On 13 November, results of the GALACTIC-HF trial were presented at the Annual Scientific Sessions of the American Heart Association (AHA), confirming the hypothesis that selectively increasing cardiac function with a cardiac myosin activator (myotrope) can improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). This lays the foundations for the anticipated approval of the first of a novel class of myotropes likely to be used as adjunct therapies, which will contribute to the diversification of the HFrEF market space.
GALACTIC-HF was a randomised, double-blind, placebo-controlled, Phase III trial that investigated the effects of Amgen’s omecamtiv mecarbil (OM) in HFrEF patients. OM is a novel, selective myotrope that directly increases systolic function. Over 8,000 patients with symptomatic chronic heart failure (HF) with ejection fractions of less than or equal to 35%, who were treated with standard-of-care (SoC) therapies, were enrolled in the trial, representing one of the broadest ranges of HFrEF patients recruited to HF trials. Patients were randomized in a 1:1 ratio to receive either oral OM or placebo as an add-on therapy to SoC. GALACTIC-HF met its primary endpoint with a significant 8% reduction in the risk of the composite outcome of time to first HF event or cardiovascular (CV) death in the OM group compared to the placebo group (p value of 0.025).
These findings represent a significant development in a field that has often been plagued by setbacks. Despite extensive research efforts, no HFrEF therapies targeting decreased systolic function have improved patient outcomes to date. Indeed, most of these agents have been associated with an increased risk of mortality, as seen with the beta-1 adrenergic receptor agonist xamoterol fumarate, the phosphodiesterase-3 inhibitor milrinone, and the sodium-potassium ATPase inhibitor flosequinan. Decreased systolic function represents the fundamental central defect and initiating factor in HFrEF. GlobalData estimates the diagnosed prevalence of HFrEF was over 11 million cases across the eight major markets (8MM) (US, France, Germany, Italy, Spain, UK, Japan and China) in 2018.
However, GALACTIC-HF’s findings still fall short of industry expectations. When considered in isolation, neither of the components of the primary composite endpoint, risk of first HF event and risk of CV death, were significantly different between the OM and placebo groups. Additionally, no significant difference was identified in the secondary endpoint, change in Kansas City Cardiomyopathy Questionnaire from baseline to week 24, between these groups. This raises questions about OM’s practice-changing potential, particularly in the context of an increasingly crowded market landscape. For example, the anti-diabetes sodium-glucose co-transporter 2 (SGLT-2) inhibitor drug class has recently received a label expansion for HFrEF. GlobalData anticipates immediate and high uptake of this drug class as an add-on therapy to SoC, which may in turn limit the uptake of other add-on therapies such as OM. The launch of AstraZeneca’s SGLT-2 inhibitor Farxiga (dapagliflozin) in HFrEF is expected to be the main driver of overall HF market growth in the 8MM throughout 2028.
However, OM’s safety data were highly encouraging, with the drug demonstrating a similar adverse event (AE) profile to placebo. Additionally, OM was not associated with significant effects on systolic blood pressure, potassium homeostasis, or renal function. This represents a strong redeeming feature that is likely to appeal to many patients, particularly as several established therapies are associated with side effects such as reduced blood pressure, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). Many patients who would derive benefit from these medications are unable to take them due to the adverse impact on blood pressure.
If OM is approved, Amgen could target it to patients with more severely reduced systolic function. Interestingly, the subgroup of patients with an ejection fraction less than or equal to 28% were found to derive the greatest benefit from the therapy. Comprehensive analyses of the effects of OM in specific subgroups are still ongoing, and are likely to be eagerly anticipated across the field.