Alex Yang

Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia The HARMONIZE Randomized Clinical Trial

IMPORTANCE Hyperkalemia is a common electrolyte abnormality that may be difficult to manage because of a lack of effective therapies. Sodium zirconium cyclosilicate is a nonabsorbed cation exchanger that selectively binds potassium in the intestine. OBJECTIVE To evaluate the efficacy and safety of zirconium cyclosilicate for 28 days in patients with hyperkalemia. DESIGN, SETTING, AND PARTICIPANTS HARMONIZE was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating zirconium cyclosilicate in outpatients with hyperkalemia (serum potassium ≥5.1 mEq/L) recruited from 44 sites in the United States, Australia, and South Africa (March-August 2014). INTERVENTIONS Patients (n = 258) received 10 g of zirconium cyclosilicate 3 times daily in the initial 48-hour open-label phase. Patients (n = 237) achieving normokalemia (3.5-5.0 mEq/L) were then randomized to receive zirconium cyclosilicate, 5 g (n = 45 patients), 10 g (n = 51), or 15 g (n = 56), or placebo (n = 85) daily for 28 days. MAIN OUTCOMES AND MEASURES The primary end point was mean serum potassium level in each zirconium cyclosilicate group vs placebo during days 8-29 of the randomized phase. RESULTS In the open-label phase, serum potassium levels declined from 5.6 mEq/L at baseline to 4.5 mEq/L at 48 hours. Median time to normalization was 2.2 hours, with 84% of patients (95% CI, 79%-88%) achieving normokalemia by 24 hours and 98% (95% CI, 96%-99%) by 48 hours. In the randomized phase, serum potassium was significantly lower during days 8-29 with all 3 zirconium cyclosilicate doses vs placebo (4.8 mEq/L [95% CI, 4.6-4.9], 4.5 mEq/L [95% CI, 4.4-4.6], and 4.4 mEq/L [95% CI, 4.3-4.5] for 5 g, 10 g, and 15 g; 5.1 mEq/L [95% CI, 5.0-5.2] for placebo; P < .001 for all comparisons). The proportion of patients with mean potassium <5.1 mEq/L during days 8-29 was significantly higher in all zirconium cyclosilicate groups vs placebo (36/45 [80%], 45/50 [90%], and 51/54 [94%] for the 5-g, 10-g, and 15-g groups, vs 38/82 [46%] with placebo; P < .001 for each dose vs placebo). Adverse events were comparable between zirconium cyclosilicate and placebo, although edema was more common in the 15-g group (edema incidence: 2/85 [2%], 1/45 [2%], 3/51 [6%], and 8/56 [14%] patients in the placebo, 5-g, 10-g, and 15-g groups). Hypokalemia developed in 5/51 (10%) and 6/56 patients (11%) in the 10-g and 15-g zirconium cyclosilicate groups, vs none in the 5-g or placebo groups. CONCLUSIONS AND RELEVANCE Among outpatients with hyperkalemia, open-label sodium zirconium cyclosilicate reduced serum potassium to normal levels within 48 hours; compared with placebo, all 3 doses of zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days. Further studies are needed to evaluate the efficacy and safety of zirconium cyclosilicate beyond 4 weeks and to assess long-term clinical outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02088073.

Association between Serum Potassium and Outcomes in Patients with Reduced Kidney Function

BACKGROUND AND OBJECTIVES Patients with CKD are more likely than others to have abnormalities in serum potassium (K(+)). Aside from severe hyperkalemia, the clinical significance of K(+) abnormalities is not known. We sought to examine the association of serum K(+) with mortality and hospitalization rates within narrow eGFR strata to understand how the burden of hyperkalemia varies by CKD severity. Associations were examined between serum K(+) and discontinuation of medications that block the renin-angiotensin-aldosterone system (RAAS), which are known to increase serum K(+). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A cohort of patients with CKD (eGFR<60 ml/min per 1.73 m(2)) with serum K(+) data were studied (n=55,266) between January 1, 2009, and June 30, 2013 (study end). Serum K(+), eGFR, and covariates were considered on a time-updated basis. Mortality, major adverse cardiovascular events (MACE), hospitalization, and discontinuation of RAAS blockers were considered per time at risk. RESULTS During the study, serum K(+) levels of 5.5-5.9 and ≥6.0 mEq/L were most prevalent at lower eGFR: they were present, respectively, in 1.7% and 0.2% of patient-time for eGFR of 50-59 ml/min per 1.73 m(2) versus 7.6% and 1.8% of patient-time for eGFR<30 ml/min per 1.73 m(2). Serum K(+) level <3.5 mEq/L was present in 1.2%-1.4% of patient-time across eGFR strata. The median follow-up time was 2.76 years. There was a U-shaped association between serum K(+) and mortality; pooled adjusted incidence rate ratios were 3.05 (95% confidence interval, 2.53 to 3.68) and 3.31 (95% confidence interval, 2.52 to 4.34) for K(+) levels <3.5 mEq/L and ≥6.0 mEq/L, respectively. Within eGFR strata, there were U-shaped associations of serum K(+) with rates of MACE, hospitalization, and discontinuation of RAAS blockers. CONCLUSIONS Both hyperkalemia and hypokalemia were independently associated with higher rates of death, MACE, hospitalization, and discontinuation of RAAS blockers in patients with CKD who were not undergoing dialysis. Future studies are needed to determine whether interventions targeted at maintaining normal serum K(+) improve outcomes in this population.

Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients : results from a phase 3 randomized, double-blind, placebo-controlled trial

Hyperkalaemia in heart failure patients limits use of cardioprotective renin–angiotensin–aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS‐9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS‐9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE—a Phase 3, double‐blind, randomized, placebo‐controlled trial. In the present study we evaluated management of serum potassium with daily ZS‐9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies.

Characterization of structure and function of ZS-9, a K+ selective ion trap.

Hyperkalemia, a condition in which serum potassium ions (K+) exceed 5.0 mmol/L, is a common electrolyte disorder associated with substantial morbidity. Current methods of managing hyperkalemia, including organic polymer resins such as sodium polystyrene sulfonate (SPS), are poorly tolerated and/or not effective. Sodium zirconium cyclosilicate (ZS-9) is under clinical development as an orally administered, non-absorbed, novel, inorganic microporous zirconium silicate compound that selectively removes excess K+ in vivo. The development, structure and ion exchange properties of ZS-9 and its hypothesized mechanism of action are described. Based on calculation of the interatomic distances between the atoms forming the ZS-9 micropores, the size of the pore opening was determined to be ∼3 Å (∼diameter of unhydrated K+). Unlike nonspecific organic polymer resins like SPS, the ZS-9 K+ exchange capacity (KEC) was unaffected by the presence of calcium (Ca2+) or magnesium ions (Mg2+) and showed>25-fold selectivity for K+ over either Ca2+ or Mg2+. Conversely, the selectivity of SPS for K+ was only 0.2–0.3 times its selectivity for Ca2+ or Mg2+in mixed ionic media. It is hypothesized that the high K+ specificity of ZS-9 is attributable to the chemical composition and diameter of the micropores, which possibly act in an analogous manner to the selectivity filter utilized by physiologic K+ channels. This hypothesized mechanism of action is supported by the multi-ion exchange studies. The effect of pH on the KEC of ZS-9 was tested in different media buffered to mimic different portions of the human gastrointestinal tract. Rapid K+ uptake was observed within 5 minutes - mainly in the simulated small intestinal and large intestinal fluids, an effect that was sustained for up to 1 hour. If approved, ZS-9 will represent a novel, first-in-class therapy for hyperkalemia with improved capacity, selectivity, and speed for entrapping K+ when compared to currently available options.

ACUTE-PHASE EFFICACY OF ZS-9 IN PATIENTS WITH BASELINE SERUM POTASSIUM LEVELS ABOVE 5.5 MEQ/L: ANALYSIS FROM A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED TRIAL

Severe hyperkalemia may be associated with cardiac arrhythmias and often requires emergent intervention including hemodialysis. Sodium zirconium cyclosilicate (ZS-9) is a nonabsorbed cation exchanger designed to specifically trap excess K+ in the gut. Here we report acute-phase efficacy in patients

TREATMENT OF HYPERKALEMIA WITH ZS-9, A SELECTIVE NONABSORBED CATION EXCHANGE RESIN, DOES NOT LEAD TO HYPOMAGNESEMIA: RESULTS FROM TWO MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED PHASE 3 TRIALS

Hyperkalemia (HK) limits optimal use of cardioprotective RAAS inhibitors. Treatment of HK with the non-selective cation exchanger sodium polystyrene sulfonate (SPS) has limited efficacy and is associated with adverse effects such as hypocalcemia, hypomagnesemia and colonic necrosis, which are

