Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial

Significance Statement Phosphate binders are currently the only medications available to reduce elevated serum phosphate in patients with ESRD receiving hemodialysis. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), acts via a non–phosphate-binding mechanism, reducing paracellular phosphate transport in the intestine. The authors found that tenapanor significantly lowered elevated serum phosphate in patients receiving hemodialysis, resulting in a mean reduction of 1.0–1.2 mg/dl over 8 weeks. Tenapanor also showed a significant benefit over placebo in patients rerandomized to either continue tenapanor treatment or receive a placebo for 4 weeks. Adverse effects were largely limited to softening of stool and more frequent bowel movements. By targeting paracellular phosphate transport’s substantial contribution to net phosphate absorption in the gut, tenapanor has the potential to improve management of mineral bone disorder in CKD. Background Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport. Methods In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week ‘withdrawal’ period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group. Results Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor’s mechanism of action. Conclusions Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.