LAS VEGAS – A novel, highly selective, oral potassium ion–binding agent called ZS-9 effectively reversed hyperkalemia in patients with underlying diabetes, heart failure, or chronic kidney disease.
ZS-9’s safety and tolerability matched those of placebo in the double-blind trial, which was the largest phase III treatment trial ever conducted in patients with hyperkalemia, Dr. Bhupinder Singh said at a meeting sponsored by the National Kidney Foundation.
Dr. Bhupinder Singh
ZS-9 is an inorganic, microporous crystal composed of zirconium silicate. It is insoluble, highly stable, and not systemically absorbed. In vitro it is more than 125 times more selective for potassium ions than is sodium polystyrene sulfate (SPS, brand name Kayexalate), the resin-based therapy traditionally used in hyperkalemia. ZS-9 also has nine times greater potassium ion binding capacity than SPS, according to Dr. Singh, of Apex Research in Riverside, Calif.
He reported on 753 patients with serum potassium levels of 5.0-6.5 mEq/L; 60% had chronic kidney disease, 40% had heart failure, and 60% had diabetes. Two-thirds of the patients were on an ACE inhibitor or an angiotensin receptor blocker (ARB). Importantly, 28% of subjects had an estimated glomerular filtration rate below 29 mL/min per 1.73 m2.
Subjects were randomized to one of four dosing regimens of ZS-9 or to placebo. For the first 48 hours of the study, patients received oral ZS-9 at doses of 1.25, 2.5, 5, or 10 g t.i.d. or placebo. Patients whose serum potassium levels normalized after 48 hours were then switched to once-daily doses of the same strengths or to placebo for 12 days in order to evaluate ZS-9’s safety and efficacy as a maintenance therapy.
The average reduction from baseline at 48 hours in serum potassium (as measured 14 hours after the last dose) was 0.46 mEq/L in the 2.5-g t.i.d. group, 0.54 mEq/L in 5-mg t.i.d. group, and 0.73 mEq/L in the 10-mg t.i.d. group. Normokalemia was attained at a similar rate in all patient subgroups, regardless of their underlying hyperkalemia-promoting disease. ZS-9 at 1.25 g t.i.d. wasn’t significantly more effective than placebo.
The higher a patient’s baseline serum potassium, the larger the absolute drop in response to a given dose. At 10 mg t.i.d., for example, patients with a baseline serum potassium level of 5.3 mEq/L or less averaged a 0.58-mEq/L reduction. Those who started at 5.4-5.5 mEq/L averaged a 0.98-mEq/L decrease, and patients with a baseline serum potassium level in excess of 5.5 mEq/L had a 1.10-mEq/L reduction.
Of patients who were on ZS-9 at 10 mg t.i.d. for the acute phase of the study, 99% were normokalemic at 48 hours.
All told, 542 patients entered the 12-day maintenance therapy phase. The two higher dosing regimens – 5 and 10 mg once daily – provided clinically and statistically significant benefit, with serum potassium levels remaining flat throughout the study period. Those who were switched double-blind to placebo after 12 days on ZS-9 immediately experienced a rise in their serum potassium. For example, patients with a serum potassium at 4.6 mEq/L during 12 days on ZS-9 at 10 mg climbed on average to a serum potassium of 5.0 mEq/L after 1 week on placebo.
Serum sodium, magnesium, and calcium did not change, nor did blood pressure or body weight in ZS-9-treated patients. There were no cases of significant hypokalemia (values below 3.0 mEq/L) in the study. Two of 11,000 serum potassium measures were less than 3.5 mEq/L. The side-effect profile of ZS-9 was basically the same as that of placebo. The incidence of nausea, vomiting, and other gastrointestinal adverse effects was actually more than twice as high with placebo than it was with active therapy, according to Dr. Singh.
Ongoing and planned studies of ZS-9 include an open-label, 12-month study and a 1-month, randomized treatment withdrawal with long-term extension.
Dr. Singh cited two major candidates for ZS-9 in clinical practice. One is in the large subgroup of patients with heart failure, diabetic kidney disease, or proteinuric nephropathy who become hyperkalemic on optimal doses of guideline-recommended therapy with an ACE inhibitor or ARB. The other potential beneficiaries are patients who would like to follow a healthy diet emphasizing vegetables, fruits, and low-fat dairy products, many of which are quite high in potassium content.
Dr. Singh reported serving as a consultant to ZS Pharma, which is developing ZS-9, as well as to Keryx Biopharmaceuticals and Concert.