Phase III outcomes bode well for novel hyperkalemia therapies

LAS VEGAS – Positive phase III results for two novel oral therapies for hyperkalemia received an enthusiastic reception at the annual meeting of the Heart Failure Society of America.

That’s because even though spironolactone and eplerenone (Inspra) have a well-established mortality benefit and a class I indication for the treatment of heart failure with reduced ejection fraction, these renin-angiotensin-aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists remain greatly underutilized on account of their associated substantial risk of hyperkalemia.

“I think the availability of new and safe therapies to treat hyperkalemia and maintain patients on a RAAS inhibitor opens up the possibility of further reductions of cardiovascular events and reductions in health care costs in these very high-risk patients,” said Dr. Bertram Pitt, professor of internal medicine at the University of Michigan, Ann Arbor.

The data we have so far is quite promising,” agreed Dr. Gregg C. Fonarow. “There is a large and unmet need for better treatments for hyperkalemia. Many patients end up on RAAS inhibitor doses below those identified in randomized controlled trials and the major guidelines as the target dose.”

“Moreover, I’m impressed that in the United States we find that two-thirds of patients who have a class I recommendation for a RAAS inhibitor according to the guidelines are not being treated with any dose of these agents at all. So I see a large potential benefit in removing that concern and providing a reliable way of greatly reducing the risk of hyperkalemia. That would really meet a very important unmet need,” according to Dr. Fonarow, professor of medicine, director of the Ahmanson-UCLA Cardiomyopathy Center, and cochief of the cardiology division at the University of California, Los Angeles.

The sole approved agent at present for treating hyperkalemia – sodium polystyrene sulfonate (Kayexalate) – is problematic. Approved by the Food and Drug Administration back in 1958 based upon weak data, this agent is nonselective, unpopular, and poorly tolerated, with loose stools or diarrhea a common complaint.

The two new agents with positive phase III results reported at the meeting are patiromer and sodium zirconium cyclosilicate, also known as ZS-9. Patiromer is a nonabsorbed polymer that exchanges calcium for potassium. Its site of action is the lumen of the colon, where potassium concentration is highest. ZS-9 is a highly stable, inert, insoluble, nonabsorbed, inorganic polymer whose selectivity for potassium is 80- to 125-fold greater than that of sodium polystyrene sulfonate.

Patiromer

Dr. Pitt presented a prespecified subgroup analysis of the pivotal, multinational, phase III randomized trial of patiromer. This analysis, intended for an audience of heart failure specialists, was restricted to patients with chronic kidney disease and hyperkalemia who were on a RAAS inhibitor. In all, 102 of them had heart failure; 141 did not. Chronic kidney disease was severe in 45% of subjects, as evident in their estimated glomerular filtration rate of less than 30 mL/min.

Mean serum potassium dropped by about 1 mEq/L over the course of 4 weeks of therapy, regardless of whether a patient had heart failure or not. The benefit occurred quickly, with a mean drop of 0.5 mEq/L seen during the first 3 days of therapy. At the 4-week mark, three-quarters of patients had a normal-range serum potassium of 3.8 mEq/L to less than 5.1 mEq/L. They were then randomized single-blind to continued patiromer or a switch to placebo for another 4 weeks. Serum potassium climbed in placebo-treated controls by an average of 0.8 mEq/L while remaining unchanged in patients on patiromer. Fifty-two percent of heart failure patients on placebo developed hyperkalemia as defined by a serum potassium level of 5.5 mEq/L or more, compared with 8% on patiromer.

The safety profile of patiromer was essentially that of placebo in the pivotal trial, with two exceptions: 3% of patients on active therapy developed mild, transient hypokalemia which was easily corrected, and 7% experienced mild nausea or diarrhea, Dr. Pitt reported.

Relypsa, the company developing the drug, announced that it submitted a New Drug Application to the Food and Drug Administration for patiromer in October, seeking an indication for hyperkalemia.

ZS-9

The ZS-9 phase III study involved 753 hyperkalemic patients, making it the largest-ever trial of a hyperkalemia therapy. Dr. Mohamed El-Shahawy presented a prespecified subgroup analysis focusing on the 300 participants with heart failure, although he noted that the results were no different in the larger group without heart failure.

