Safety and Efficacy of Tenapanor for Long-term Serum Phosphate Control in Maintenance Dialysis: A 52-Week Randomized Phase 3 Trial (PHREEDOM)

Abstract

Background: Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia.

Methods: In this 52-week phase 3 study (NCT03427125), participants receiving maintenance dialysis with both hyperphosphatemia (serum phosphate 6.0-10.0 mg/dl) and a 1.5 mg/dl increase after phosphate binder washout were randomized (3:1) to tenapanor 30 mg twice daily for 26 weeks (randomized treatment period) or sevelamer carbonate (52-week safety control). Participants completing 26 weeks of treatment with tenapanor were rerandomized (1:1) to tenapanor or placebo for 12 weeks (randomized withdrawal period), and were eligible to enter the 14-week safety extension period. With input from the US Food and Drug Administration, the primary efficacy end point was the difference in the change in serum phosphate from the end of the randomized treatment period to the end of the randomized withdrawal period, among participants who achieved ≥1.2 mg/dl decrease in serum phosphate during the randomized treatment period (efficacy analysis set). Efficacy was also evaluated in the intention-to-treat (ITT) analysis set.

Results: Of 564 eligible participants randomized to receive tenapanor (n=423) or sevelamer carbonate (n=141) during the randomized treatment period, 255 (60%) in the tenapanor group subsequently were rerandomized to tenapanor (n=128) or placebo (n=127) during the randomized withdrawal period. In the efficacy analysis set (n=131), the difference in estimated mean change in serum phosphate level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was -1.4 mg/dl (P<0.0001); in the ITT analysis set (n=243), the estimated mean difference was -0.7 mg/dl (P=0.002). Loosened stools were the most frequently reported adverse event (53% during the randomized treatment period). Serious adverse events were reported more frequently for participants treated with sevelamer carbonate (16%-23% across the three study periods) compared with tenapanor (11%-17%).

Conclusions: Tenapanor reduced serum phosphate concentrations and maintained control of serum phosphate in participants receiving maintenance dialysis, with an acceptable safety and tolerability profile.

Keywords: FGF23; NHE3; dialysis; hyperphosphatemia; mineral metabolism; phosphate; phosphate uptake; tenapanor.

Conflict of interest statement

A.J. Bleyer reports no affiliation with Ardelyx, Inc. aside from his role as Principal Investigator in the PHREEDOM study. A.L. Silva reports receiving research funding from Ardelyx, Inc. D.E. Weiner reports being the Medical Director of Clinical Research for Dialysis Clinic, Inc., with support paid to his institution by Dialysis Clinic, Inc.; he reports consulting for Akebia, Cara Therapeutics, Janssen Biopharmaceuticals, and Tricida, and has no affiliation with or received funding from Ardelyx, Inc., aside from his role as site Principal Investigator in several tenapanor trials. D.P. Rosenbaum reports being an employee of, and having an ownership interest in, Ardelyx, Inc. G.A. Block reports being a Director for Ardelyx, Inc. and is the Associate Chief Medical Officer for US Renal Care, Inc. G.M. Chertow reports being a consultant to, and has equity ownership interest in, Ardelyx, Inc. R.I. Lynn has no affiliation with Ardelyx, Inc. aside from his role as Principal Investigator in the PHREEDOM and NORMALIZE studies. Y. Yang reports being an employee of Ardelyx, Inc.

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Overview of study design. The safety analysis set included all participants who received at least one dose of the study drugs for the study period. RTP, randomized treatment period; RWP, randomized withdrawal period; SEP, safety extension period.

Figure 2.

Overview of participant flow through the trial. The safety analysis set included all participants who received at least one dose of the study drug for the study period. The ITT analysis set included all participants who met the study inclusion criteria, received at least one dose of tenapanor and/or placebo, and had at least one post-treatment serum phosphate measurement for the study period. The efficacy analysis set included all ITT participants who met the entry criteria, received at least one dose of tenapanor during the 26-week RTP, completed the RTP, and achieved a reduction of ≥1.2 mg/dl in serum phosphate concentration from baseline to the end of the RTP. Participants from the site with a serious GCP breach were excluded from all analysis sets. Participants receiving tenapanor or placebo were to be withdrawn if they had serum phosphate ≤2.5 mg/dl at any time, serum phosphate ≥10.0 mg/dl at any time after week 2 of the RTP, serum phosphate ≥9.0 mg/dl for two consecutive visits during the RTP or SEP, or serum phosphate ≥9.0 mg/dl during the RWP. The primary reason for discontinuation from the study is listed. GCP, Good Clinical Practice.

Figure 3.

Change in serum phosphate concentration in participants receiving tenapanor during the 26-week RTP. Serum phosphate concentration in participants receiving tenapanor over the 26-week RTP for the (A) ITT analysis set and (B) the subset of participants who achieved a reduction of ≥1.2 mg/dl in serum phosphate from baseline at week 26 and continued into the randomized withdrawal period. Data are mean serum phosphate concentrations ±SD.

Figure 4.

Change in serum phosphate concentration over the RWP. Data are provided for the (A) efficacy analysis set and (B) ITT analysis set. ***P<0.001, *P≤0.002 versus placebo. Bar chart data show LS mean change (95% confidence interval±SEM) in serum phosphate concentration from period-specific baseline to the end of the RWP. Line graph data show LS mean change (±SEM and P value) from period-specific baseline in serum phosphate concentration at postbaseline visits during the RWP. LS, least squares.