Hyperphosphatemia in Chronic Kidney Disease: The Search for New Treatment Paradigms and the Role of Tenapanor

Figures & data

Figure 1 Schematic representation of intestinal phosphate transport.

Notes: Phosphate is absorbed through two different mechanisms in the gastrointestinal tract. Active transcellular transport involves specific transporters such as the sodium-dependent phosphate 2b transport protein (NaPi2b), which can be inhibited by some molecules currently under evaluation for hyperphosphataemia management (Niacin and Nicotinamide in rat models, DS-2330b and ASP3325 in clinical studies). Passive paracellular phosphate transport happens through tight junction complexes along the concentration gradient and involves the sodium/hydrogen exchanger isoform 3 (NHE3), which transports sodium ions into cells in exchange for hydrogen ions; it has been reported that NHE3 inhibition by Tenapanor induces not only a sodium and water retention in the lumen but also an intracellular proton retention with following pH-related conformational change in specific tight junction proteins called claudins and reduction in the transepithelial permeability to phosphate.

Table 1 Clinical Trials Evaluating the Effects of Tenapanor in Haemodialysis Patients

Ref.	Study Design	Population	Active Treatment	Control	Follow-Up Duration	Main Results
75	Phase 2 multicentre randomized, double-blind, placebo-controlled study	162 HD pts with hyperphosphataemia (of whom 115 completed the study)	Six tenapanor regimens (3 or 30 mg once daily or 1, 3, 10, or 30 mg twice daily)	Placebo	4 wks	Dose-dependent reduction in serum phosphate Most common adverse event in the active group: diarrhoea
77	Phase 2, double-blind, parallel-group, dose-finding study	207 HD patients with hyperphosphataemia	4 groups (Tenapanor 5 mg twice daily, 10 mg twice daily, 30 mg twice daily or 30 mg twice daily dose-titration)	Placebo	6 wks	Dose-responsive serum phosphate-lowering action Most common drug-related adverse event: diarrhoea, mostly mild and tolerable
78	Phase 3 randomized, double-blind trial	219 randomized HD pts with hyperphosphataemia (of which 152 completed both study phases)	Twice-daily oral tenapanor (3, 10, or 30 mg for 8 wks) Rerandomization of pts to previously assigned dose or placebo for a 4-wk withdrawal period	Placebo	8 wks + 4 wks	Significant reduction in mean serum phosphate (decrease of 1.00, 1.02, and 1.19 mg/dl in the three dose groups) Mean increase of 0.85 mg/dl in the placebo group vs a mean increase of 0.02 mg/dl in the pooled active group Adverse events: softened stool, slight increase in bowel movement frequency
79	Phase 3 double-blind trial	236 HD pts with hyperphosphatemia already treated with phosphate binders (of which 235 included in the full analysis and 228 completed treatment period)	Twice-daily oral tenapanor 30 mg plus phosphate binder	Placebo plus phosphate binder	4 wks	Greater mean change in serum phosphorus levels in the tenapanor plus binder group compared to placebo plus binder group (−0.84 vs - 0.19 mg/dl, P < 0.001) Most common adverse events in the active group: diarrhoea, nausea
80	Double-blind, multicentre, randomized trial	47 HD pts with hyperphosphataemia not responding to phosphate binders	Twice-daily tenapanor 30 mg plus phosphate binder	Placebo plus phosphate binder	6 wks	Decrease in mean serum phosphorus from 6.77 mg/dL to 4.67 mg/dL in the tenapanor group and from 7.01 mg/dL to 6.69 mg/dL in the placebo group Most common adverse event: diarrhoea (65.2% and 8.3% of pts in the tenapanor and placebo groups, respectively)
81	Multicentre, phase 3 trial	564 HD pts with hyperphosphataemia and 1.5 mg/dl phosphate increase after phosphate binder washout	Twice daily tenapanor 30 mg for 26 wks, then rerandomization to tenapanor or placebo for 12 weeks and eligibility for the 14-wk safety extension period	Sevelamer carbonate	52 wks comprising three periods: - a 26-wk open-label randomized therapy period - a 12-wk double-blind placebo-controlled randomized withdrawal period - a 14-wk open-label safety extension period	Statistically significant difference in estimated mean change in serum phosphate level between tenapanor and placebo (−1.4 mg/dl, P < 0.0001) Most frequent adverse event in tenapanor group: loose stools; serious adverse events more common in the sevelamer carbonate group

Abbreviations: HD, haemodialysis; pts, patients; wks, weeks.