During the acute phase of the study, when participants were randomized double-blind to one of four t.i.d. doses of ZS-9 or placebo, serum potassium fell in patients on ZS-9 in a dose-dependent fashion. A reduction in serum potassium was observed as early as 1 hour after the first dose. In the highest-dose group, at 10 g three times daily, mean serum potassium fell from 5.3 mEq/L to 4.5 mEq/L.

In the subsequent extended phase of the study, patients on ZS-9 t.i.d. in the acute phase were rerandomized to once-daily ZS-9 or placebo for 12 days. Patients on ZS-9 at 5 g or 10 g once daily maintained normokalemia, while those switched to placebo became hyperkalemic once again by day 12, according to Dr. El-Shahawy of the Academic Medical Research Institute, Los Angeles.

The side-effect profile of ZS-9 was similar to that of placebo, with no significant hypokalemia or GI side effects being noted, he added.

A large, long-term study of ZS-9 for maintenance of normokalemia is ongoing.

Dr. Fonarow noted that another, entirely different approach to reducing the risk of hyperkalemia involves the development of novel, nonsteroidal, cardioselective mineralocorticoid receptor antagonists.

He cited a promising phase II study of one such agent, known for now as BAY 94-8862. That study was conducted in patients with heart failure and mild to moderate chronic kidney disease. Patients assigned to the novel agent had significantly smaller rises in serum potassium than those randomized to spironolactone. Yet BAY 94-8862 reduced levels of B-type natriuretic peptide, amino-terminal brain natriuretic peptide, and albuminuria at least as much as did spironolactone, and with significantly lower rates of worsening renal failure (Eur. Heart J. 2013;34:2453-63).

Once new and better therapies for hyperkalemia enter clinical practice, Dr. Fonarow said, the priorities will be to get patients on RAAS inhibitor therapy who should be on it but now aren’t, as well as to augment dosing up to target levels in those now on suboptimal doses. But access to improved treatments for hyperkalemia also opens the door to another intriguing possibility.

“Could the ability to raise doses of RAAS inhibitors even higher than current target doses without causing hyperkalemia further enhance remodeling and improve clinical outcomes? That could indeed be the case. It’s something we’ll want to test in prospective trials,” he said.

Dr. Fonarow reported serving as a consultant to and/or advisory board member for Medtronic, Novartis, Johnson & Johnson, Bayer, and Amgen. Dr. El-Shahawy is on an advisory board for ZS Pharma and has received research grants from that company as well as Amgen, GlaxoSmithKline, Celgene, and Abbvie. Dr. Pitt reported serving as a consultant to Pfizer, Bayer, Lilly, Relypsa, and Sarfez.

bjancin@frontlinemedcom.com

LAS VEGAS – Positive phase III results for two novel oral therapies for hyperkalemia received an enthusiastic reception at the annual meeting of the Heart Failure Society of America.

That’s because even though spironolactone and eplerenone (Inspra) have a well-established mortality benefit and a class I indication for the treatment of heart failure with reduced ejection fraction, these renin-angiotensin-aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists remain greatly underutilized on account of their associated substantial risk of hyperkalemia.

“I think the availability of new and safe therapies to treat hyperkalemia and maintain patients on a RAAS inhibitor opens up the possibility of further reductions of cardiovascular events and reductions in health care costs in these very high-risk patients,” said Dr. Bertram Pitt, professor of internal medicine at the University of Michigan, Ann Arbor.

The data we have so far is quite promising,” agreed Dr. Gregg C. Fonarow. “There is a large and unmet need for better treatments for hyperkalemia. Many patients end up on RAAS inhibitor doses below those identified in randomized controlled trials and the major guidelines as the target dose.”

“Moreover, I’m impressed that in the United States we find that two-thirds of patients who have a class I recommendation for a RAAS inhibitor according to the guidelines are not being treated with any dose of these agents at all. So I see a large potential benefit in removing that concern and providing a reliable way of greatly reducing the risk of hyperkalemia. That would really meet a very important unmet need,” according to Dr. Fonarow, professor of medicine, director of the Ahmanson-UCLA Cardiomyopathy Center, and cochief of the cardiology division at the University of California, Los Angeles.

