Omecamtiv mecarbil: New player in HF treatment?

Omecamtiv mecarbil (OM), an investigational selective cardiac myosin activator, may reduce the risk of heart failure (HF)-related events or cardiovascular (CV) deaths in patients with chronic HFrEF*, according to the late-breaking GALACTIC-HF** trial presented at AHA 2020.

“OM is the first in a class of heart medicines called myotropes that selectively target cardiac muscle to improve cardiac performance,” said study lead author Prof John Teerlink from the University of California San Francisco, US, in a press release. “In the phase II study that led to GALACTIC-HF, OM increased measures of cardiac performance and function. GALACTIC-HF focused on evaluating the effect of this potential medication on outcomes in patients with chronic HF.”

At a median follow-up of 21.8 months, the incidence of the primary composite outcome of HF event or CV death was lower with OM vs placebo (37 percent vs 39 percent; hazard ratio [HR], 0.92; p=0.03). [AHA 2020, session LBS.01; N Engl J Med 2020;doi:10.1056/NEJMoa2025797]

“[T]he 8 percent lower relative risk … [was] modest but significant … [and] was observed across a broad range of both inpatients and outpatients, including those with moderate or severe HF symptoms and a reduced EF, systolic blood pressure, and renal function,” noted the researchers.

At week 24, change in baseline level of NT-proBNP*** – a hormone that is usually increased with worsening HF – was 10 percent lower with OM vs placebo.

The OM and placebo arms had similar incidences of death from CV causes (19.6 percent vs 19.4 percent; HR, 1.01; p=0.86) or any cause (25.9 percent [both]; HR, 1.00). While this implies that OM did not increase the risk of clinical adverse events (AEs), the researchers underlined these effects on mortality as “surprising”, considering the reduced NT-proBNP level seen in the study, as well as data showing improvements in left ventricular volume and function, and reductions in heart rate and NT-proBNP with OM. [Lancet 2016;388:2895-2903]

“[Moreover,] a prior meta-analysis suggested that treatments that reduce ventricular volumes and increase [EF] are likely to reduce mortality. [In another] meta-analysis, a relationship between a decrease in the NT-proBNP level and a reduction in HF hospitalizations was observed,” they added. [J Am Coll Cardiol 2010;56:392-406; JACC Heart Fail 2018;6:564-569]

Nonetheless, the incidences of adjudicated major cardiac ischaemic events were similar between the OM and the placebo arms (4.9 percent vs 4.6 percent), as were the discontinuation rates (20.6 percent vs 21.9 percent) primarily due to an AE (9.0 percent vs 9.3 percent).

Also, despite the small increase (by 4 ng/L) in baseline plasma level of cardiac troponin I with OM vs placebo at week 24, the similar rates of death and cardiac ischaemic events suggest that OM does not increase the risk of clinical AEs, noted the researchers.

Despite the exclusion of older (>85 years) and clinically unstable patients, as well as the underrepresentation of ethnic groups, GALACTIC-HF saw >8,000 patients with chronic HF (mean age 64 years, 79 percent male) who were either currently hospitalized for HF (25 percent) or had a history of emergency department visit or hospitalization for HF within a year prior to screening. Participants were randomized 1:1 to receive oral placebo or OM 25, 37.5, or 50 mg BID on top of standard HF therapy.

“[Identifying] medicines that increase cardiac performance has been a goal of HF therapeutics for more than a century,” said the researchers. However, most drugs that have been developed have been tied to increased rates of ventricular arrhythmias, myocardial ischaemia, or death. [Eur J Heart Fail 2019;21:1064-1078; JACC Heart Fail 2020;8:329-340]

“[GALACTIC-HF] provides substantial evidence characterizing the efficacy and safety of this novel therapy … [T]hese findings will inform potential future implementation of OM to treat chronic HF,” said Teerlink.

The US FDA has granted Fast Track designation for OM as new treatment alternative for HF. [https://www.amgen.com/newsroom/press-releases/2020/05/fda-grants-fast-track-designation-for-omecamtiv-mecarbil-in-heart-failure, accessed December 12, 2020]