Laird Harrison

September 13, 2014

SAN FRANCISCO, CA — The experimental drug ZS-9 (ZS Pharma) can safely lower patients' potassium levels, a phase 3 clinical trial has shown[1,2,3].

"We're pretty excited about it," principal investigator Dr Bhupinder Singh (Creighton University School of Medicine, NE) told heartwire. "You see a dose-dependent, very nice reduction in potassium."

Singh, executive director of research and medical affairs at ZS Pharma, presented the results here at the American Heart Association (AHA) High Blood Pressure Research Scientific Sessions 2014 .

The drug was also safe and effective in several subgroups of patients, including those on renin-angiotensin-aldosterone system inhibition therapy (RAASi) and those with heart failure, chronic kidney disease, or diabetes, Singh reported.

Hyperkalemia kills many patients with heart failure and chronic kidney disease. RAASi therapy increases the risk of hyperkalemia, limiting the use of this class of drugs, which includes ACE inhibitors, angiotensin-receptor blockers, and mineralocorticoid-receptor antagonists. The drugs are effective for controlling hypertension and other conditions.

The only product approved by the US Food and Drug Administration to treat hyperkalemia is sodium polystyrene sulfonate with sorbitol, but the drug can cause severe gastrointestinal (GI) symptoms.

A microporous zirconium silicate compound, ZS-9 can selectively entrap monovalent cations, including excess potassium and ammonium ions, in the GI tract. However, it does not swell in the GI tract, limiting GI symptoms.

To test the safety and effectiveness of ZS-9, Singh and colleagues recruited 753 patients with hyperkalemia and divided them into five groups, one of which received placebo while the others took various doses of the compound ranging from 1.25 to 10 g/day.

About two thirds of patients were on RAASi therapy, 60% had chronic kidney disease, 41% had heart failure, and 58% had diabetes. Researchers defined normal potassium as 3.5 to 5.0 mEq/L.

Potassium levels declined in 48 hours in all groups, including placebo. But the sharpest decline was in the 143 patients taking the 10-g dose. Singh presented data only for the 10-g ZS-9 group and the 158 patients in the placebo group.

In both groups, the mean potassium level was 5.3 mEq/L at baseline. Mean change in potassium level at 48 hours was –0.73 mEq/L in the 10-g ZS-9 group and –0.25 mEq/L in the placebo group (p<0.001).

After 48 hours, mean potassium reached normal levels in the 10-g ZS-9 group. Patients on RAASi therapy and those with chronic kidney disease, heart failure, and diabetes also achieved normal mean levels.

Starting on the third day of treatment, potassium levels rose in the placebo group but stayed constant in the 10-g ZS-9 group at about 4.5 mEq/L for 15 days.

Patients appeared to tolerate ZS-9 well, with similar rates of adverse events, including GI symptoms, in the placebo and treatment groups.

The drug does not appear to lower potassium to unsafe levels, said Singh. The greatest reductions in potassium were in patients who started with the highest levels of potassium, and the smallest reductions were in those who started with the lowest levels. "It looks like the effect is self-limiting," he said.

"This looks good," poster session moderator Dr Raymond Townsend (Hospital of the University of Pennsylvania, Philadelphia) told heartwire . "[Hyperkalemia] is an important clinical problem," he said. "It's the bane of nephrology."

He was impressed with the low rate of adverse reactions in patients taking ZS-9 because of the contrast with polystyrene sulfonate. "Tolerability is the issue," he said.

ZS Pharma hopes to submit a new drug application next year, said Singh.

Meanwhile, at least one other company, Relypsa, is developing a drug for the same indication, Townsend said.

The study was funded by ZS Pharma.  Singh is an employee of ZS Pharma. Townsend received an honorarium from Relypsa.


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