The sole approved agent at present for treating hyperkalemia – sodium polystyrene sulfonate (Kayexalate) – is problematic. Approved by the Food and Drug Administration back in 1958 based upon weak data, this agent is nonselective, unpopular, and poorly tolerated, with loose stools or diarrhea a common complaint.

The two new agents with positive phase III results reported at the meeting are patiromer and sodium zirconium cyclosilicate, also known as ZS-9. Patiromer is a nonabsorbed polymer that exchanges calcium for potassium. Its site of action is the lumen of the colon, where potassium concentration is highest. ZS-9 is a highly stable, inert, insoluble, nonabsorbed, inorganic polymer whose selectivity for potassium is 80- to 125-fold greater than that of sodium polystyrene sulfonate.

Patiromer

Dr. Pitt presented a prespecified subgroup analysis of the pivotal, multinational, phase III randomized trial of patiromer. This analysis, intended for an audience of heart failure specialists, was restricted to patients with chronic kidney disease and hyperkalemia who were on a RAAS inhibitor. In all, 102 of them had heart failure; 141 did not. Chronic kidney disease was severe in 45% of subjects, as evident in their estimated glomerular filtration rate of less than 30 mL/min.

Mean serum potassium dropped by about 1 mEq/L over the course of 4 weeks of therapy, regardless of whether a patient had heart failure or not. The benefit occurred quickly, with a mean drop of 0.5 mEq/L seen during the first 3 days of therapy. At the 4-week mark, three-quarters of patients had a normal-range serum potassium of 3.8 mEq/L to less than 5.1 mEq/L. They were then randomized single-blind to continued patiromer or a switch to placebo for another 4 weeks. Serum potassium climbed in placebo-treated controls by an average of 0.8 mEq/L while remaining unchanged in patients on patiromer. Fifty-two percent of heart failure patients on placebo developed hyperkalemia as defined by a serum potassium level of 5.5 mEq/L or more, compared with 8% on patiromer.

The safety profile of patiromer was essentially that of placebo in the pivotal trial, with two exceptions: 3% of patients on active therapy developed mild, transient hypokalemia which was easily corrected, and 7% experienced mild nausea or diarrhea, Dr. Pitt reported.

Relypsa, the company developing the drug, announced that it submitted a New Drug Application to the Food and Drug Administration for patiromer in October, seeking an indication for hyperkalemia.

ZS-9

The ZS-9 phase III study involved 753 hyperkalemic patients, making it the largest-ever trial of a hyperkalemia therapy. Dr. Mohamed El-Shahawy presented a prespecified subgroup analysis focusing on the 300 participants with heart failure, although he noted that the results were no different in the larger group without heart failure.

During the acute phase of the study, when participants were randomized double-blind to one of four t.i.d. doses of ZS-9 or placebo, serum potassium fell in patients on ZS-9 in a dose-dependent fashion. A reduction in serum potassium was observed as early as 1 hour after the first dose. In the highest-dose group, at 10 g three times daily, mean serum potassium fell from 5.3 mEq/L to 4.5 mEq/L.

In the subsequent extended phase of the study, patients on ZS-9 t.i.d. in the acute phase were rerandomized to once-daily ZS-9 or placebo for 12 days. Patients on ZS-9 at 5 g or 10 g once daily maintained normokalemia, while those switched to placebo became hyperkalemic once again by day 12, according to Dr. El-Shahawy of the Academic Medical Research Institute, Los Angeles.

The side-effect profile of ZS-9 was similar to that of placebo, with no significant hypokalemia or GI side effects being noted, he added.

A large, long-term study of ZS-9 for maintenance of normokalemia is ongoing.

Dr. Fonarow noted that another, entirely different approach to reducing the risk of hyperkalemia involves the development of novel, nonsteroidal, cardioselective mineralocorticoid receptor antagonists.

