was the proportion of patients with serum phosphate concentrations lower than 5.5 mg/dL during the RTP.
Patients in all three tenapanor groups experienced significant drops in mean serum phosphate (reductions of 1.00 mg/dL, 1.02 mg/dL, and 1.19 mg/dL among those in the 3-mg, 10-mg, and 30-mg dose groups, respectively).
At the end of 8 weeks, the investigators randomly reassigned patients in the active drug groups to receive either the dose they had been previously assigned (n = 82) or placebo (n = 82) for 4 weeks (randomized withdrawal period; RWP). The patients' serum phosphate concentrations were measured throughout the trial.
During the 4-week RWP, those in the pooled tenapanor group experienced a mean increase in serum phosphate of 0.02 mg/dL, vs a mean increase of 0.85 mg/dL in the placebo group.
Diarrhea was the most commonly reported adverse event and led 18 patients (8.3%) to discontinue the study.
"It's a very small pill, and there is very minimal dyspepsia, nausea, or vomiting," said Anjay Rastogi, MD, PhD, clinical chief of nephrology, University of California, Los Angeles, who was not involved in the trial.
"Hyperphosphatemia is a very big challenge in nephrology," said Rastogi. Diabetes is "the biggest cause of kidney failure in the United States," and for patients with both diabetes and kidney failure, who also often have cardiovascular disease, "their eating options become very limited.... Phosphorous is in all the food. One of the challenges...is making sure that they stay adherent to their diet but also don't get malnourished and [that they] have a decent quality of life," he explained.
Strengths of the study include a diverse patient population and the ability to titrate down the highest study dose if patients experienced severe gastrointestinal effects. Adherence to study dosing was "excellent," the authors write.
One study limitation is the fact that the FDA asked the researchers to revise the primary outcome from change in serum phosphate between baseline and RTP completion to change in serum phosphate between end of RTP and RWP completion. In addition, the study's primary efficacy endpoint (mean change in serum phosphate) is a surrogate endpoint.
The researchers say taking one small tablet twice daily will reduce patients' pill burden dramatically compared with having to take as many as a dozen phosphate binder pills each day. However, it is unclear what proportion of patients might be successfully treated with tenapanor monotherapy.
"One conclusion from this body of work is the erroneous and pejorative labelling of patients as 'non-compliant' when their serum phosphate fails to conform to clinical expectations despite prescribed phosphate-restricted dietary limits and phosphate binders. The nearly universal finding that phosphate binders provide a maximal serum phosphate reduction of approximately 2.0 mg/dL at their highest dose suggests that novel mechanisms will be required to achieve further improvements in population phosphate control," the authors explain.
The study was funded by Ardelyx. Block has received consulting fees from and has ownership interest in Ardelyx. Rosenbaum and Yan are employees of and have ownership interest in Ardelyx. Chertow reports receiving consulting fees and owning stock in Ardelyx. Rastogi has disclosed no relevant financial relationships.
J Am Soc Nephrol. Published online March 7, 2019. Abstract
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Cite this: Tenapanor Reduces Serum Phosphate in Patients on Dialysis - Medscape - Mar 08, 2019.