New heart failure inotrope could be ‘Holy Grail’

AMSTERDAM – The novel intravenous inotropic agent omecamtiv mecarbil achieved greater reduction in dyspnea scores and less likelihood of worsening heart failure at the highest dose studied, compared with placebo, in patients with acute decompensated heart failure in a phase II, dose-ranging study.

The drug also demonstrated a strong dose-dependent increase in systolic ejection time, no evidence of a proarrhythmic effect, and a greater reduction in heart rate with a larger increase in blood pressure than in placebo-treated controls, Dr. John R. Teerlink reported at the annual congress of the European Society of Cardiology.

Bruce Jancin/IMNG Medical Media

In the overall population on omecamtiv mecarbil, however, which included the patients in the low- and intermediate-dose arms of this dose-ranging study, the dyspnea response rate wasn’t better than with placebo. Hence, the drug’s future is uncertain.

In a press release following Dr. Teerlink’s presentation, Amgen, cosponsor of the phase II ATOMIC-AHF (Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure) trial, said that no decision has been made as to whether to move omecamtiv mecarbil into phase III clinical trials. Dr. Teerlink thinks the drug has earned a shot.

"I personally believe this drug has continued to demonstrate its promise all along the way. It could replace milrinone and dobutamine in the hospital to improve cardiac performance," predicted Dr. Teerlink, professor of medicine at the University of California, San Francisco, and director of the heart failure program at the San Francisco Veterans Affairs Medical Center.

Omecamtiv mecarbil is a novel selective cardiac myosin activator. It increases the entry rate of myosin into the force-producing state with actin. It boosts cardiac output through prolongation of the duration of systole and increased stroke volume, with no change in myocardial contractility and no increases in myocardial oxygen demand or myocyte calcium.

"It’s essentially producing more hands pulling on the rope," the cardiologist explained.

Discussant Theresa A. McDonagh said omecamtiv mecarbil has drawn great interest within the heart failure field because current inotropes are recognized as "very inadequate."

"It is truly a new inotrope, a drug that acts on the sarcomere itself. It does seem to be free of the nemesis of other inotropes: increased heart rate, greater myocardial oxygen consumption, arrhythmia production, and increased mortality in heart failure. It appears to be the Holy Grail, and may be capable of replacing dobutamine and milrinone," said Dr. McDonagh, professor of heart failure at King’s College London.

"I think this [ATOMIC-AHF trial] is a very promising start for omecamtiv mecarbil in acute heart failure," she added.

ATOMIC-AHF included 613 patients with a left ventricular ejection fraction of 40% or less who were hospitalized for acute heart failure with dyspnea at rest or with minimal exertion despite intravenous diuretic therapy. The study was conducted at 106 sites on three continents. Participants were randomized to 48 hours of intravenous placebo or omecamtiv mecarbil in three different ascending dose regimens.

The primary efficacy endpoint, dyspnea at 6, 24, and 48 hours across the three doses, compared with the pooled placebo group, was not met.

However, patients in the highest-dose omecamtiv mecarbil study arm had a 51% rate of significant improvement in dyspnea on a self-rated 7-point Likert scale at 48 hours, a significantly better response than the 37% rate in matched placebo-treated controls (P = .03). This comparison was a prespecified secondary endpoint in the study.

In addition, patients in the middle- and high-dose omecamtiv mecarbil arms had roughly a 45% reduction in the 7-day incidence of worsening heart failure, compared with the 17% rate in controls.

Not only was there no evidence of a proarrhythmic effect with omecamtiv mecarbil, the drug was associated with a 50% reduction in the incidence of supraventricular tachyarrhythmias, compared with placebo, he continued.

A modest increase in troponin I levels was noted in the omecamtiv mecarbil–treated group, but it was unrelated to plasma drug concentrations, which Dr. Teerlink found reassuring. Nevertheless, Dr. McDonagh said the small increases in troponin "should herald some caution amid the enthusiasm here."

The drug’s mechanism of action, which results in greater systolic ejection time, always raises the concern that it might also shorten diastole and compromise coronary perfusion. However, the observed reduction in heart rate makes that seem less likely, she added.

The ATOMIC-AHF study population was narrowly defined and of a profile commonly seen in clinical practice. They had an estimated glomerular filtration rate of about 50 mL/min, and they presented with dyspnea but didn’t have an acute coronary syndrome.