He cited a promising phase II study of one such agent, known for now as BAY 94-8862. That study was conducted in patients with heart failure and mild to moderate chronic kidney disease. Patients assigned to the novel agent had significantly smaller rises in serum potassium than those randomized to spironolactone. Yet BAY 94-8862 reduced levels of B-type natriuretic peptide, amino-terminal brain natriuretic peptide, and albuminuria at least as much as did spironolactone, and with significantly lower rates of worsening renal failure (Eur. Heart J. 2013;34:2453-63).

Once new and better therapies for hyperkalemia enter clinical practice, Dr. Fonarow said, the priorities will be to get patients on RAAS inhibitor therapy who should be on it but now aren’t, as well as to augment dosing up to target levels in those now on suboptimal doses. But access to improved treatments for hyperkalemia also opens the door to another intriguing possibility.

“Could the ability to raise doses of RAAS inhibitors even higher than current target doses without causing hyperkalemia further enhance remodeling and improve clinical outcomes? That could indeed be the case. It’s something we’ll want to test in prospective trials,” he said.

Dr. Fonarow reported serving as a consultant to and/or advisory board member for Medtronic, Novartis, Johnson & Johnson, Bayer, and Amgen. Dr. El-Shahawy is on an advisory board for ZS Pharma and has received research grants from that company as well as Amgen, GlaxoSmithKline, Celgene, and Abbvie. Dr. Pitt reported serving as a consultant to Pfizer, Bayer, Lilly, Relypsa, and Sarfez.

bjancin@frontlinemedcom.com

LAS VEGAS – Positive phase III results for two novel oral therapies for hyperkalemia received an enthusiastic reception at the annual meeting of the Heart Failure Society of America.

That’s because even though spironolactone and eplerenone (Inspra) have a well-established mortality benefit and a class I indication for the treatment of heart failure with reduced ejection fraction, these renin-angiotensin-aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists remain greatly underutilized on account of their associated substantial risk of hyperkalemia.

“I think the availability of new and safe therapies to treat hyperkalemia and maintain patients on a RAAS inhibitor opens up the possibility of further reductions of cardiovascular events and reductions in health care costs in these very high-risk patients,” said Dr. Bertram Pitt, professor of internal medicine at the University of Michigan, Ann Arbor.

The data we have so far is quite promising,” agreed Dr. Gregg C. Fonarow. “There is a large and unmet need for better treatments for hyperkalemia. Many patients end up on RAAS inhibitor doses below those identified in randomized controlled trials and the major guidelines as the target dose.”

“Moreover, I’m impressed that in the United States we find that two-thirds of patients who have a class I recommendation for a RAAS inhibitor according to the guidelines are not being treated with any dose of these agents at all. So I see a large potential benefit in removing that concern and providing a reliable way of greatly reducing the risk of hyperkalemia. That would really meet a very important unmet need,” according to Dr. Fonarow, professor of medicine, director of the Ahmanson-UCLA Cardiomyopathy Center, and cochief of the cardiology division at the University of California, Los Angeles.

The sole approved agent at present for treating hyperkalemia – sodium polystyrene sulfonate (Kayexalate) – is problematic. Approved by the Food and Drug Administration back in 1958 based upon weak data, this agent is nonselective, unpopular, and poorly tolerated, with loose stools or diarrhea a common complaint.

The two new agents with positive phase III results reported at the meeting are patiromer and sodium zirconium cyclosilicate, also known as ZS-9. Patiromer is a nonabsorbed polymer that exchanges calcium for potassium. Its site of action is the lumen of the colon, where potassium concentration is highest. ZS-9 is a highly stable, inert, insoluble, nonabsorbed, inorganic polymer whose selectivity for potassium is 80- to 125-fold greater than that of sodium polystyrene sulfonate.

Patiromer

Dr. Pitt presented a prespecified subgroup analysis of the pivotal, multinational, phase III randomized trial of patiromer. This analysis, intended for an audience of heart failure specialists, was restricted to patients with chronic kidney disease and hyperkalemia who were on a RAAS inhibitor. In all, 102 of them had heart failure; 141 did not. Chronic kidney disease was severe in 45% of subjects, as evident in their estimated glomerular filtration rate of less than 30 mL/min.

