PHILADELPHIA (FRONTLINE MEDICAL NEWS) – ZS-9, an investigational cation exchanger designed to trap potassium in the gut, effectively and rapidly restores and maintains normokalemia in hyperkalemic patients with diabetes and significant renal impairment, according to a subgroup analysis of data from a randomized, placebo-controlled phase III trial.
Treatment with the first-in-class insoluble, nonabsorbed zirconium silicate, which was designed and engineered to have a three-dimensional crystalline lattice structure that preferentially traps potassium ions, was shown to have clinically and statistically significant benefit at daily oral doses of 5 mg and 10 mg, compared with placebo in the overall study population of 753 patients with hyperkalemia and underlying diabetes, heart failure, or chronic kidney disease.
The current analysis included 366 patients who had diabetes and an estimated glomerular filtration rate less than 60 mL/min/1.73m2. The patients, who had baseline potassium levels of 5.0-6.5 mEq/L (mean of 5.3 mEq/L) were randomized to oral ZS-9 at doses of 1.25, 2.5, 5, or 10 g or placebo given three times daily for the first 48 hours. Following this acute phase, those with a potassium level of 3.5-5.0 mEq/L were rerandomized to either the same ZS-9 acute-phase dose once daily for days 3-15 or placebo.
In the subgroup, ZS-9 treatment was associated with a significant decrease in potassium at 48 hours (decreases of -0.45, -0.59, and -0.81 mEq/L in the 2.5-, 5-, and 10-g groups, respectively, compared with +0.24 mEq/L in the placebo group, Dr. Bhupinder Singh reported at the meeting sponsored by the American Society of Nephrology.
During the maintenance phase, patients receiving a 10-g dose of ZS-9 maintained normokalemia (4.5 mEq/L at day 3 vs. 4.6 mEq/L at day 15) vs. placebo (4.4 mEq/L at day 3, vs. 5.1 mEq/L at day 15). Similar results were seen in the 5-mg treatment group, Dr. Singh of Apex Research, Riverside, Calif. said.
“Hyperkalemia is a common and serious complication in patients with diabetes who have chronic kidney disease, particularly those who are treated with renin-angiotensin-aldosterone system (RAAS) inhibitors. Even mild to moderate hyperkalemia has been recently shown to be associated with increased mortality,” Dr. Singh said, noting that concerns about the seriousness of hyperkalemia have likely led to under-prescription of RAAS inhibitors, which have been proven to have cardio- and renoprotective action, but which are associated with hyperkalemia.
In head-to-head in vitro studies, ZS-9 has been shown to be more than 125 times more selective than sodium polystyrene sulfonate (SPS) – the current mainstay of treatment for hyperkalemia), and to have more than 9 times the potassium-binding capacity.
In the current analysis, ZS-9 was associated with a “fairly acute” effect, reducing potassium levels significantly within 1 hour, and to less than 5 mEq/L within 4 hours. The study also was published Nov. 21 in the New England Journal of Medicine ( doi:10.1056/NEJMoa1411487 ).
In both the overall study population and the subgroup with diabetes and chronic kidney disease, ZS-9 discontinuation at the end of the study was associated with recurrence of hyperkalemia, indicating a need for continued use. The adverse event profile was similar in the treatment and placebo groups in both studies.
The findings suggest that long-term treatment with ZS-9 may allow continuation of chronic RAAS inhibition in patients with diabetes and chronic kidney disease, Dr. Sing said, adding that long-term treatment studies are underway.
This study was funded by ZS Pharma Inc., which is developing ZS-9. Dr. Singh is a consultant to ZS Pharma Inc.