ZS-9 MAINTAINS NORMOKALEMIA IN HYPERKALEMIC PATIENTS DESPITE CONTINUING RAAS INHIBITORS: A SUBGROUP ANALYSIS FROM A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED TRIAL

Hyperkalemia (HK) frequently develops in patients (pts) with heart failure or chronic kidney disease treated with RAAS inhibitors (RAASi). Continuation of these cardiorenal protective agents is desirable but limited by HK. Sodium zirconium cyclosilicate (ZS-9), a nonabsorbed cation exchanger that

ZS-9, A NOVEL SELECTIVE CATION TRAP, LEADS TO A RAPID AND PREDICTABLE RATE OF DECLINE IN SERUM POTASSIUM IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND HYPERKALEMIA

background: Hyperkalemia (HK) increases mortality and limits use of life-saving RAAS inhibitors, yet current therapies are limited. ZS-9 is a nonsystemic cation exchanger designed to entrap excess potassium (K+). In a Phase 2 trial in chronic kidney disease (CKD) patients with HK, ZS-9 10g led to a rapid and sustained decrease in serum K+ (s-K+), with a favorable safety profile (Ash et al. ASN 2013). Here we present mean rate of s-K+ decline.

FP008ACHIEVEMENT OF NORMAL SERUM POTASSIUM WITH SODIUM ZIRCONIUM CYCLOSILICATE (ZS-9) IN A SUBGROUP OF PATIENTS WITH STAGE 4/5 CHRONIC KIDNEY DISEASE AND BASELINE POTASSIUM ≥5.5 MMOL/L FROM THE PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED HARMONIZE STUDY

Introduction and Aims: Hyperkalaemia (serum K+ >5.0 mmol/L) is associated with increased risk of mortality (Goyal, 2012; Torlen, 2012) and limits renin-angiotensin-aldosterone system (RAAS) inhibitor therapies in patients with heart failure, diabetes, and chronic kidney disease (CKD). Hyperkalaemia becomes more frequent as renal function deteriorates. Current treatments with non-specific resins such as sodium polystyrene sulfonate have questionable efficacy and are associated with serious gastrointestinal (GI) adverse events (AEs). Sodium zirconium cyclosilicate (ZS-9) is a non-absorbed, selective cation exchanger that traps excess K+ in the GI tract and has demonstrated efficacy and safety in three prospective randomized placebo-controlled trials (Ash, KI 2015; Packham, NEJM 2014; Kosiborod, JAMA 2014). In the Phase 3 HARMONIZE study, treatment of hyperkalaemic patients with ZS-9 resulted in acute reduction of serum K+ within 48 hours, followed by maintenance of normokalaemia for 28 days (Kosiborod, JAMA 2014). Here we present a subgroup analysis of patients with Stage 4/5 CKD and baseline K+ ≥5.5 mmol/L from the HARMONIZE study. Methods: HARMONIZE was a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate long-term efficacy and safety of ZS-9 in patients with hyperkalaemia (serum K+ ≥5.1 mmol/L). All patients received 10g of ZS-9 thrice daily (TID) for 48 hours in the acute open-label phase (N=258). Patients achieving normokalaemia (serum K+ 3.5-5.0 mmol/L) were then re-randomized to one of 3 ZS-9 doses (5, 10, or 15 g) once daily (QID) or placebo for 28 days in the maintenance phase. In this study, we evaluated the mean change in serum K+ during the acute phase and proportion of patients achieving normokalaemia at 24 and 48 hours. Results: Of 258 patients, 64 had Stage 4/5 CKD and baseline K+ ≥5.5 mmol/L. Mean baseline K+ was 5.9 mmol/L. Significant reductions in serum K+ (-0.2, -0.5, -0.6, -0.8, and -1.3 mmol/L) were observed at 1, 2, 4, 24, and 48 hours, respectively (P<0.001; Figure). The proportion of patients achieving normokalaemia was 69% and 93% by 24 and 48 hours, respectively. ZS-9 was generally well tolerated with a low rate of AEs in the overall study population. Conclusions: Our study demonstrated that ZS-9 rapidly restored normokalaemia in patients with Stage 4/5 CKD and high baseline serum K+. Thus, ZS-9 may fulfil an important unmet clinical need in this population of high-risk patients and may potentially minimize the need for emergency intervention with renal replacement therapy.