The Evolving Landscape of Heart Failure Therapies

Heart failure (HF) is a leading cause of disability worldwide and has a major impact on the global economy and healthcare systems. It is estimated that around 64 million people worldwide live with HF and about half will die within 5 years of disease diagnosis. HF is a major cause of hospitalizations in patients aged 65 and above. The severity of the disease warrants the development of innovative solutions to address the current treatment gap.

Based on left ventricular ejection fraction, HF is classified as HF with reduced ejection fraction (HFrEF), mildly reduced ejection fraction (HFmrEF), and preserved ejection fraction (HFpEF). Sodium-glucose transport protein 2 (SGLT-2) inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and renin-angiotensin system inhibitors are the four main therapeutic classes included in guideline-directed medical therapy for HFrEF.  Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and angiotensin receptor-neprilysin inhibitors (ARNIs) are recommended as first-line agents in HFrEF. SGLT-2 inhibitors, mineralocorticoid receptor antagonists, and ARNIs are recommended (class 2) for HFpEF.

The Paradigm of Heart Failure Therapy has Evolved Considerably Over the Past Decades

Therapeutic approaches in the 1970s focused on the empirical management of HF involving the relief of symptoms such as edema and dyspnea. The effect of hemodynamics on HF progression was unknown at that time. The Vasodilator in Heart Failure Trial (V-HeFT) was the first study to demonstrate the role of hemodynamics in HF progression. The study, published in 1986, showed that vasodilators such as hydralazine and isosorbide dinitrate can reduce mortality outcomes in patients with chronic HF. However, these effects on mortality were not observed with other vasodilators such as prazosin, prompting that additional mechanisms are involved in HF progression.

The Studies of Left Ventricular Dysfunction (SOLVD) biomarker study and other similar studies shifted the focus of HF therapy from hemodynamic to neurohormonal modulation. The SOLVD biomarker study found that neurohumoral activation precedes the development of HF symptoms. In 1987, the COoperative North Scandinavian ENalapril SUrvival (CONSENSUS) study found a beneficial effect on mortality with angiotensin-converting enzyme (ACE) inhibitor enalapril.

Further research in HF found the beneficial effects of beta-blockers in decreasing morbidity and mortality. More recent developments in the treatment landscape involve the use of ARNI and SGLT-2 inhibitors.

Current Market Leaders

Entresto (Sacubitril and Valsartan) - Novartis

A combination of sacubitril and valsartan, Novartis' blockbuster Entresto was first approved by the US Food and Drug Administration (FDA) to treat HFrEF in July 2015. It is also approved to treat symptomatic HF with systemic left ventricular systolic dysfunction in pediatric patients. In February 2021, Entresto was FDA-approved to treat patients with HFpEF, a form of HF that has very limited treatment options. Entresto, a major growth driver for Novartis, made $4.64bn in sales in 2022. However, the blockbuster drug is set to face generic competition in the coming years with several of its patents expiring in the next few years.

Jardiance (Empagliflozin) - Boehringer Ingelheim/Eli Lilly

Jardiance (empagliflozin) is an SGLT-2 inhibitor that was initially approved for type 2 diabetes. In 2021, Jardiance was FDA-approved to reduce the risk of cardiovascular death plus hospitalisation for HF in adults with HFrEF. In 2022, the FDA approved Jardiance to treat adults with HFpEF. As per Boehringer Ingelheim, Jardiance generated 5.8 billion euros ($6.1 billion) of sales in 2022. Apart from type 2 diabetes and HF, Jardiance is also approved for chronic kidney disease.

Verquvo (Vericiguat) - Bayer / Merck Sharp & Dohme’s

Verquvo (vericiguat), from Merck and Bayer, won FDA approval in January 2021 for HFrEF patients. The drug is proven to significantly reduce the risk of cardiovascular death or hospitalization due to HFrEF in patients who have had a recent worsening HF event. Vericiguat is a soluble guanylate cyclase (sGC)-stimulator that restores the deficient NO-sGC-cGMP pathway - a key pathway responsible for Hf progression. A crowded HF market and Verquvo’s indication for a selected patient population, make the drug capable of only modest revenue.

Farxiga/ Forxiga (Dapagliflozin) - AstraZeneca

Just like Jardiance, Farxiga (dapagliflozin) is an SGLT-2 inhibitor that is FDA-approved to cut the risk of cardiovascular (CV) death, HF hospitalisation, and urgent HF visits in HF patients regardless of their left ventricular ejection fraction status. Previously, the drug was approved in HFrEF. Apart from HF, Farxiga is approved for type 2 diabetes and chronic kidney disease.

Jardiance had an edge ahead of Farxiga due to its early FDA nod to treat HF patients regardless of left ventricular ejection fraction. However, despite this, Farxiga has been growing tremendously across its approved indications. In 2022, Farxiga generated a global revenue of $4.3 billion across its three indications, growing 46% year over year.

Kerendia/Firialta (Finerenone) - Bayer

Finerenone is a non-steroidal, selective mineralocorticoid receptor antagonist that has been shown to block the harmful effects of MR overactivation, which contributes to CKD progression and cardiovascular damage. Kerendia (finerenone) is approved by the US FDA for reducing the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for HF in adult patients with chronic kidney disease associated with type 2 diabetes. As per Bayer’s company reports, Kerendia generated a revenue of 67 million euros ($73 million) in Q2 2023.

