ATLANTA – A novel first-in-class agent that selectively binds cations appears safe and effective for the treatment of hyperkalemia in patients with chronic kidney disease, according to findings from a phase II, dose-ranging proof-of-concept study.
Preliminary data from a phase III study of 753 patients, which was initiated based on the positive findings in the phase II study, similarly demonstrate the safety and efficacy of the selective monovalent cation trap known as ZS-9 (ZS Pharma), Dr. Stephen R. Ash reported at Kidney Week 2013, sponsored by the American Society of Nephrology.
In 90 patients from the phase II study who were randomized to receive either placebo or one of three ZS-9 doses (0.3 g in 12 patients, 3 g in 24 patients, and 10 g in 24 patients), active treatment was associated with significantly greater dose-dependent reductions in serum potassium (K+) than was placebo, said Dr. Ash of Indiana University, Lafayette.
The mean serum K+ level at baseline for both the placebo group and the combined active treatment groups was 5.1 mEq/L. Within 48 hours of treatment initiation, 63% of patients in the 10-g ZS-9 group met the primary end point of at least a 1.0-mEq/L reduction in serum K+, compared with only 17% of patients in the placebo group.
The dose reduction in the 10-g group was "rapid and substantial," with a significant decrease, compared with placebo, occurring within 1 hour of the initial dose. Levels were 0.92-mEq/L lower than baseline after 38 hours (4 hours after the last dose), and 0.68-mEq/L lower than baseline at 48 hours (14 hours after the last dose). The levels remained significantly lower than placebo for an additional 3.5 days after the last dose, Dr. Ash said.
"At every point in the trial for these 10-g–dose patients, the serum potassium was lower in the treatment group than in the control group. ... At 38 hours, almost 90% of the patients who were on the 10-g dose had a serum potassium [level] of less than 4.5," he said.
Participants had mild to moderate chronic kidney disease with a glomerular filtration rate of 30-60 mL/min per 1.73 m2, and mild to moderate hyperkalemia, with serum K+ levels of 5-6 mEq/L.
Treatment with the tasteless, odorless substance, which was delivered orally as a suspension in water three times daily at meal times, was well tolerated. No serious adverse events were reported, and no significant gastrointestinal issues, hypokalemia, hypomagnesemia, or hypocalcemia were observed.
Only one adverse event, a mild case of constipation in the 3-g–dose group, was thought to have a causal relationship to the study drug. No patients withdrew from the study.
The preliminary data from the pivotal randomized, controlled phase III trial also suggest a rapid and dose-dependent reduction in serum K+ in patients treated with ZS-9. In that study, patients were randomized to receive placebo or ZS-9 at doses of 1.25 g, 2.5 g, 5 g, or 10 g three times daily for the initial 48 hours.
Patients whose serum K+ levels normalized during that initial phase of treatment were then randomized to receive placebo or one of the four active drug doses administered daily for 12 days.
Patients in the phase III trial had serum K+ levels of 5-6.5 mEq/L. Those in the 2.5-g, 5-g, and 10-g groups met the primary endpoint, with significantly greater reductions in serum K+, compared with those on placebo, at 48 hours.
The mean serum K+ reduction was 0.73 mEq/L at the 10-g dose at 48 hours. The gastrointestinal adverse event rate was 5.1% in the placebo group patients, and 3.5% in the treatment group.
Final results from the phase III trial are expected in the coming months.
The findings are important because currently only one treatment – sodium polystyrene sulfonate (SPS), an organic polymer resin that nonselectively binds cations – is approved in the United States for the treatment of hyperkalemia – a serious condition that is associated with significant mortality and morbidity in patients with cardiovascular disease or chronic kidney disease.
"Even marginally high potassium levels, such as over 4.5, however, have an increased risk of death and ventricular fibrillation," Dr. Ash explained.
Further, hyperkalemia limits the ability to use cardioprotective and renoprotective agents such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, he said.
The efficacy of SPS for lowering serum K+ levels is questionable, and the agent has been associated with several serious adverse effects, including sodium loading, colonic necrosis, and other fatal gastrointestinal effects, Dr. Ash explained.
ZS-9 differs from traditional nonspecific and nonselective cation exchange organic polymer resins in that it is an inorganic cation exchanger – a result of advances in chemistry for the development of highly selective drug therapies.