Acute Efficacy and Safety of Sodium Zirconium Cyclosilicate (Zs-9) in Patients with Moderate or Severe Hyperkalemia: A Pooled Analysis from Two Phase 3 Trials

Background:   Hyperkalemia (HK; serum K⁺ ≥5.0mEq/L) is a common electrolyte imbalance, associated with an increase in all-cause mortality and hospitalization.  Moderate to severe HK (K ⁺ levels ≥5.5mEq/L) is often managed in the emergency department or hospital, where available treatment options include methods to temporarily lower K⁺ (e.g., insulin-glucose and beta 2 agonists), use of cation exchange resin such as sodium polystyrene sulfonate [SPS] or initiation of acute dialysis. There is an unmet need for safe and effective therapies to rapidly restore and maintain normal serum K⁺. ZS-9 is a non-absorbed cation exchanger that selectively traps K⁺ throughout the gastrointestinal (GI) tract.  In 2 large double-blind, placebo-controlled, randomized Phase 3 trials (ZS-003, and HARMONIZE), ZS-9 rapidly normalized and maintained serum K⁺ in HK patients. Here we present a pooled subgroup analysis of patients with K⁺ ≥5.5mEq/L.

Methods:   Patients received ZS-9 three times daily (TID) during a 48 hour acute phase, followed by a once daily maintenance dosing for 12 days (ZS-003) or 28 days (HARMONIZE) in an ambulatory care setting. Our pooled analysis examined 170 patients with moderate to severe HK at baseline (K⁺ ≥5.5mEq/L) who received 10 grams (g) of ZS-9 TID, Potassium was measured at 0, 1, 2, 4, 24, and 48 hours after the first dose. Paired t-tests were used to evaluate change from baseline.

Results:   Mean K⁺ decreased from 5.83mEq/L at baseline to 4.59mEq/L at 48h after 10g ZS-9 with TID administration. Significant K⁺ reductions were observed at all time points after initial dosing (Figure; trend: p<0.0001); 72% and 95% of patients normalized by 24h and 48h, respectively. ZS-9 was generally well tolerated. In the QD maintenance phase, GI AE rates of adverse events were 3.5% for ZS-9 and 6.6% for placebo; constipation and diarrhea were most common.

Conclusions:   In patients with baseline K⁺ ≥5.5mEq/L from two Phase 3 studies, rapid and significant lowering of serum K⁺ levels were observed at 1 hr after the initial ZS-9 dose. These results suggest ZS-9 is a possible non-invasive option for the acute management of patients with moderate to severe HK. Further studies with ZS-9 are warranted to determine if use of this therapy to treat HK in ED/hospitalized patients can reduce hospital admissions, length of stay and improve patient satisfaction.