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Sodium Zirconium Cyclosilicate: A Novel Potassium Binder

By: Andrew Leong, Staff Writer

Hyperkalemia is defined as a serum potassium level of greater than 5.0 mmol/L.1 In a majority of cases, the cause is renal in nature with over half of all patients with hyperkalemia suffering from chronic kidney disease.2 Other causes include an increase in diet potassium, tumor lysis syndrome, and medications such as spironolactone and ACE-inhibitors. Without treatment, hyperkalemia can lead to life-threatening cardiac arrhythmias.

Currently, there are two types of treatment for hyperkalemia. One type temporarily shifts extracellular potassium to intracellular spaces. This includes insulin, beta-2-adrenergic agonists, and calcium.3 The other type seeks to remove potassium from the body by binding to it to form a complex, which is then excreted. In the United States, sodium polystyrene sulfonate (SPS) is the only binder we use in the treatment of hyperkalemia. It non-specifically binds to a number of critical ions besides potassium, including magnesium and calcium. The drug is also often concurrently used with sorbitol, an osmotic laxative. When used together, a patient will often have unwanted diarrhea and, worse, be at risk of colonic necrosis, a potentially fatal adverse effect associated with severe gastrointestinal bleeding.

ZS Pharma, a pharmaceutical company, plans to add a new agent—one that does not have the aforementioned concerns of its predecessors—to the list of treatments for hyperkalemia. The new agent, sodium zirconium cyclosilicate (ZS-9), is a non-absorbed cation exchanger that entraps excess potassium ions throughout the GI tract.4 On April 15, 2015, the company announced publications for ZS-9 in two peer reviewed medical journals. These publications articulate the results and analysis of their phase 2 and 3 trials.5

The phase 2 trial was published in Kidney International on February 4, 2015. It was a randomized, double-blind, placebo-controlled trial that sought to show that ZS-9 is safe and efficient for the treatment of hyperkalemia in patients with stage 3 chronic kidney disease. Along with the placebo group, there were three other treatment groups: 0.3 grams, 3 grams, and 10 grams. The results of the study demonstrated that ZS-9 dose-dependently reduces serum potassium. The primary efficacy endpoint—the rate of serum potassium decline in the first 48 hours—was met in the 3 gram group (P = 0.048) and the 10 gram group (P < 0.0001) compared to placebo. At 38 hours, the 10 gram group had a reduction average of 0.92 ± 0.52 mEq/L. Moreover, ZS-9 was found to be well-tolerated. Adverse effects were transient and did not require treatment and included mild constipation, nausea, and vomiting. Diarrhea was only observed in two patients. Although, this being a phase 2 trial, sample sizes were small (12 – 30 per group).6

The phase 3 trial was published in The New England Journal of Medicine on April 16, 2015. It was a multicenter, two-stage, double-blind trial that sought to further the goals of the phase 2 trial by increasing the sample size (753) and exploring other doses (1.25, 2.5, 5, or 10 grams). The results solidified that ZS-9 dose-dependently reduces serum potassium. At 48 hours, there were reduction averages of 0.46 mmol/L (95% confidence interval [CI], −0.53 to −0.39) in the 2.5 gram group, 0.54 mmol/L (95% CI, −0.62 to −0.47) in the 5 gram group, and 0.73 mmol/L(95% CI, −0.82 to −0.65) in the 10 gram group, as compared with a reduction average of 0.25 mmol per liter (95% CI, −0.32 to −0.19) in the placebo group (P<0.001 for all comparisons). The reduction average from baseline at 1 hour after the first 10 gram dose of ZS-9 was 0.11 mmol/L (95% CI, −0.17 to −0.05), as compared to an increase of 0.01 mmol/L (95% CI, −0.05 to 0.07) in the placebo group (P=0.009). Regardless of the severity of hyperkalemia or the presence other comorbidities, all three dosage groups reached normal serum potassium levels within 48 hours (P < 0.001 for all comparisons with placebo). Additionally, in the subgroup of patients with diabetes, heart failure, and eGFR < 60mL/min/1.73m2, normal serum potassium levels were achieved, on average, within 4 hours (P<0.001).7

The company also published another phase 3 trial, known as HARMONIZE (HyperkAlemia RandoMized interventiON multI-dose ZS-9 maintEnance), in The Journal of the American Medical Association on November 17, 2014. The trial, as the name suggests, sought to show the long-term efficacy of ZS-9 as opposed to the short-term focus of the other trials. The trial was split first into a 48-hour open-label, acute phase; patients that achieved normokalemia were then entered into a double-blind, randomized, placebo-controlled maintenance phase for 28 days. The acute phase results solidified past results: a significant change in potassium (−0.2 mEq/L; 95% CI, −0.3 to −0.2) was noted 1 hour after the first 10 gram dose compared with baseline (P<0.001). At 2 and 4 hours after the first dose, mean change in potassium was −0.4 mEq/L (95% CI, −0.5 to −0.4) and −0.5 mEq/L (95% CI, −0.6 to −0.5), respectively (P<0.001 for both time points). The maintenance phase demonstrated that all three doses (5, 10 and 15 grams) maintained mean potassium at lower levels than placebo over the 28 day course (P≤0.0001 for all doses); 80%, 90%, and 94% of patients, respectively, maintained normokalemia. The most common adverse effects patients experienced were anemia, constipation, edema, hypokalemia, nasopharyngitis, and upper respiratory tract infections.8,9

ZS-9 seems to be a promising alternative to SPS—one that does not induce diarrhea or colonic necrosis. ZS Pharma plans to conduct longer term safety and tolerability study while it waits for FDA approval in the first half of 2016.10



  1. Hypokalemia and Hyperkalemia. Cleveland Clinic Web site. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/hypokalemia-and-hyperkalemia/. Published August 2010. Accessed June 30, 2015.
  2. Phillips BM, Milner S, Zouwail S, et al. Severe hyperkalaemia: demographics and outcome. Clin Kidney J. 2014;7(2):127-33.
  3. Allon M, Copkney C. Albuterol and insulin for treatment of hyperkalemia in hemodialysis patients. Kidney Int. 1990;38(5):869-72.
  4. ZS-9. ZS Pharma Web site. http://www.zspharma.com/clinical-development/zs9/. Accessed June 30, 2015.
  5. ZS Pharma Announces Publications in Peer-Reviewed Medical Journals. ZS Pharma Web site. http://investors.zspharma.com/releasedetail.cfm?ReleaseID=906811. Published April 15, 2015. Accessed June 30, 2015.
  6. Ash SR, Singh B, Lavin PT, Stavros F, Rasmussen HS. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient. Kidney Int. 2015.
  7. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222-31.
  8. ZS Pharma Presents Positive Results from HARMONIZE (ZS004), a Second Phase 3 Clinical Trial of ZS-9 in Patients with Hyperkalemia, at the American Heart Association Scientific Meeting and Announces Simultaneous Publication of Results in JAMA. ZS Pharma Web site. http://investors.zspharma.com/releasedetail.cfm?ReleaseID=883265. Published November 17, 2014. Accessed June 30, 2015.
  9. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA. 2014;312(21):2223-33.
  10. Potassium Busters Have Arrived. AJKD blog Web site. http://ajkdblog.org/2014/12/22/potassium-busters-have-arrived/. Published December 22, 2014. Accessed May 2, 2015.

[pubmed_related keyword1=’sodium’ keyword2=’zirconium’ keyword3=’cyclosilicate’]


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