Patients with chronic kidney disease being treated with dialysis are at risk of developing hyperphosphataemia. This elevation of phosphorus levels is associated with cardiovascular morbidity and mortality
It is typically treated with phosphate binders, although another approach would be to administer an inhibitor of paracellular phosphate absorption.
Ardelyx is developing a drug that acts in this way; tenapanor acts locally within the gut to inhibit sodium–hydrogen exchanger 3 (NHE3).1 It causes a conformational change in the epithelial cell junctions, reducing the paracellular uptake of phosphate via its primary pathway of absorption.
In a randomised, double-blind Phase III trial, 219 patients receiving maintenance haemodialysis with hyperphospataemia were given 3, 10 or 30 mg oral doses of tenapanor twice a day for 8 weeks.2
They were then rerandomised to receive the same dose or a placebo for a 4-week withdrawal period. Of the 152 patients who completed both study phases, all three treatment groups had significant decreases in mean serum phosphate of –1.00, –1.02 and –1.19 mg/dL, respectively.
In the withdrawal period, there was a mean increase of 0.85 mg/dL in the placebo group, compared with 0.02 mg/dL in the pooled tenapanor groups. The main adverse event was a softening in the stool and a modest increase in frequency of bowel movements, resulting from the drug’s mechanism of action.
Its effectiveness in combination with phosphate binders was also evaluated in a double-blind Phase III trial.3
The study enrolled 236 patients undergoing maintenance dialysis with hyperphosphataemia, with serum phosphorus levels of 5.5–10 mg/dL despite treatment with phosphate binders (including sevelamer, nonsevelamer or a combination).
Subjects were given 30 mg of oral tenapanor or a placebo twice a day for 4 weeks in addition to the phosphate binder.
Of the 228 patients who completed the treatment, those given tenapanor achieved a larger mean change in serum phosphorus concentration after 4 weeks, with a mean reduction of 0.84 mg/dL for the tenapanor group and a 0.19mg/dL mean drop for the placebo group.
The most common adverse event was diarrhoea, leading to four discontinuations in the tenapanor group and two in the placebo group.
Four further Phase III studies have been started in Japan by Kyowa Kirin. These include a double-blind parallel group comparative study, a phosphate binder combination parallel group comparative study, a single arm study in patients on peritoneal dialysis and a long-term study in patients switching form phosphate binders.