"This study population is an area of great unmet need in heart failure, with mortality rates of about 10% during their hospitalization and 30% at 1 year following discharge," according to Dr. McDonagh.

Nevertheless, it will be important in phase III testing to see how the drug performs in a broader group of heart failure patients, including those with lower estimated glomerular filtration rates, she added.

In an interview, Dr. Teerlink said that before a decision is reached regarding advancement of omecamtiv mecarbil to phase III studies, investigators and the study sponsors first want to see the data from an ongoing phase II dose-finding study of an oral formulation of the drug in chronic heart failure patients. This study, COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure), is still enrolling patients.

"We’ll get the combined data from ATOMIC-AHF and COSMIC-HF and then decide what phase III should look like. There are a lot of options here: IV [intravenous] alone, IV transitioning to chronic oral therapy, or even oral alone," he explained.

"One of the greatest challenges of the ATOMIC-AHF trial has been managing expectations," according to Dr. Teerlink. "Omecamtiv mecarbil is probably one of the most interesting new chemical entities in cardiovascular medicine now, and consequently expectations are very high in the scientific and lay communities."

The studies are sponsored by Amgen and Cytokinetics. Dr. Teerlink has received research grants and/or consulting fees from those companies as well as a handful of others. Dr. McDonagh reported no financial conflicts.

bjancin@frontlinemedcom.com

AMSTERDAM – The novel intravenous inotropic agent omecamtiv mecarbil achieved greater reduction in dyspnea scores and less likelihood of worsening heart failure at the highest dose studied, compared with placebo, in patients with acute decompensated heart failure in a phase II, dose-ranging study.

The drug also demonstrated a strong dose-dependent increase in systolic ejection time, no evidence of a proarrhythmic effect, and a greater reduction in heart rate with a larger increase in blood pressure than in placebo-treated controls, Dr. John R. Teerlink reported at the annual congress of the European Society of Cardiology.

Bruce Jancin/IMNG Medical Media

In the overall population on omecamtiv mecarbil, however, which included the patients in the low- and intermediate-dose arms of this dose-ranging study, the dyspnea response rate wasn’t better than with placebo. Hence, the drug’s future is uncertain.

In a press release following Dr. Teerlink’s presentation, Amgen, cosponsor of the phase II ATOMIC-AHF (Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure) trial, said that no decision has been made as to whether to move omecamtiv mecarbil into phase III clinical trials. Dr. Teerlink thinks the drug has earned a shot.

"I personally believe this drug has continued to demonstrate its promise all along the way. It could replace milrinone and dobutamine in the hospital to improve cardiac performance," predicted Dr. Teerlink, professor of medicine at the University of California, San Francisco, and director of the heart failure program at the San Francisco Veterans Affairs Medical Center.

Omecamtiv mecarbil is a novel selective cardiac myosin activator. It increases the entry rate of myosin into the force-producing state with actin. It boosts cardiac output through prolongation of the duration of systole and increased stroke volume, with no change in myocardial contractility and no increases in myocardial oxygen demand or myocyte calcium.

"It’s essentially producing more hands pulling on the rope," the cardiologist explained.

Discussant Theresa A. McDonagh said omecamtiv mecarbil has drawn great interest within the heart failure field because current inotropes are recognized as "very inadequate."

"It is truly a new inotrope, a drug that acts on the sarcomere itself. It does seem to be free of the nemesis of other inotropes: increased heart rate, greater myocardial oxygen consumption, arrhythmia production, and increased mortality in heart failure. It appears to be the Holy Grail, and may be capable of replacing dobutamine and milrinone," said Dr. McDonagh, professor of heart failure at King’s College London.

"I think this [ATOMIC-AHF trial] is a very promising start for omecamtiv mecarbil in acute heart failure," she added.

ATOMIC-AHF included 613 patients with a left ventricular ejection fraction of 40% or less who were hospitalized for acute heart failure with dyspnea at rest or with minimal exertion despite intravenous diuretic therapy. The study was conducted at 106 sites on three continents. Participants were randomized to 48 hours of intravenous placebo or omecamtiv mecarbil in three different ascending dose regimens.

