Tenapanor Improves Long-Term Control of Hyperphosphatemia in Patients Receiving Maintenance Dialysis: the NORMALIZE Study

Abstract

Key Points:

1. Tenapanor is a first-in-class, minimally systemic sodium–hydrogen exchanger 3 inhibitor with a mechanism of action distinct from phosphate binders.

2. Tenapanor alone or with phosphate binders led to 35%–49% of patients achieving serum phosphate ≤4.5 mg/dl over an 18-month period versus 22% at baseline.

3. Tenapanor alone or with phosphate binders may help adults with CKD on maintenance dialysis achieve normal serum phosphate concentrations.

Background: Most patients with ESKD and hyperphosphatemia have difficulty controlling serum phosphate (sP) concentrations despite maintenance dialysis, dietary restriction, and phosphate binder treatment. NORMALIZE evaluated the efficacy and safety of tenapanor 30 mg twice daily alone or in combination with phosphate binders to achieve sP within the adult population reference range (2.5–4.5 mg/dl).

Methods: Patients who completed the Phase 3 PHREEDOM study could enroll in NORMALIZE. Patients enrolled in NORMALIZE who had received tenapanor during the PHREEDOM study (n=111) added sevelamer carbonate if sP was >4.5 mg/dl. Patients who had received sevelamer carbonate during the PHREEDOM study (n=61) added tenapanor and decreased sevelamer carbonate if sP was ≤4.5 mg/dl, per protocol titration schedule. Patients were followed in NORMALIZE for up to 18 months. We assessed efficacy in the full analysis set, defined as patients who received ≥1 dose of study drug and had ≥1 post-treatment sP measurement (n=171). We assessed safety in all patients who received ≥1 dose of study drug (n=172).

Results: At the end point visit, 57 of 171 patients (33%) in the full analysis set achieved sP between 2.5 and 4.5 mg/dl. Eight of 23 patients (35%) who were on tenapanor alone at the end point visit achieved sP between 2.5 and 4.5 mg/dl. The mean reduction from PHREEDOM baseline to end of NORMALIZE in sP was 2.0 mg/dl. Serum intact fibroblast growth factor-23 was significantly reduced; serum intact parathyroid hormone was significantly reduced among patients with intact parathyroid hormone ≥300 pg/ml at PHREEDOM baseline. The most commonly reported treatment-emergent adverse event was diarrhea in 38 of 172 patients (22%), which led to tenapanor discontinuation in four patients (2%).

Conclusions: Tenapanor alone or in combination with phosphate binders helped adult patients on maintenance dialysis achieve normal sP concentrations. Safety was consistent with previous studies of tenapanor.

Clinical trial registry name and registration number: A Long-Term Study to Evaluate the Ability of Tenapanor Alone or in Combination With Sevelamer to Treat to Goal Serum Phosphorus in Patients With ESKD on Dialysis (NORMALIZE), NCT03988920.

Trial registration: ClinicalTrials.gov NCT03427125 NCT03988920 NCT02675998 NCT03824597 NCT04549597.

Graphical abstract

Figure 1

Primary and secondary analyses of sP. Error bars show standard error. ^aValues at PHREEDOM BL, NORMALIZE BL, and the end point visit are based on the total number of patients shown. Month 18 data are based on 124 patients in the FAS, 89 patients in group 1 (T/T+S), and 35 patients in group 2 (S+T). BL, baseline; FAS, full analysis set; sP, serum phosphate; S+T, sevelamer+tenapanor; T/T+S, tenapanor or tenapanor+sevelamer.

Figure 2

Mean sP at NORMALIZE BL and each postbaseline visit. Error bars show standard error.

Figure 3

Proportion of patients achieving sP concentrations ≤4.5 and <5.5 mg/dl. Percentages calculated on basis of the proportion of patients meeting the sP response criterion divided by the number of observations for the time point shown.

Figure 4

Relative changes in iFGF23 and iPTH. Values at PHREEDOM BL and NORMALIZE BL are based on the total number of patients shown. Patient numbers for month 18 and the end point visit are specified in the footnotes. ^aMedians are based on 122 patients at month 18 and 163 patients at the end point visit. ^bMedians are based on 87 patients at month 18 and 108 patients at the end point visit. ^cMedians are based on 35 patients at month 18 and 55 patients at the end point visit. ^dMedians are based on 122 patients at month 18 and 122 patients at the end point visit. ^eMedians are based on 47 patients at month 18 and 61 patients at the end point visit. iFGF23, intact fibroblast growth factor 23; iPTH, intact parathyroid hormone.