A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient

Abstract

Hyperkalemia contributes to significant mortality and limits the use of cardioprotective and renoprotective renin-angiotensin-aldosterone blockers. Current therapies are poorly tolerated and not always effective. Here we conducted a phase 2 randomized, double-blind, placebo-controlled dose-escalation study to assess safety and efficacy of ZS-9. This oral selective cation exchanger that preferentially entraps potassium in the gastrointestinal tract was given to patients with stable Stage 3 chronic kidney disease and hyperkalemia (5.0 to 6.0 mEq/l) during a 2-day period. Of 90 eligible patients with mean baseline serum potassium of 5.1 mEq/l, 30 were randomized to placebo, 12-0.3 g, 24-3 g, or 24 to 10 g of ZS-9 three times daily for 2 days with regular meals. None withdrew and ZS-9 dose-dependently reduced serum potassium. The primary efficacy end point (rate of serum potassium decline in the first 48 h) was met with significance in the 3- and 10-g cohorts. From baseline, mean serum potassium was significantly decreased by 0.92±0.52 mEq/l at 38 h. Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/- 21.8 vs. +8.9 +/- 22.9 mEq per 24h) from placebo at day 2. In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment. Thus, ZS-9 was well-tolerated in patients with stable chronic kidney disease and hyperkalemia leading to a rapid, sustained reduction in serum potassium.

Figure 1

Patient disposition. eGFR, estimated glomerular filtration rate; ZS-9, sodium zirconium cyclosilicate.

Figure 2

Rate of decline in serum potassium over the first 48 h of treatment with 0.3-g (n=12), 3-g (n=24), and 10-g ZS-9 (n=24) or placebo (n=30)—intent-to-treat population. This model prediction uses every serum K⁺ data point from each patient. Although the rate of decline is actually a curve, during the 48-h time frame of interest, it appears linear as presented here. The plotted rates of decline in serum K⁺ also visually illustrate the dose–response relationship. Triangles indicate study drug administration (six doses in 34 h). ZS-9, sodium zirconium cyclosilicate.

Figure 3

Mean serum potassium over 6 days in the placebo (left) and 10-g ZS-9 (right) groups. *Indicates significant difference compared with the respective placebo group (P<0.05). Triangles indicate study drug administration (six doses in 48 h). Shaded portion indicates range of normal serum potassium levels. Bars indicate 95% confidence interval. ZS-9, sodium zirconium cyclosilicate.

Figure 4

Mean change from baseline in 24-h urinary excretion of potassium (a) and sodium (b). *Indicates significant difference compared with placebo. NS, not significant; ZS-9, sodium zirconium cyclosilicate.

Figure 5

Serum parameters in 10-g ZS-9 (n=24) versus placebo (n=30) over 7 days. Mean change from baseline in (a) blood urea nitrogen, (b) serum bicarbonate, and (c) serum creatinine. Triangles indicate study drug administration (six doses in 48 h), and * indicates significant difference compared with placebo, P<0.05. ZS-9, sodium zirconium cyclosilicate.

Figure 6

Blood pressure over 4 days in 10-g ZS-9 (n=24) versus placebo (n=30). Systolic and diastolic blood pressure in patients in the (a) placebo group and (b) ZS-9 10-g dose group. ZS-9, sodium zirconium cyclosilicate.