The primary efficacy endpoint, dyspnea at 6, 24, and 48 hours across the three doses, compared with the pooled placebo group, was not met.

However, patients in the highest-dose omecamtiv mecarbil study arm had a 51% rate of significant improvement in dyspnea on a self-rated 7-point Likert scale at 48 hours, a significantly better response than the 37% rate in matched placebo-treated controls (P = .03). This comparison was a prespecified secondary endpoint in the study.

In addition, patients in the middle- and high-dose omecamtiv mecarbil arms had roughly a 45% reduction in the 7-day incidence of worsening heart failure, compared with the 17% rate in controls.

Not only was there no evidence of a proarrhythmic effect with omecamtiv mecarbil, the drug was associated with a 50% reduction in the incidence of supraventricular tachyarrhythmias, compared with placebo, he continued.

A modest increase in troponin I levels was noted in the omecamtiv mecarbil–treated group, but it was unrelated to plasma drug concentrations, which Dr. Teerlink found reassuring. Nevertheless, Dr. McDonagh said the small increases in troponin "should herald some caution amid the enthusiasm here."

The drug’s mechanism of action, which results in greater systolic ejection time, always raises the concern that it might also shorten diastole and compromise coronary perfusion. However, the observed reduction in heart rate makes that seem less likely, she added.

The ATOMIC-AHF study population was narrowly defined and of a profile commonly seen in clinical practice. They had an estimated glomerular filtration rate of about 50 mL/min, and they presented with dyspnea but didn’t have an acute coronary syndrome.

"This study population is an area of great unmet need in heart failure, with mortality rates of about 10% during their hospitalization and 30% at 1 year following discharge," according to Dr. McDonagh.

Nevertheless, it will be important in phase III testing to see how the drug performs in a broader group of heart failure patients, including those with lower estimated glomerular filtration rates, she added.

In an interview, Dr. Teerlink said that before a decision is reached regarding advancement of omecamtiv mecarbil to phase III studies, investigators and the study sponsors first want to see the data from an ongoing phase II dose-finding study of an oral formulation of the drug in chronic heart failure patients. This study, COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure), is still enrolling patients.

"We’ll get the combined data from ATOMIC-AHF and COSMIC-HF and then decide what phase III should look like. There are a lot of options here: IV [intravenous] alone, IV transitioning to chronic oral therapy, or even oral alone," he explained.

"One of the greatest challenges of the ATOMIC-AHF trial has been managing expectations," according to Dr. Teerlink. "Omecamtiv mecarbil is probably one of the most interesting new chemical entities in cardiovascular medicine now, and consequently expectations are very high in the scientific and lay communities."

The studies are sponsored by Amgen and Cytokinetics. Dr. Teerlink has received research grants and/or consulting fees from those companies as well as a handful of others. Dr. McDonagh reported no financial conflicts.

bjancin@frontlinemedcom.com

AMSTERDAM – The novel intravenous inotropic agent omecamtiv mecarbil achieved greater reduction in dyspnea scores and less likelihood of worsening heart failure at the highest dose studied, compared with placebo, in patients with acute decompensated heart failure in a phase II, dose-ranging study.

The drug also demonstrated a strong dose-dependent increase in systolic ejection time, no evidence of a proarrhythmic effect, and a greater reduction in heart rate with a larger increase in blood pressure than in placebo-treated controls, Dr. John R. Teerlink reported at the annual congress of the European Society of Cardiology.

Bruce Jancin/IMNG Medical Media

In the overall population on omecamtiv mecarbil, however, which included the patients in the low- and intermediate-dose arms of this dose-ranging study, the dyspnea response rate wasn’t better than with placebo. Hence, the drug’s future is uncertain.

In a press release following Dr. Teerlink’s presentation, Amgen, cosponsor of the phase II ATOMIC-AHF (Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure) trial, said that no decision has been made as to whether to move omecamtiv mecarbil into phase III clinical trials. Dr. Teerlink thinks the drug has earned a shot.

"I personally believe this drug has continued to demonstrate its promise all along the way. It could replace milrinone and dobutamine in the hospital to improve cardiac performance," predicted Dr. Teerlink, professor of medicine at the University of California, San Francisco, and director of the heart failure program at the San Francisco Veterans Affairs Medical Center.