Mean serum potassium dropped by about 1 mEq/L over the course of 4 weeks of therapy, regardless of whether a patient had heart failure or not. The benefit occurred quickly, with a mean drop of 0.5 mEq/L seen during the first 3 days of therapy. At the 4-week mark, three-quarters of patients had a normal-range serum potassium of 3.8 mEq/L to less than 5.1 mEq/L. They were then randomized single-blind to continued patiromer or a switch to placebo for another 4 weeks. Serum potassium climbed in placebo-treated controls by an average of 0.8 mEq/L while remaining unchanged in patients on patiromer. Fifty-two percent of heart failure patients on placebo developed hyperkalemia as defined by a serum potassium level of 5.5 mEq/L or more, compared with 8% on patiromer.

The safety profile of patiromer was essentially that of placebo in the pivotal trial, with two exceptions: 3% of patients on active therapy developed mild, transient hypokalemia which was easily corrected, and 7% experienced mild nausea or diarrhea, Dr. Pitt reported.

Relypsa, the company developing the drug, announced that it submitted a New Drug Application to the Food and Drug Administration for patiromer in October, seeking an indication for hyperkalemia.

ZS-9

The ZS-9 phase III study involved 753 hyperkalemic patients, making it the largest-ever trial of a hyperkalemia therapy. Dr. Mohamed El-Shahawy presented a prespecified subgroup analysis focusing on the 300 participants with heart failure, although he noted that the results were no different in the larger group without heart failure.

During the acute phase of the study, when participants were randomized double-blind to one of four t.i.d. doses of ZS-9 or placebo, serum potassium fell in patients on ZS-9 in a dose-dependent fashion. A reduction in serum potassium was observed as early as 1 hour after the first dose. In the highest-dose group, at 10 g three times daily, mean serum potassium fell from 5.3 mEq/L to 4.5 mEq/L.

In the subsequent extended phase of the study, patients on ZS-9 t.i.d. in the acute phase were rerandomized to once-daily ZS-9 or placebo for 12 days. Patients on ZS-9 at 5 g or 10 g once daily maintained normokalemia, while those switched to placebo became hyperkalemic once again by day 12, according to Dr. El-Shahawy of the Academic Medical Research Institute, Los Angeles.

The side-effect profile of ZS-9 was similar to that of placebo, with no significant hypokalemia or GI side effects being noted, he added.

A large, long-term study of ZS-9 for maintenance of normokalemia is ongoing.

Dr. Fonarow noted that another, entirely different approach to reducing the risk of hyperkalemia involves the development of novel, nonsteroidal, cardioselective mineralocorticoid receptor antagonists.

He cited a promising phase II study of one such agent, known for now as BAY 94-8862. That study was conducted in patients with heart failure and mild to moderate chronic kidney disease. Patients assigned to the novel agent had significantly smaller rises in serum potassium than those randomized to spironolactone. Yet BAY 94-8862 reduced levels of B-type natriuretic peptide, amino-terminal brain natriuretic peptide, and albuminuria at least as much as did spironolactone, and with significantly lower rates of worsening renal failure (Eur. Heart J. 2013;34:2453-63).

Once new and better therapies for hyperkalemia enter clinical practice, Dr. Fonarow said, the priorities will be to get patients on RAAS inhibitor therapy who should be on it but now aren’t, as well as to augment dosing up to target levels in those now on suboptimal doses. But access to improved treatments for hyperkalemia also opens the door to another intriguing possibility.

“Could the ability to raise doses of RAAS inhibitors even higher than current target doses without causing hyperkalemia further enhance remodeling and improve clinical outcomes? That could indeed be the case. It’s something we’ll want to test in prospective trials,” he said.

Dr. Fonarow reported serving as a consultant to and/or advisory board member for Medtronic, Novartis, Johnson & Johnson, Bayer, and Amgen. Dr. El-Shahawy is on an advisory board for ZS Pharma and has received research grants from that company as well as Amgen, GlaxoSmithKline, Celgene, and Abbvie. Dr. Pitt reported serving as a consultant to Pfizer, Bayer, Lilly, Relypsa, and Sarfez.

bjancin@frontlinemedcom.com