Potential new drug treatments for congestive heart failure

ABSTRACT

Introduction: The prevalence of heart failure (HF) has increased globally in recent decades. Advances in our understanding of underlying pathophysiologic mechanisms have given rise to new therapies for treating the growing HF population. Nonetheless, morbidity and mortality associated with HF and its financial implications are daunting. Thus, novel therapies that can improve the natural history of HF patients are urgently needed.

Areas covered: This article reviews new investigational drugs being developed for the treatment of both acute decompensated heart failure (ADHF) and chronic heart failure with reduced ejection fraction (HFrEF). It presents the background of these drugs with a focus on their mechanism of action, their pharmacology, evidence from clinical studies and their potential role in HF management.

Expert opinion: The mortality benefit associated with serelaxin treatment in the RELAX-HF trial is being tested in RELAX-AHF II, while two other drugs, ularitide and TRV027, are also being evaluated in ADHF patients. Two new agents for the treatment of chronic HFrEF, LCZ696 and ivabradine, have been recently been approved for use by the FDA and four novel agents which have shown considerable promise in early studies, omecamtiv mecarbil, vericiguat, finerenone, and neuregulin, are currently being evaluated in late-phase clinical trials.

KEYWORDS:

• Acute decompensated heart failure
• serelaxin
• ularitide
• TRV027
• chronic congestive heart failure
• omecamtiv mecarbil
• vericiguat
• finerenone
• neuregulin

Article highlights

• The medical and socioeconomic burdens of HF continue to tax the US and the rest of the world.

• Neprilysin inhibition and If channel antagonism are successes in a field that has witnessed many failures over recent years.

• In patients with AHF, Serelaxin, a recombinant form of relaxin-2, is associated with more rapid relief of dyspnea than standard therapy alone. In the Phase 3 RELAX-AHF study, administration of Serelaxin over the first 48 hours after admission for an episode of AHF resulted in a significant reduction in cardiovascular and all-cause mortality at 180-d from drug administration. RELAX-AHF II which is designed to confirm the mortality benefits is currently undergoing enrollment.

• Ularitide, a synthetic form of urodilantin, a kidney natriuretic peptide hormone decreases PCWP with significant improvement in symptoms. TRUE-AHF is enrolling AHF patients to determine the effects of this agent on heart failure symptoms and outcomes.

• TRV027, a biased ligand for the AT1 receptor, inhibits Ang II while stimulating β-arrestin signaling and early results indicate improvement in cardiac function. The effects of TRV027 will be tested for symptomatic relief, re-hospitalization and mortality benefit in the ongoing BLAST-HF study.

• Omecamtiv mecarbil is a myosin activator that improves LV stroke volume and cardiac output. Although it increases systolic ejection time clinically important evidence of myocardial ischemia does not appear to occur at doses associated with favorable effects on cardiac function.

• Soluble guanylyl cyclase decrease NT-proBNP levels and has shown some clinical benefits in early studies.

• Finerenone, a non-steroidal MRA, targets mineralocorticoid receptors with a predilection for cardiac tissue (as opposed to the affinity of kidney tissue for both spironolactone and eplerenone) and has been associated with protection against hyperkalemia. The ARTS-HF trial provided evidence that both CV hospitalization and all-cause death may be reduced with this agent.

• Stimulation of the neuregulin pathway with IV recombinant human NRG-1, improves cardiac systolic function and is associated improvement in 6-minute walk test and quality of life.

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Declaration of interest

B Greenberg is a consultant for Novartis, Trevena, Amgen Inc, Bayer Healthcare and Zensun. He is also on the speaker’s bureau for Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.