FO012NORMALIZATION OF SERUM BICARBONATE WITH SODIUM ZIRCONIUM CYCLOSILICATE (ZS-9) IN THE PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED HARMONIZE STUDY

Abstract

Introduction and Aims: Metabolic acidosis is a common complication of patients ( pts) with chronic kidney disease (CKD) and is associated with progression of disease and mortality. Increase in serum bicarbonate (HCO3) may delay disease progression in CKD pts (Kovesdy 2012). For diabetic CKD pts, even small increases in HCO3 can enhance insulin sensitivity. Sodium zirconium cyclosilicate (ZS-9) is a non-absorbed, cation exchanger that demonstrated acute normalization and maintenance of serum potassium (K+) in 3 prospective randomized placebo-controlled clinical studies in pts with hyperkalemia (HK; Ash, KI 2015, Packham, NEJM 2014 and Kosiborod, JAMA 2014). Due to the engineered pore size of ∼3A˚ within its crystal lattice structure, ZS-9 has a high specificity for K+. Ammonium (NH4+) has an ionic radius almost identical to that of K+, and thus, ZS-9 has a similarly high specificity for NH4+, potentially leading to improvement in metabolic acidosis. In the clinical setting, significant increases in serum HCO3 have been observed in pts receiving ZS-9 for up to 14 days (Ash, KI 2015, Packham, NEJM 2014). Here we evaluate the effect of ZS-9 on serum HCO3 from the Phase 3 HARMONIZE study. Methods: HARMONIZE was a multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate long-term efficacy and safety of ZS-9 in pts with HK (serum K+ ≥ 5.1 mmol/L; Kosiborod, JAMA 2014). All pts received 10 g ZS-9 TID for 48h in the acute open label phase. Pts achieving normal K+ (3.5-5.0 mmol/L) were randomized to one of 3 ZS-9 doses (5, 10, 15 g QID) or placebo for 28 days in the maintenance phase. Levels of serum HCO3 were measured at baseline and at the end of the acute phase (48h) and on maintenance phase Days 15, 29, and 35. Results: At baseline, mean HCO3 was 22.7±4.2 mmol/L. By Day 15 of the maintenance phase, HCO3 increased in the ZS-9 dose groups by 1.0 (7%), 3.0 (16%), and 2.6 mmol/ L (14%) from acute phase baseline in the 5g, 10g, and 15g dose groups, respectively, compared with 0.4 mmol/L (2%) with placebo (p<0.05 for 10g and 15g; Figure, panel A). These effects were sustained through Day 29. In addition, after treatment with ZS-9, the proportion of pts whose HCO3 levels were below the normal range (22-30 mmol/L) improved from 33% at study entry to only 17% at the end of the 48h acute phase, and reached 9%, 10%, and 2% (Figure, panel B) by the end of the 28-day maintenance phase for the 5g, 10g, and 15g doses of ZS-9, respectively. No improvement was observed in pts on placebo from time of randomization to end of study. Conclusions: Significant and sustained increases in serum HCO3 were observed in pts receiving once daily ZS-9 10g and 15g. Treatment with ZS-9 also led to normalization of HCO3, with a smaller proportion of pts below normal levels, compared to placebo. These results suggest that in addition to its role in normalizing serum K+, ZS-9 may also serve to ameliorate metabolic acidosis. Longer-term studies are warranted to evaluate whether treatment with ZS-9 may delay kidney disease progression in addition to addressing HK. (Figure Presented).