Tenapanor as Therapy for Hyperphosphatemia in Maintenance Dialysis Patients: Results from the OPTIMIZE Study

Abstract

Key Points:

1. Tenapanor, a first-in-class local inhibitor of sodium/hydrogen exchanger isoform 3, acts as a phosphate absorption inhibitor by decreasing paracellular phosphate absorption.

2. Tenapanor alone or with phosphate binders achieved P ≤ 5.5 mg/dl over 10 weeks in 34%–38% of patients taking phosphate binders at baseline.

3. Tenapanor can help adults with CKD on maintenance dialysis achieve normal serum phosphate concentrations.

Background: OPTIMIZE was a randomized, open-label study evaluating different tenapanor initiation methods. OPTIMIZE evaluated tenapanor alone and in combination with phosphate binders (PBs) to achieve target serum phosphate (P) ≤5.5 mg/dl.

Methods: Patients with inadequately controlled P receiving maintenance dialysis from 42 US locations who were taking PBs with baseline P > 5.5 mg/dl and ≤ 10.0 mg/dl, or were PB-naive with baseline P > 4.5 mg/dl and ≤ 10.0 mg/dl, were included in OPTIMIZE. Participants taking PBs at baseline were randomized to switch from PBs to tenapanor (Straight Switch; n=151) or reduce PB dosage by ≥50% and add tenapanor (Binder Reduction; n=152); PB-naive patients started tenapanor alone (Binder-Naive; n=30). Participants received tenapanor 30 mg twice a day for 10 weeks (part A), followed by an elective, 16-week open-label extension (part B). Outcomes included changes from baseline in P, intact fibroblast growth factor 23, parathyroid hormone, serum calcium, and medication burden; patient-reported outcomes; and safety.

Results: By part A end point, 34.4% (Straight Switch), 38.2% (Binder Reduction), and 63.3% (Binder-Naive) of patients achieved P ≤ 5.5 mg/dl. Mean P reduction and median pill burden reduction from baseline to part A end point were 0.91±1.7 mg/dl and 4 pills/d for the Straight Switch and 0.99±1.8 mg/dl and 1 pill/d for the Binder Reduction group. The mean P reduction for Binder-Naive patients was 0.87±1.5 mg/dl. Among Straight Switch and Binder Reduction patients who completed patient experience questionnaires, 205 of 243 (84.4%) reported an improved phosphate management routine. Diarrhea was the most common adverse event (133 of 333 [39.9%]).

Conclusions: Tenapanor as monotherapy or in combination with PBs effectively lowered P toward the target range in patients who were PB-naive or who were not at goal despite PB use.

Clinical Trial registration number: NCT04549597.

Trial registration: ClinicalTrials.gov NCT02081534 NCT02675998 NCT03427125 NCT03824587 NCT03988920 NCT04549597.

Graphical abstract

Figure 1

Patient disposition. In part A, 333 patients were enrolled, with 151 randomized to Straight Switch and 152 to Binder Reduction; 30 Binder-Naive participants entered the study directly. Patients who received at least one dose of tenapanor during the study were included in the safety analysis set. The full analysis set included patients who received at least one dose of tenapanor and had at least one postbaseline P value during the study.

Figure 2

Serum phosphate reduction and responder rates in the Straight Switch and Binder Reduction cohorts. Change in P levels from baseline to part A end point^a and mean P levels by visit during part A period (A) and P responder rates at baseline and part A end point^a (B) for Straight Switch and Binder Reduction cohorts. (A) Error bars for mean P value represent SEM. (B) Error bars for P responder rates at the part A end point represent Clopper–Pearson 95% confidence intervals. Responder rates were derived on the basis of observed cases. ^aFor all patients, the part A end point is the last observed value during part A, which could occur before week 10, if the patient withdrew early. BL, baseline; P, serum phosphate.

Figure 3

Median total daily pill number of phosphate-lowering medication at baseline, week 10, and part A end point in the Straight Switch and Binder Reduction cohorts^a. The boxplot represents median total daily pill number (the combined number of tenapanor and PB tablets). The lines inside the boxes indicate the median values. The top and bottom edges of the boxes indicate the interquartile range (IQR) from the 25th to 75th percentile. The whiskers extend 1.5 times the IQR. ^aFor all patients, the part A end point is the last observed value during part A, which could occur before week 10, if the patient withdrew early. PB, phosphate binder.

Figure 4

Serum phosphate reduction and responder rates in the Binder-Naive cohort.^a Change in P levels from baseline to part A end point^a and mean P levels by visit during part A period (A) and P responder rates at baseline and part A end point^a (B) for the Binder-Naive cohort. (A) Error bars for mean P value represent SEM. (B) Error bars for P responder rates at the part A end point represent Clopper–Pearson 95% confidence intervals. Responder rates were derived on the basis of observed cases. ^aFor all patients, the part A end point is the last observed value during part A, which could occur before week 10, if the patient withdrew early.

Figure 5

Patient-reported outcomes. Data reported are for the combined patients from the Straight Switch and Binder Reduction groups who completed the patient experience questionnaire; the Binder-Naive group was not included in this analysis because the selected questions were not applicable to this population. Columns show the percentage of patients who responded to each question. Breakdown of responses can be found in Supplemental Table 4.