ZS-9 (sodium zirconium cyclosilicate) is a selective oral sorbent that traps potassium ions throughout the gastrointestinal tract. It is being developed by ZS Pharma for the treatment of hyperkalemia (elevated serum potassium levels).
Hyperkalemia occurs in 3 to 10% of hospitalized patients but is often mild. Hyperkalemia can arise from impaired renal function, potassium-sparing diuretics and renin-angiotensin system blockers (e.g., ACE inhibitors, angiotensin receptor blockers, spironolactone) and diabetes mellitus.
There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe. However, if hyperkalemia causes any ECG change it is considered a medical emergency due to a risk of potentially fatal abnormal heart rhythms (arrhythmia) and is treated urgently. serum potassium concentrations greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively.
Hyperkalemia, particularly if severe, is a marker for an increased risk of death. However, there is disagreement regarding whether a modestly elevated serum potassium level directly causes significant problems. One viewpoint is that mild to moderate hyperkalemia is an secondary effect that denotes significant underlying medical problems. Accordingly, these problems are both proximate and ultimate causes of death, and adjustment of potassium may not be helpful. Alternatively, hyperkalemia may itself be an independent risk factor for cardiovascular mortality.
Several approaches are used in treatment of hyperkalemia, but currently the only product approved by the U.S. Food and Drug Administration (FDA) to treat hyperkalemia is sodium polystyrene sulfonate (Kayexalate), an organic ion-exchange resin that nonspecifically binds cations (e.g., calcium, potassium, magnesium) in the gastrointestinal tract. The effectiveness of sodium polystyrene sulfonate has been questioned: a study in healthy subjects showed that laxatives alone were almost as effective in increasing potassium secretion as laxatives plus Kayexalate. In addition, use of sodium polystyrene sulfonate, particularly if formulated with high sorbitol content, is uncommonly but convincingly associated with colonic necrosis.
Mechanism of action
ZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety. 12 zirconium silicates were screened by an iterative optimization process. ZS-9 selectively captures potassium ions by mimicking the actions of physiologic potassium channels. ZS-9 is an inorganic cation exchanger crystalline with a high capacity to entrap monovalent cations, specifically potassium and ammonium ions, in the GI tract. ZS-9 is not systemically absorbed; accordingly, the risk of systemic toxicity may be minimized.
A phase 2 clinical trial in 90 patients with chronic kidney disease and mild-to-moderate hyperkalemia found a significantly greater reduction in serum potassium with ZS-9 than placebo. ZS-9 was well tolerated, with a single adverse event (mild constipation).
A double-blind, phase 3 clinical trial in 753 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin-angiotensin system blockers compared ZS-9 with placebo. Patients were randomly assigned to receive either ZS-9 (1.25g, 2.5g, 5g, or 10g) or placebo 3 times daily for 48 hours (acute phase). Patients who achieved normokalemia (serum potassium of 3.5-4.9mmol/L) were randomly assigned to receive ZS-9 or placebo once daily for 12 additional days (maintenance phase). At the end of the acute phase, serum potassium significantly decreased in the 2.5g, 5g, and 10g ZS-9 groups. During the maintenance phase, once daily 5g or 10g ZS-9 maintained serum potassium at normal levels. Adverse events, including specifically gastrointestinal effects, were similar with either ZS-9 or placebo.
A double-blind, phase 3 clinical trial in 258 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin-angiotensin system blockers compared ZS-9 with placebo. All patients received 10g ZS-9 three times daily for 48 hours in the initial open-label phase. Patients who achieved normokalemia (serum potassium 3.5-5.0mEq/L) were randomly assigned to receive either ZS-9 (5g, 10g, or 15g) or placebo once daily for 28 days (double-blind phase). 98% of patients (n=237) achieved normokalemia during the open-label phase. During the double-blind phase, once daily 5g, 10g, and 15g ZS-9 maintained serum potassium at normal levels in a significantly higher proportion of patients (80%, 90%, and 94%, respectively) than placebo (46%). Adverse events were generally similar with either ZS-9 or placebo. Hypokalemia occurred in more patients in the 10g and 15g ZS-9 groups (10% and 11%, respectively), versus none in the 5g ZS-9 or placebo groups.
- ZS-9. ZS-Pharma. 
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