Omecamtiv mecarbil is a novel selective cardiac myosin activator. It increases the entry rate of myosin into the force-producing state with actin. It boosts cardiac output through prolongation of the duration of systole and increased stroke volume, with no change in myocardial contractility and no increases in myocardial oxygen demand or myocyte calcium.

"It’s essentially producing more hands pulling on the rope," the cardiologist explained.

Discussant Theresa A. McDonagh said omecamtiv mecarbil has drawn great interest within the heart failure field because current inotropes are recognized as "very inadequate."

"It is truly a new inotrope, a drug that acts on the sarcomere itself. It does seem to be free of the nemesis of other inotropes: increased heart rate, greater myocardial oxygen consumption, arrhythmia production, and increased mortality in heart failure. It appears to be the Holy Grail, and may be capable of replacing dobutamine and milrinone," said Dr. McDonagh, professor of heart failure at King’s College London.

"I think this [ATOMIC-AHF trial] is a very promising start for omecamtiv mecarbil in acute heart failure," she added.

ATOMIC-AHF included 613 patients with a left ventricular ejection fraction of 40% or less who were hospitalized for acute heart failure with dyspnea at rest or with minimal exertion despite intravenous diuretic therapy. The study was conducted at 106 sites on three continents. Participants were randomized to 48 hours of intravenous placebo or omecamtiv mecarbil in three different ascending dose regimens.

The primary efficacy endpoint, dyspnea at 6, 24, and 48 hours across the three doses, compared with the pooled placebo group, was not met.

However, patients in the highest-dose omecamtiv mecarbil study arm had a 51% rate of significant improvement in dyspnea on a self-rated 7-point Likert scale at 48 hours, a significantly better response than the 37% rate in matched placebo-treated controls (P = .03). This comparison was a prespecified secondary endpoint in the study.

In addition, patients in the middle- and high-dose omecamtiv mecarbil arms had roughly a 45% reduction in the 7-day incidence of worsening heart failure, compared with the 17% rate in controls.

Not only was there no evidence of a proarrhythmic effect with omecamtiv mecarbil, the drug was associated with a 50% reduction in the incidence of supraventricular tachyarrhythmias, compared with placebo, he continued.

A modest increase in troponin I levels was noted in the omecamtiv mecarbil–treated group, but it was unrelated to plasma drug concentrations, which Dr. Teerlink found reassuring. Nevertheless, Dr. McDonagh said the small increases in troponin "should herald some caution amid the enthusiasm here."

The drug’s mechanism of action, which results in greater systolic ejection time, always raises the concern that it might also shorten diastole and compromise coronary perfusion. However, the observed reduction in heart rate makes that seem less likely, she added.

The ATOMIC-AHF study population was narrowly defined and of a profile commonly seen in clinical practice. They had an estimated glomerular filtration rate of about 50 mL/min, and they presented with dyspnea but didn’t have an acute coronary syndrome.

"This study population is an area of great unmet need in heart failure, with mortality rates of about 10% during their hospitalization and 30% at 1 year following discharge," according to Dr. McDonagh.

Nevertheless, it will be important in phase III testing to see how the drug performs in a broader group of heart failure patients, including those with lower estimated glomerular filtration rates, she added.

In an interview, Dr. Teerlink said that before a decision is reached regarding advancement of omecamtiv mecarbil to phase III studies, investigators and the study sponsors first want to see the data from an ongoing phase II dose-finding study of an oral formulation of the drug in chronic heart failure patients. This study, COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure), is still enrolling patients.

"We’ll get the combined data from ATOMIC-AHF and COSMIC-HF and then decide what phase III should look like. There are a lot of options here: IV [intravenous] alone, IV transitioning to chronic oral therapy, or even oral alone," he explained.

"One of the greatest challenges of the ATOMIC-AHF trial has been managing expectations," according to Dr. Teerlink. "Omecamtiv mecarbil is probably one of the most interesting new chemical entities in cardiovascular medicine now, and consequently expectations are very high in the scientific and lay communities."

The studies are sponsored by Amgen and Cytokinetics. Dr. Teerlink has received research grants and/or consulting fees from those companies as well as a handful of others. Dr. McDonagh reported no financial conflicts.

bjancin@frontlinemedcom.com