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Once-daily ZS-9 alleviated hyperkalemia
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NEW YORK — Higher doses of ZS-9, a novel nonpolymer, nonabsorbed cation exchanger, were effective at reducing serum potassium in patients with hyperkalemia who were taking renin-angiotensin-aldosterone system inhibitors.
Bhupinder Singh, MD, FASN, from Apex Research of Riverside in Riverside, Calif., presented a subgroup analysis from a phase 3, multicenter, randomized, double blind, placebo-controlled trial of ZS-9 (ZS Pharma) at the American Society of Hypertension Annual Scientific Meeting. He reported changes in serum potassium in the subgroup (n=502) prescribed renin-angiotensin-aldosterone system inhibitors.
“We know that hyperkalemia is associated with significant mortality in patients with CVD and chronic kidney disease, and it limits the use of long-term cardioprotective and renal-protective renin-angiotensin-aldosterone system inhibitors,” Singh said during the presentation. “Current hyperkalemia therapy is poorly tolerated and not consistently effective. It would be great to have an agent which would be safe and effective and predictable in lowering potassium levels, which can allows us to optimize renin-angiotensin-aldosterone system inhibitor therapy and liberalize diet for our patients.”
The patients, who had serum potassium between 5 mEq/L and 6.5 mEq/L, were randomly assigned to one of five groups for the 48-hour acute phase of the trial. Three times daily, they received placebo or ZS-9 1.25 g, 2.5 g, 5 g or 10 g.
At the end of the acute phase, patients with serum potassium of 3.5 mEq/L to 5 mEq/L were re-randomly assigned in the extended phase of the trial. Those who had received ZS-9 were re-randomly assigned to the same dose of the study drug or placebo once daily. Those who had received placebo were re-randomly assigned to ZS-9 1.25 g or 2.5 g once daily. The extended phase lasted 12 days, Singh said.
Renin-angiotensin-aldosterone system inhibitor therapy remained constant. Approximately 40% to 50% of patients were taking ACE inhibitors, 25% angiotensin receptor blockers and 3% to 7% spironolactone or eplerenone. A few patients were taking combinations, Singh said.
Dose-dependent potassium reduction
At 48 hours, patients assigned ZS-9 5 g had a decrease in serum potassium of –0.53 mEq/L and those assigned ZS-9 10 g had a decrease in serum potassium of –0.73 mEq/L vs. –0.24 mEq/L for those assigned placebo (P<.001 for both comparisons).
“There was a clear dose-dependent reduction in potassium” at 48 hours, Singh said. “In the 10-g-dose group, we saw that potassium normalized in the majority of patients around 4 hours. At 48 hours, about 99% of those patients had normokalemia. We also achieved significance in the 2.5 g dose and the 5 g dose compared to placebo.”
Two hundred sixty-three members of the subgroup entered the extended phase of the trial. Of those initially assigned ZS-9 10 g, patients who continued on the study drug at that dose maintained normokalemia, whereas those switched to placebo saw an increase in serum potassium. The researchers observed similar results for patients initially assigned ZS-9 5 g.
“We achieved statistical significance in the 5 g [once-daily] and 10 g [once-daily] groups, but not in the 2.5 g [once-daily] group,” Singh said. “It was pretty much a dose-dependent response.”
Favorable safety profile
Adverse event profiles were similar between the ZS-9 groups and the placebo group. There was no dose-dependent increase in gastrointestinal adverse events, which had been a concern after the phase 2 study, Singh said, adding that there also were no cases of hypokalemia.
“The favorable safety profile of ZS-9 may be attributed to its inorganic crystal structure, with improved [gastrointestinal] tolerability due to lack of water absorption and swelling of polymeric compound,” he said. “The compound is very stable and insoluble. You’d have to take 15,000 of those tablets to approximate our daily zirconium intake that we get from our food and water.” – by Erik Swain
For more information:
Singh B. Abstract LB-P-04. Presented at: American Society of Hypertension 2014 Annual Scientific Meeting; May 16-20, 2014; New York.
Disclosure: The study was funded by ZS Pharma. Singh reports receiving research funding from ZS Pharma for work on phase 2 and phase 3 trials of ZS-9.