Omecamtiv’s Benefit in HFrEF Trial Gets Lukewarm Reception

Novel oral agent omecamtiv mecarbil modestly reduced heart failure events in heart failure with reduced ejection fraction (HFrEF) atop usual therapies, according to the GALACTIC-HF trial.

The primary endpoint of combined cardiovascular death and hospitalization or other urgent treatment for heart failure occurred in 37.0% of omecamtiv mecarbil recipients over a median 21.8 months, compared with a 39.1% incidence among those randomly assigned placebo (HR 0.92, 95% CI 0.86-0.99).

“The modest but significant lowering of the incidence of the primary outcome was observed across a broad range of both inpatients and outpatients, including those with moderate or severe heart-failure symptoms and a reduced ejection fraction, systolic blood pressure, and renal function,” according to a group led by John Teerlink, MD, of San Francisco Veterans Affairs Medical Center and the University of California San Francisco.

GALACTIC-HF was presented at the virtual meeting of the American Heart Association (AHA) and a full manuscript simultaneously published in the New England Journal of Medicine. Topline results had been announced in October.

“While this medication appeared to be safe and well tolerated, the magnitude of benefit was very small and overall disappointing,” commented Gregg Fonarow, MD, of UCLA.

“The data are not particularly encouraging,” said Paul Hauptman, MD, of University of Tennessee Graduate School of Medicine in Knoxville, who was also not part of the study.

To the drug’s defense, Teerlink highlighted the signal of greater treatment effect in patients with an ejection fraction of 28% or less (HR 0.84, 95% CI 0.77-0.92), as opposed to a higher ejection fraction (HR 1.04, 95% CI 0.94-1.16; P=0.003 for interaction).

The cardiac contractility drug appeared safe given the similar rates of cardiac ischemic and ventricular arrhythmia events between study arms.

Yet omecamtiv mecarbil showed no benefit in cardiovascular death (19.6% vs 19.4% for placebo, HR 1.01, 95% CI 0.92-1.11) nor any secondary outcomes in the randomized trial, including improvement in health status as measured by the Kansas City Cardiomyopathy Questionnaire total symptom score.

Thus, GALACTIC-HF was far from a home run in the field of HFrEF, where treatment choices abound.

Omecamtiv mecarbil joins not the group of established heart failure therapies with survival benefit (e.g., angiotensin receptor-neprilysin inhibitors, ACE inhibitors, beta-blockers, mineralocorticoid receptor antagonists) — but the list of new heart therapies with varying survival and health status benefits (e.g., SGLT2 inhibitors, vericiguat), commented Paul Heidenreich, MD, MS, of Stanford University School of Medicine and the VA Palo Alto Health Care System, California, during an AHA press conference.

“There may be a limited role for this agent in clinical practice, if FDA approved, for selected patients who have not responded well to other foundational HFrEF therapies,” Fonarow told MedPage Today.

Yet “given the supportive data for sacubitril/valsartan [Entresto] and at least two SLGT2 inhibitors, plus the distinct possibility that vericiguat gets the FDA nod for patients with advanced HF symptoms, it is not clear how omecamtiv gains traction, even if approved,” argued Hauptman.

The novel agent represents the first cardiac myosin activator, a new class of myotropes that improve myocardial function by directly augmenting cardiac sarcomere function. The drug boosts cardiac contractility by increasing the number of myosin heads that can bind to the actin filament and initiate a power stroke at the start of systole, Teerlink and colleagues explained.

“The real advantage of omecamtiv mecarbil is it doesn’t compete with any of the current therapies,” Teerlink said during the media briefing. He called the drug a “useful adjunct” and cited its lack of effect on potassium, renal function, blood pressure, and heart rate.

GALACTIC-HF included 8,256 adults with an ejection fraction of 35% or less who at the time of screening were either hospitalized for heart failure or had gone to the emergency department or had been hospitalized for heart failure within the prior year.

Average age was 64.5 years. Mean ejection fraction was 26.6% at baseline. Over half of participants were in New York Heart Association class II.

Patients were randomized to oral omecamtiv mecarbil or placebo on top of standard therapy. Drug dose was adjusted according to plasma levels of the drug.

The authors noted that background therapy was “generally excellent,” as nearly one in five people were on sacubitril/valsartan at baseline. Only 2% were on SGLT2 inhibitors.

Plasma cardiac troponin I levels were 4 ng/L higher on omecamtiv mecarbil than placebo.

GALACTIC-HF was limited by the exclusion of people over age 85 and those who were clinically unstable. Women and Black patients were underrepresented, comprising 21% and 7% of the cohort, respectively.