ABSTRACT
INTRODUCTION: Simplified, but effective, hyperphosphatemia treatments with novel mechanisms of action, tolerable safety profiles, and low pill burden are needed for patients undergoing hemodialysis. Tenapanor is a calcium (Ca)-free, nonmetal, nonpolymeric drug that reduces phosphate absorption by selectively inhibiting intestinal sodium-hydrogen exchanger 3. As the serum phosphorus (P) level-lowering effect of tenapanor has not been evaluated in Japanese patients with hyperphosphatemia undergoing hemodialysis, we evaluated its efficacy and safety in this population. METHODS: This was a multicenter, phase 2, double-blind, placebo-controlled, parallel-group, dose-finding study. Change in serum P level from baseline at week 6 was the primary end point. RESULTS: Overall, 207 patients were randomized to 5 groups (placebo [n = 41] and tenapanor 5-mg taken twice daily [BID] [n = 42], 10-mg BID [n = 41], 30-mg BID [n = 42], and 30-mg BID dose-titration [n = 41]) and treated for 6 weeks. Mean changes from baseline at week 6 in serum P level were 0.64, -0.93, -1.36, -1.92, and -1.99 mg/dl in the placebo and tenapanor groups, respectively. Serum P level was significantly decreased from baseline in all tenapanor groups compared with placebo (P < 0.001, for each dose). Diarrhea was the most frequent drug-related adverse event (AE) with an incidence of 9.8%, 50.0%, 65.9%, 76.2%, and 65.9% in the respective placebo and tenapanor groups. CONCLUSION: In Japanese patients undergoing hemodialysis, tenapanor was found to have a dose-responsive, serum P level-lowering effect. Diarrhea was the most frequent drug-related AE; most cases were mild and generally tolerable. Tenapanor may become a first-in-class therapeutic agent for patients with hyperphosphatemia.
ABSTRACT
INTRODUCTION: Phosphate binders are used to treat hyperphosphatemia. Some patients have inappropriately controlled serum phosphorus levels, which may occur for many reasons, including a high pill burden and adverse events (AEs). Tenapanor selectively inhibits the passive paracellular transfer of phosphate in the gastrointestinal tract, thereby reducing serum phosphorus levels. This novel mechanism of action may contribute to improved phosphate management. The efficacy and safety of tenapanor have not been evaluated in Japanese patients with high serum phosphorus levels despite treatment with phosphate binders. This study aimed to assess the efficacy and safety of add-on tenapanor therapy for reducing serum phosphorus levels in this population. METHODS: This multicenter, double-blind, randomized, placebo-controlled trial enrolled patients with refractory hyperphosphatemia undergoing hemodialysis. Patients were randomly assigned in a 1:1 ratio to receive tenapanor or placebo as an add-on to their phosphate binder regimen for 6 weeks. Change in serum phosphorus levels at week 6 (day 43) compared with the baseline value (day 1, week 0) (primary endpoint), achievement of target serum phosphorus levels (serum phosphorus level ≤6.0 or ≤5.5 mg/dL), and safety, based on all AEs and drug-related AEs, were among the outcomes evaluated. RESULTS: In total, 24 patients were randomly assigned to the placebo group and 23 to the tenapanor group. The mean serum phosphorus level decreased from 7.01 mg/dL on day 1 to 6.69 mg/dL on day 43 in the placebo group and from 6.77 mg/dL on day 1 to 4.67 mg/dL on day 43 in the tenapanor group. In the placebo and tenapanor groups (modified intent-to-treat population), the mean (standard deviation) change in the serum phosphorus level at day 43 (last observation carried forward [LOCF]) was 0.08 (1.52) mg/dL and -1.99 (1.24) mg/dL, respectively, with a between-group difference of -2.07 (95% confidence interval: -2.89, -1.26; p < 0.001). The target achievement rate (serum phosphorus level ≤6.0 mg/dL at week 6 [LOCF]) was 37.5 and 87.0% in the placebo and tenapanor groups, respectively. Diarrhea was the most common drug-related AE, and it occurred in 8.3 and 65.2% of patients in the placebo and tenapanor groups, respectively. No specific AEs were observed with add-on tenapanor or with phosphate binders. DISCUSSION/CONCLUSION: Therapy with existing phosphate binders and add-on tenapanor resulted in a significant decrease in serum phosphorus level compared with the placebo group in patients with refractory hyperphosphatemia despite treatment with phosphate binders. No new safety signals were raised, and add-on tenapanor was generally well tolerated.