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

Abstract

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.

An expert update on novel therapeutic targets for hyperphosphatemia in chronic kidney disease: preclinical and clinical innovations

“…Growing evidence from animal experiments suggests that these current treatment options may be associated with maladaptive responses of the intestinal phosphate transport machinery that could add to clinically insufficient phosphate control in many patients. Tenapanor, a small-molecule NHE3 inhibitor, represents a new drug candidate with a mode of action that is distinct from phosphate binders and it has already demonstrated robust phosphate lowering activity in a short-term phase III study [100]. Nicotinamide, a modulator of the intestinal NaPi2b expression, has been evaluated in several clinical studies in recent years.…”

“…Still, the reduction of intestinal phosphate absorption is predominantly based on reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition. When tenapanor was administered to patients undergoing hemodialysis, the increases of both serum phosphate and FGF-23 were prevented in a dosedependent manner compared to placebo [99][100][101]. However, to date, we do not know whether tenapanor offers any added value compared to current standard of care (i.e.…”

Inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut: A new antihypertensive concept

“…Antihypertensive effects of intestinal NHE3-inhibiton could be of special interest in CKD-patients, in which conventional medical treatment strategies which often have renal targets lack efficiency. Even though intestinal NHE3-inhibition increased sodium stool content and decreased phosphate uptake in CKD-patients under hemodialysis, blood pressure was not reported to be affected by the treatment [36] , [37] . Nevertheless, blood pressure remains to be a difficult parameter to assess under hemodialysis and future clinical studies are warranted to investigate antihypertensive effects also in such special cohorts.…”

“…In addition to increased stool sodium excretion, tenapanor has also been found to increase the excretion of stool phosphate and as a result reduced serum phosphate concentrations which has beneficial implications for patients with CKD-related hyperphosphatemia [34] , [35] , [36] . In a randomized phase 3 trial in patients with CKD, tenapanor treatment for 8 weeks could reduce elevated serum phosphate levels while receiving maintenance hemodialysis [36] . Tenapanor however could in another CKD cohort not change interdialytic weigh gain despite of increased sodium stool content [37] .…”

Increase in phosphaturia by inhibition of renal sodium-dependent phosphate cotransporter NPT2a

“…In the gut, phosphate is absorbed by passive paracellular diffusion and active transcellular transport, mainly via NPT2b, the major sodium phosphate co-transporter in the small intestine (1). Active phosphate absorption is enhanced by 1,25(OH) 2 vitamin D. Intestinal phosphate absorption can be reduced by several approaches (1), including reduction of dietary phosphate intake, chelation of phosphate in the gut lumen (2), specific inhibition of NPT2b activity by small-molecule inhibitors (3), non-specific inhibition of NPT2b by niacin or its derivative nicotinamide (2), and reduction of passive paracellular phosphate flux via inhibition of the sodium/hydrogen exchanger 3 (4). The first two approaches are the mainstay of phosphate management in patients with chronic kidney disease (CKD), but are often insufficient to achieve optimal phosphate control.…”