Sustained Phosphate Reduction Assessed by Phosphate Area under the Curve with Tenapanor Is Associated with Reduced Fibroblast Growth Factor 23 in Patients with CKD and Hyperphosphatemia on Dialysis

Background: The 2017 KDIGO CKD-MBD guidelines recommend that strategies for managing hyperphosphatemia (HP) be based on the use of serial measurements. Average phosphate (P) area under the curve (AUC) has been identified as a stronger predictor of outcomes than other P estimates. Intact fibroblast growth factor 23 (iFGF23) is elevated in end-stage kidney disease and is associated with increased cardiovascular mortality, but is often not well correlated to single-point estimates of P. Tenapanor (TEN) is approved to reduce serum P in adults with CKD as add-on therapy in patients (pts) who have an inadequate response to P binders (PBs) or who are intolerant of any dose of PBs. We used P AUC to assess whether better long-term P control with TEN is associated with lower iFGF23. Methods: In a secondary analysis of the Ardelyx-supported PHREEDOM study, a 52-week, phase 3 trial of TEN as a monotherapy for HP in adults on maintenance dialysis, pts with P ≥6.0 and ≤10.0 mg/dL and a P increase ≥1.5 mg/dL after PB washout were treated for 26 weeks with TEN 30 mg bid during an open-label randomized treatment period (RTP). Correlation analyses between average daily P AUC above 4.5 mg/dL over the RTP and iFGF23 at the end of the RTP were performed along with summaries of changes in iFGF23 by P AUC categories. Results: In the full analysis set (n=407), TEN reduced P by 1.3 (SD: 1.8) mg/dL on average at the end of the RTP. Median iFGF23 was reduced from 6417.5 pg/mL at baseline to 5051.6 pg/mL at the end of the RTP (median percent change: −23.2%). There was a positive correlation between average daily P AUC and iFGF23 (ρ=0.499, P<0.001). A trend of higher median iFGF23 was seen across categories of P AUC. Greater percent reductions from baseline in iFGF23 were seen in P AUC categories representative of better P control than categories representative of worse control (Table). Conclusion: Improved P control with TEN, as measured by P AUC, was associated with lower iFGF23. Funding: Commercial Support - Ardelyx, Inc. iFGF23 at Week 26 and Change From Baseline (CFB) by P AUC Category Above 4.5 mg/dL - P AUC category: >0–0.5 mg/dL P AUC category:>0.5–1 mg/dL P AUC category:>1–2 mg/dL P AUC category:>2 mg/dL iFGF23 at Week 26, median 623 pg/mL 2450 pg/mL 4127 pg/mL 10866 pg/mL iFGF23 CFB, % −36% −48% −19% −12%