NaPi-IIb Inhibition for Hyperphosphatemia in CKD Hemodialysis Patients

Abstract

Introduction: Chronic kidney disease (CKD) has a prevalence of 9.1% globally, and frequently results in elevated serum phosphate, increasing cardiovascular morbidity and mortality risk in hemodialysis (HD) patients. DS-2330b, an oral NaPi-IIb inhibitor, reduced intestinal phosphate absorption in preclinical studies, but its effect in patients with CKD is unknown. This 2-part, randomized, placebo- and active-controlled, single- and repeated-dose, phase 1b study evaluated safety and efficacy of DS-2330b in patients with CKD on HD.

Methods: Part A, a 2-period, 2-way study, evaluated safety and pharmacokinetics of DS-2330b 250 mg in solution and tablet formulations. Part B assessed the safety of DS-2330b in solution (chosen based on results of part A) and its effect on serum phosphate. Patients were randomized to placebo 3 times daily (TID), DS-2330b 400 mg TID, DS-2330b 400 mg with sevelamer 1.6 g TID, and sevelamer 1.6 g with placebo TID for 14 days. Safety endpoints included adverse event (AE) monitoring.

Results: Six patients completed part A. Two patients experienced serious AEs considered unrelated to DS-2330b treatment. Thirty-two patients enrolled and completed part B. Serum phosphate mean change from baseline ± SD was -2.2±1.5 mg/dl versus -1.9 ± 1.1 mg/dl for DS-2330b monotherapy versus placebo. Patients receiving DS-2330b with sevelamer or sevelamer with placebo experienced the greatest serum phosphate decrease from baseline. Nine patients (28.1%) experienced ≥1 treatment-emergent AE (TEAE); 7 patients experienced drug-related TEAEs. The TEAE incidence was comparable between DS-2330b and control groups.

Conclusions: DS-2330b, alone or in combination with sevelamer, was safe and well tolerated but did not demonstrate clinically meaningful efficacy in HD patients.

Keywords: NaPi-IIb inhibitor; chronic kidney disease; clinical study; hemodialysis; hyperphosphatemia.

Graphical abstract

Figure 1

Study design schematic. Part A was an open-label, randomized, 2-way crossover study with a single dose of DS-2330b 250 mg in PIB or tablet formulation in 2 periods. All patients stayed in a CPU during each treatment period. There were at least 7 days of washout between treatments. Part B was a double-blinded, randomized, placebo- and active-controlled study with 4 arms. Placebo is the same solution used to dispense DS-2330b PIB; Placebo is matching to DS-2330b PIB. CPU, clinical pharmacology unit; Pi, phosphate; PIB, powder in bottle; TAB, tablet; TID, 3 times daily.

Figure 2

Study schedule for part B. Patients with CKD were screened within a 4-week period before enrollment. Screened patients began a 2- to 3-week washout of all phosphate binders. Patients who met serum phosphate of 6.0 mg/dl to 10.0 mg/dl, and demonstrated a >1.0 mg/dl serum phosphate increase from screening were enrolled. The follow-up period was 21–24 days after the first treatment. CKD, chronic kidney disease; PK, pharmacokinetics.

Figure 3

Changes in serum phosphate at baseline and day 15 of treatment in part B. PBO treatment arm (dark blue bar) received placebo to DS-2330b TID. DS-2330b treatment arm (light blue bar) received 400 mg DS-2330b in PIB formulation TID; DS-2330b + sevelamer group (green bar) received 400 mg DS-2330b PIB formulation co-administered with 1.6 g open-label sevelamer TID; Sevelamer + placebo treatment arm (orange bar) received open-label 1.6 g sevelamer co-administered with placebo TID. All treatment was given TID after each meal from day 1 to day 14. The data are shown as mean ± SD. CFB, change from baseline; PBO, placebo; Pi, phosphate; PIB, powder in bottle; TID, 3 times daily.

Figure 4

Change in serum phosphate from baseline over time throughout study. PBO treatment arm (dark blue circles) received placebo to DS-2330b 400 mg TID. DS-2330b treatment arm (light blue squares) received 400 mg DS-2330b PIB formulation TID; DS-2330b + sevelamer group (green triangles) received 400 mg DS-2330b PIB formulation co-administered with 1.6 g open-label sevelamer TID; sevelamer + PBO treatment arm (orange triangles) received open-label 1.6 g sevelamer co-administered with placebo TID. The blood samples were collected after 10 hours of overnight before breakfast. On days 2, 4, 7, 9, and 11 (HD days), the samples were collected at pre-HD. The data are shown as mean ± SD. BL, baseline; HD, hemodialysis; PBO, placebo; Pi, phosphate; PIB, powder in bottle; TID, 3 times daily.

Figure 5

Analysis of DS-2330a plasma concentration during DS-2330b monotherapy and co-administration of DS-2330b with sevelamer on (a) day 1 and (b) day 13 of treatment. Blood samples for pharmacokinetic analysis were collected at predose (before breakfast), and each timepoints presented in the figure on day 1 and day 13 (both non-HD day). The 24-hour postdose sample was collected at pre-HD on day 2 and day 14. The patients fasted at least 4 hours after the morning dose. The data are shown as mean ± SD. HD, hemodialysis.

Figure 6

Relationship of serum phosphate change from baseline versus FGF-23 change from baseline (ratio) at day 13 of treatment. Serum phosphate change from baseline (mg/dl) shown in x-axis. The ratio of FGF-23 level at day 13 over day 1 is shown in y-axis. Placebo is represented by dark blue circles, DS-2330b by light blue squares, DS-2330b + sevelamer by green triangles, and sevelamer + placebo by orange triangles in the figure. r = 0.740. BL, baseline; FGF-23, fibroblast growth factor-23; PBO, placebo; Pi, phosphate.

Figure 7

Relationship of serum phosphate change from baseline and iPTH change from baseline at day 13. Serum phosphate change from baseline (mg/dl) shown in x-axis. Change of iPTH levels (pg/ml) from day 1 to day 13 is shown in y-axis. Placebo is represented by dark blue circles, DS-2330b by light blue squares, DS-2330b + sevelamer by green triangles, and sevelamer + placebo by orange triangles in the figure. r = 0.262. BL, baseline; iPTH, intact parathyroid hormone; Pi, phosphate.