New Drug For Hyperkalemia Selectively Traps Potassium Interview with:
David K. Packham, M.B., B.S., M.D
Royal Melbourne Hospital
Melbourne Renal Research Group VIC 3073, Australia,

Medical Research: What is the background for this study? What are the main findings?

Dr. Packham:  ZS-9 represents a new mechanism of action for addressing hyperkalemia. Unlike traditional nonspecific organic polymer cationexchangers, ZS-9 is a non-absorbed, inorganic crystalline potassium-selective cation exchanger that traps excess potassium in the gastrointestinal tract. It has been evaluated in three prospective, randomized, double-blind, placebo-controlled studies with over 1100 patients to date, representing the largest ever clinical development program for hyperkalemia.

ZS-003 was the first of two pivotal Phase 3 studies that evaluated the safety and efficacy of ZS-9 in patients with hyperkalemia. In ZS-003, treatment of patients with an oral suspension of ZS-9 (2.5, 5, or 10 grams, three times a day) resulted in statistically significant and clinically meaningful reductions in serum potassium, compared with placebo, during the “acute phase” (first 48 hours), with 99 percent of patients achieving normal potassium levels with the highest 10 gram dose. During the next 12 days of the trial (the “maintenance phase”), ZS-9 (5 or 10 grams) given once daily could maintain the corrected potassium levels achieved during the acute phase. In contrast, patients who were randomized back to placebo after achieving normal potassium reverted back to hyperkalemia. The tolerability profile has been favorable, with adverse event rates from ZS-9 similar to that of placebo.

Medical Research: What should clinicians and patients take away from your report?

Dr. Packham:  Hyperkalemia increases the risk of mortality and limits use of life-saving renin angiotensin-aldosterone inhibitors (RAASi) in patients with heart failure (HF), chronic kidney disease (CKD), and diabetes mellitus (DM). Current therapies for hyperkalemia include loop diurectics and nonspecific organic polymer resins (eg, sodium polystyrene sulfonate); however, these have inconsistent, questionable efficacy and carry significant gastrointestinal intolerability. From our studies, ZS-9 has been observed to rapidly and predictably lower and maintain normal serum potassium levels, while demonstrating a favorable safety and tolerability profile. ZS-9 offers potential promise for a safe and effective new therapy which will enable life saving cardio- and renoprotective RAAS therapies in patients with heart failure, CKD, and DM. Furthermore, other observations suggest that ZS-9 has may improve serum bicarbonate, thus demonstrating potential to improve metabolic acidosis, a key factor in the progression of kidney disease.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Packham:  There are 4 potential areas for future research under consideration:

  • Emergency department setting for acute therapy of hyperkalemia: Subgroup analyses of our studies have consistently shown that the potassium lowering effect of ZS-9 is rapid (within an hour) and has greatest potency among patients with the severest cases of hyperkalemia (ie, serum potassium ≥6mEq/l). Based on our observations in these studies, we believe that ZS-9 has potential to be an alternative therapy to emergent dialysis in emergency or hospital settings.
  • Long term safety and efficacy: ZS-005 is an ongoing study that is evaluating ZS-9 as long-term (≥12-month) therapy for patients who require chronic treatment for hyperkalemia.
  • Dialysis patients: The ability to address hyperkalemia on non-dialysis days, reduce the pre-dialysis potassium levels to enable lower potassium baths, and liberate diet are exciting considerations for a non-polymer based therapy, such as ZS-9, which does not adversely interact with polymer phosphate binders.
  • Transplant patients: Anti-rejection medications carry the risk of hyperkalemia and threaten the ability to optimize transplant medications. Maintenance of normal potassium in transplant patients with ZS-9 may permit optimal use of transplant medications.
  • ACEi, ARB, and Mineralocorticoid Dose Optimization: Hyperkalemia is often the rate-limiting side effect of these important RAAS medications. Clinical studies of ZS-9 have demonstrated that its effect is independent of concomitant use of RAAS therapies. Dose optimization may be permitted for such therapies that are no longer limited because of hyperkalemia.


Sodium Zirconium Cyclosilicate in Hyperkalemia

David K. Packham, M.B., B.S., M.D., Henrik S. Rasmussen, M.D., Ph.D., Philip T. Lavin, Ph.D., Mohamed A. El-Shahawy, M.D., M.P.H., Simon D. Roger, M.D., Geoffrey Block, M.D., Wajeh Qunibi, M.D., Pablo Pergola, M.D., Ph.D., and Bhupinder Singh, M.D.

N Engl J Med 2015; 372:222-231 January 15, 2015 DOI: 10.1056/NEJMoa1411487

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