Abstract 508: Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Once-Daily ZS-9 for Treatment of Hyperkalemia: Maintenance of Serum K + in Subgroup Analysis of Patients on RAAS Therapy

Abstract

Renin-angiotensin-aldosterone system inhibitors (RAASi) increase the risk of hyperkalemia (HK; serum potassium [K + ] ≥5 mEq/L), often leading to treatment discontinuation, despite proven benefit in chronic kidney disease (CKD) and heart failure patients. There is an unmet need for safe, effective HK treatments which have sustained reduction in K + . ZS-9 is a novel, nonabsorbed cation exchanger specifically designed to entrap excess K + . Change in serum K + in the subgroup of patients receiving RAASi in a Phase 3 trial of ZS-9 are presented. Patients (N=753) with K + 5.0-6.5 mEq/L were randomized (1:1:1:1:1) to ZS-9 (1.25, 2.5, 5 or 10 g) or placebo orally 3x daily (TID) for 48 hr (acute phase), following which patients with K + 3.5-5.0 mEq/L (n=542) were simultaneously randomized 1:1 to the same dose of ZS-9 given during the acute phase or placebo 1x daily (QD) on Days 3-15 (extended phase). Patients who were on placebo during the acute phase were re-randomized to 1.25 or 2.5g ZS-9 QD. RAASi therapy was maintained during the study. Unpaired t-test was used to compare serum K + in the RAASi subset that were treated with the two highest doses of ZS-9 (5 or 10g) vs placebo. A total of 502 of 753 patients (67%) were on RAASi at baseline (ACE inhibitor 66%; angiotensin receptor blocker, 36%; spironolactone 9%). Mean baseline K + was 5.3 mEq/L. At 48 hr, significantly greater decreases in K + were seen with both ZS-9 dose groups (n=95 each for 5g or 10g; -0.53 and -0.73 mEq/L, respectively) vs placebo (n=98; -0.24 mEq/L; p<0.001). Of the 502 patients on RAASi, 263 entered the extended phase, including 37 patients who continued on 5g QD, 43 who switched to placebo, 43 who continued on 10g QD, and 39 who switched to placebo. During the extended phase, normokalemia was maintained in the10g dose group, whereas K + levels increased in patients who switched to placebo (K + 4.6 vs 5.0 mEq/L, respectively; p<0.001). Similar results were observed in patients who continued on 5g ZS-9 QD, compared with those who switched to placebo (K + 4.8 vs. 5.1 mEq/L, respectively; p=0.002), at the end of the extended phase. ZS-9 (5 or 10g) achieved and maintained mean serum K + <5.0 mEq/L in patients on RAASi, thus potentially enabling optimal dosing of cardio- and reno-protective RAASi in patients with heart failure or CKD.