Several trials are investigating the role of finerenone in the treatment of HF across a broad spectrum of patients and clinical settings. With more than 15,000 patients in total, the new studies will evaluate the efficacy and safety of finerenone in HFrEF, HFpEF and mildly reduced (HfmrEF).

Heart Failure Therapies in Development

Dapansutrile (OLT1177) - Olatec Therapeutics

Heart failure has a pro-inflammatory pathology caused by enhanced IL-1β activity and mediated by the NLRP3 inflammasome. Dapansutrile (OLT1177) is a selective NLRP3 inflammasome inhibitor targeting IL-1β. In HF, IL-1β is responsible for reversible cardiac dysfunction. IL-1β processing via the NLRP3 inflammasome and the downstream signaling via IL‑1 receptor leads to the development of coronary heart disease, myocardial remodeling and HF. Dapansutrile was found to be well tolerated in subjects with stable systolic HF symptomatic for NYHA functional classification II-III and left ventricular ejection fraction (LVEF) ≤40% in a phase 1b trial.

Myeloperoxidase inhibitor (AZD4831) - AstraZeneca

Myeloperoxidase (MPO) plays a key role in atherogenesis. Elevated levels of MPO are found to be associated with cardiopathies and chronic HF progression. MPO is also involved in microvascular inflammation seen in HFpEF. MPO also contributes to fibrosis and vascular endothelial dysfunction. MPO inhibitors thus can have the potential to improve cardiovascular disease conditions on both the macrovascular and microvascular levels.

Phase I trial of the novel oral MPO inhibitor AZD4831 found the drug candidate to be safe and tolerable in NYHA class II-IV HFmrEF/pEF patients. The drug also demonstrated improved symptomatic and biomarker endpoints in a phase IIa trial. Phase IIb and phase III trials of the drug are currently underway.

Omecamtiv mecarbil - Cytokinetics

Omecamtiv mecarbil is a selective, small-molecule cardiac myosin activator, being developed for the treatment of HFrEF. In HFrEF, initial loss or dysfunction of cardiomyocytes results in reduced contractile function and increased cardiac wall stress, ultimately generating increased ventricular remodeling from neurohormonal activation. Selective cardiac myosin activators such as Omecamtiv mecarbil help augment cardiac contractility and reduce the increased cardiac wall stress observed in HFrEF.

In May 2020, the FDA fast-tracked Omecamtiv mecarbil to speed its approval. However, in early 2023, the FDA issued a Complete Response Letter for Omecamtiv mecarbil citing that additional clinical trials are required to establish substantial evidence of effectiveness with benefits that outweigh the risks.

HF Treatment Paradigm has Evolved but Unmet Needs Remain

HF treatment paradigm has evolved considerably in recent years. Novel treatment options across the full spectrum of ejection fraction and new treatment algorithms have changed the therapeutic landscape of this deadly condition that affects millions of people. As per Global Data, the HF market is expected to be worth $53 bn by 2032 across the seven major markets (France, Germany, Italy, Japan, Spain, the UK, and the US). Despite these advances, there is a considerable level of unmet need. HFpEF, acute HF, and treatments for patients with multiple comorbidities represent major unmet needs.  Especially, the management of HFpEF is a challenge as several studies have failed to show a clear benefit with therapies that have well-established use in other HF subtypes. Currently, SGLT2 inhibitors remain the most promising treatment for HFpEF.

Pharmaceutical companies are working endlessly towards developing drugs with novel mechanisms and the HF pipeline looks promising. However, HF is a complex clinical syndrome with multiple concomitant pathophysiologies, which makes developing drugs with unique mechanisms of action a challenge. Anti-inflammatory and immunomodulating strategies will take time to be converted into clinically effective approaches. MicroRNAs and gene therapies are other areas that researchers are working on. However, the transition of these innovations from lab to clinical practice has a long way to go.

The pressing need to improve the quality of life, reduce the rates of hospitalizations, and prolong the life of HF patients has also led to innovations outside the realm of pharmacotherapy. This includes devices that can be used in guiding medical therapy to avoid HF exacerbations.

References

1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016 [published correction appears in Lancet. 2017 Oct 28;390(10106):e38]. Lancet. 2017;390(10100):1211-1259.

2. Writing Group Members, Mozaffarian D, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association [published correction appears in Circulation. 2016 Apr 12;133(15):e599]. Circulation. 2016;133(4):e38-e360.

3. Kim AH, Jang JE, Han J. Current status on the therapeutic strategies for heart failure and diabetic cardiomyopathy. Biomed Pharmacother. 2022;145:112463.

4. Mascolo A, di Mauro G, Cappetta D, et al. Current and future therapeutic perspective in chronic heart failure. Pharmacol Res. 2022;175:106035.

5. Heart Failure in Major Markets, Disease Management, Epidemiology, Pipeline Assessment, Unmet Needs and Drug Forecast to 2032.  Available at: https://www.globaldata.com/store/report/heart-failure-major-market-analysis/. Accessed: January 2024.

About the Author

Neeta Ratanghayra

Freelance Medical Writer

Neeta Ratanghayra is a freelance medical writer, who creates quality medical content for Pharma and healthcare industries. A Master’s degree in Pharmacy and a strong passion for writing made her venture into the world of medical writing. She believes that effective content forms the media through which innovations and developments in pharma/healthcare can be communicated to the world.