New drugs in preclinical and early stage clinical development in the treatment of heart failure

ABSTRACT

Introduction: Heart failure (HF) represents a major health problem because of its high prevalence, high rates of hospitalizations, and mortality and significant healthcare costs. HF comprises a heterogeneous group of syndromes with different pathophysiology, clinical presentations, and response to therapy. Basic research has identified multiple putative therapeutic targets involved in the pathogenesis of HF and many promising drugs are under development.

Areas covered: This review summarizes the main drugs currently in preclinical and clinical development for HF treatment. Drugs were identified by search of MEDLINE and PubMed and trials from registries (clinicaltrials.gov, clinicaltrialsregister.eu, pubmed.gov) from 2010.

Expert opinion: Despite significant advances in the pharmacological treatment of HF with reduced ejection fraction, no treatment has yet convincingly shown to improve outcomes in patients with HF with preserved ejection fraction and acute HF. Many promising drugs emerged in preclinical models and small phase 2 trials, but with a few exceptions, they fail to meet the primary endpoints in larger adequately powered phase 3 trials. Which new drugs will prove valuable remains uncertain. Improving clinical outcomes, delaying or preventing HF worsening and reducing hospital admissions should be prioritized in future drug development programs.

Trial registration: ClinicalTrials.gov identifier: NCT02173548.

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KEYWORDS:

• Heart failure
• novel investigational drugs
• clinical trials
• acute heart failure
• reduced ejection fraction
• preserved ejection fraction

Article highlights

• Heart failure (HF) is a heterogeneous, multifactorial, and progressive syndrome that represents a major global health problem due to its high prevalence, high rates of hospital admission and mortality, and significant healthcare costs.

• In the last decade new potential therapeutic targets involved in the pathogenesis of HF have been identified and new drugs with novel mechanisms of action (MOA) are currently under preclinical or clinical development.

• A repeated finding is that positive/optimistic results found in preclinical models and early phase II trials were not confirmed in phase III studies. This finding emphasizes the translational gap between basic drug discovery, early clinical research, and pivotal RCTs.

• With only two notable exceptions, the new drugs fail to show an incremental benefit in patients with HF with reduced ejection fraction.

• No treatment has yet been shown, convincingly, to improve clinical outcomes in patients with HF with preserved ejection fraction (HFpEF) or worsening chronic HF (including acutely decompensated HF). Thus, HFpEF and acute HF can be considered at the present time as ‘therapeutic orphan syndromes’.

• These poor results reflect the limited efficacy of current therapeutic approaches and our poor understanding of the pathophysiology of HF, which encompasses multiple syndromes with different phenotypic pathways of progression and response to specific therapies.

• A better understanding of the complex pathophysiology of HF is the first step to develop new drugs delay or prevent the progression of myocardial dysfunction, facilitate reverse remodeling and reduce the morbidity and mortality associated to HF.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank P Vaquero for her invaluable technical assistance.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One of the reviewers on this manuscript has acted as a consultant for Bayer, Astra Zeneca, Sanofi, and scpharmaceuticals and holds stock options for Relypsa. Other peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by grants from the Ministerio de Ciencia e Innovación (SAF2017-88116-P), Instituto de Salud Carlos III [PI16/00398 and CIBER-Cardiovascular (CB16/11/00303)], Comunidad de Madrid (B2017/BMD-3738), Sociedad Española de Cardiología, and BBVA Foundation.