Potassium-Binding Agent Relieves Hyperkalemia in Phase 3 Study

December 04, 2014

CHICAGO, IL — A polymer-based oral agent that sequesters potassium in the intestine, zirconium cyclosilicate, or ZS-9 (ZS Pharma), given to patients with hyperkalemia brought serum potassium levels into the normal range within hours of the first dose for most patients and sustained the benefit over a month, in a phase 3 trial reported here at the American Heart Association (AHA) 2014 Scientific Sessions[1]. The study's top-line results had been released 2 months earlier and reported at the time by heartwire .

The effect was seen at all of three tested dosage levels of the drug, which had "a tolerability profile that was comparable to that of placebo," according to the study, published November 17, 2014 in the Journal of the American Medical Association to coincide with its presentation at the meeting by lead author Dr Mikhail Kosiborod (Saint Luke's Mid America Heart Institute, Kansas City, MO).

The positive results applied consistently across prespecified patient subgroups, including those with heart failure or diabetes and those on renin-angiotensin-aldosterone-system (RAAS) inhibitors, observed Kosiborod. And, he said, potassium levels fell more sharply among patients who started out with the highest levels. (Hyperkalemia is a frequent side effect of ACE inhibitors, angiotensin-receptor blockers [ARBs], and especially aldosterone inhibitors, all widely used by patients with hypertension or heart failure.)

As the assigned discussant after presentation of the trial, called Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance (HARMONIZE), Dr Bertram Pitt (University of Michigan School of Medicine, Ann Arbor) pointed out that despite the apparent short-term efficacy of ZS-9, little is known about the longer-term effects of an agent that might be taken for years.

And, Pitt noted, there was a suggestion of edema as a side effect, observed in 14% of patients taking the highest dosage. As the drug works by exchanging potassium for sodium ions, "we have to at least ask the question, is [the edema] related to the sodium? Perhaps not, but we need an explanation for the increased edema."

"No Evidence of Sodium-Loading"

Pitt proposed further questions regarding both ZS-9 and another investigational ion-exchanging potassium sequestrant, patiromer (Relypsa): how should serum potassium and renal function be monitored while patients are on the agents? What are the risk/benefit and cost implications of giving them long term, compared with standard measures such as RAAS-inhibitor dosage reduction or discontinuation?

"We have looked at this very carefully, and there does not appear to be any evidence of sodium loading" from treatment with ZS-9, Kosiborod replied during the subsequent discussion. "There was no change in body weight, no change in blood pressure, and no change in urinary sodium excretion."

As to whether ZS-9 interferes with other drug therapy, Kosiborod noted that "patients who have hyperkalemia have a lot of comorbidities and are on multiple medications for chronic kidney disease [CKD], heart failure, hypertension, and so on." But, he said, "We have not seen any evidence of drug-drug interactions that are clinically meaningful in any way."

Both potassium-binding agents are fairly advanced in the research needed to move toward possible approval. In addition to the phase 3 HARMONIZE trial, a larger placebo-controlled study of patients given ZS-9 demonstrated a similar degree of efficacy and safety over 12 days of treatment[2]. In another placebo-controlled study, for which Pitt was senior investigator, patiromer given for 4 weeks seemed to safely control potassium levels in patients on RAAS inhibitors who had CKD[3]. Both studies had been previously reported by heartwire based on presentations at the Heart Failure Society of America 2014 Scientific Meeting in September.

Open-Label and Double-Blind Phases

HARMONIZE had enrolled 258 patients with serum potassium levels of at least 5.1 mEq/L at 44 centers in the US, Australia, and South Africa, following them for 48 hours after initiating open-label oral ZS-9 at 10 g three times daily.

Potassium levels dropped by a mean of 0.4 mEq/L after 2 hours, from a baseline mean of 5.6 mEq/L. The total mean decline reached 0.5 mEq/L after 4 hours (P<0.001 vs baseline for both). Mean levels had fallen to 4.5 mEq/L at 48 hours.

Normokalemia (3.5–5.0 mEq/L) had been achieved by 84% of patients at 24 hours and 98% by 48 hours, at which time the mean was 4.5 mEq/L, Kosiborod reported. Of those achieving normokalemia, 237 were randomized in double-blind fashion to receive ZS-9 at one of three dosage levels or placebo and were followed through day 29. Potassium levels were significantly reduced vs placebo at all three dosages (P<0.001 for each).

Outcomes with ZS-9 at Three Dosages vs Placebo Over 29 Days

End points 5 g (n=45) 10 g (n=51) 15 g (n=56) Placebo (n=85)
K day 29, mEq/L (P vs placebo) 4.8 (<0.001) 4.5(<0.001) 4.4 (<0.001) 5.1
Normokalemic day 29, % (P vs placebo) 71.1 (0.01) 76.0 (0.002) 85.2 (<0.001) 47.6
Edema, % 2.2 5.9 14.3 2.4
K=potassium level

Hypokalemia, defined as potassium <3.5 mEq/L, was seen in 9.8% of the 10-mg/day group and 10.7% of the 15-mg/day group, as compared with none in the 5-mg/day and placebo groups. In no case did potassium levels fall below 3.0 mEq/L, and hypokalemia resolved after treatment, the group reported. "Nevertheless, monitoring for hypokalemia and appropriate dose optimization should be incorporated with higher doses of zirconium cyclosilicate."

The current findings "suggest that zirconium cyclosilicate may represent a promising new therapy for the acute and short-term (ie, 28-day) treatment of outpatients with mild hyperkalemia," writes Dr Bradley S Dixon (VA Medical Center and University of Iowa, Iowa City) in an accompanying editorial[4].

"However, longer-term studies are needed to assess the clinical benefits and risks that may be related to more extended use of this product, especially among hospitalized patients, as well as those with more severe hyperkalemia, other medical conditions, and other medications that affect potassium homeostasis."

HARMONIZE was funded by ZS Pharma, for which Kosiborod discloses having served as a consultant. Disclosures for the coauthors are listed in the article. Pitt discloses receiving fees from Pfizer, Bayer, AstraZeneca, Stealth Peptides, Sarfez, Novartis, Johnson & Johnson, Oxygen Biotherapeutics, Eli Lilly, Relypsa, Tricida, scPharmaceuticals, DaVinci Therapeutics, and Aura Sense; he also reports a pending patent "related to site-specific delivery of eplerenone to the myocardium." Dixon discloses having received grants or personal fees from Proteon Therapeutics, Shire Regenerative Medicine, Novita Therapeutics, Humacyte, Reata Pharmaceuticals, AbbVie, Flow Forward Medical, and Metactive Medical.

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