What drugs are in development for Heart failure with normal ejection fraction?

Overview of Heart Failure with Normal Ejection Fraction (HFpEF)

Definition and Pathophysiology
Heart failure with normal ejection fraction—or more commonly, heart failure with preserved ejection fraction (HFpEF)—is defined as a clinical syndrome in which patients experience typical symptoms of heart failure (such as dyspnea, exercise intolerance, and fluid retention) despite having a left ventricular ejection fraction (LVEF) that remains in the normal or near‐normal range (typically ≥50%). The condition is characterized not by impaired systolic contraction but by abnormalities in diastolic relaxation and filling. In patients with HFpEF, the myocardium is often stiffened because of increased fibrosis, hypertrophy, and interstitial remodeling. The pathophysiology is complex and involves contributions from systemic inflammation, endothelial dysfunction, comorbidities (such as obesity, diabetes, and hypertension), and perturbations in myocardial energy metabolism and calcium handling. Additionally, perturbations in nitric oxide bioavailability and cyclic guanosine monophosphate (cGMP) signaling lead to impaired vasodilation and altered ventricular‐arterial coupling. Thus, the underlying mechanisms include myocardial stiffness, chronic low‐grade inflammation, and impaired signaling at both the cellular and microvascular levels, making HFpEF a multisystem disorder rather than a simple myocardial disease.

Epidemiology and Clinical Importance
HFpEF now represents approximately 50% of all heart failure cases worldwide, a proportion that has increased in recent years likely due to the aging population and rising prevalence of key comorbid conditions such as hypertension, obesity, and diabetes. Epidemiological studies have shown a high mortality rate that can rival that of heart failure with reduced ejection fraction (HFrEF); for example, several registries have reported a five‐year mortality rate of around 75% in HFpEF patients. The clinical importance of HFpEF is underscored not only by its prevalence but also by its association with frequent hospitalizations, significant healthcare costs, and impaired quality of life. Because many patients with HFpEF have multiple comorbidities, treatment strategies must address both cardiac dysfunction and systemic abnormalities in order to improve outcomes.

Current Therapeutic Landscape for HFpEF

Existing Treatment Options
At present, the treatment options for HFpEF are largely supportive and focus on symptom control and management of underlying comorbidities rather than on reversing the primary disease process. Diuretics remain a cornerstone for reducing congestion, and antihypertensive medications (such as ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists) are used to control high blood pressure. Additionally, recent large randomized trials have demonstrated that sodium–glucose co‐transporter 2 (SGLT2) inhibitors, such as empagliflozin, can reduce the composite endpoint of cardiovascular death or heart failure hospitalization in patients with HFpEF. Some agents that had previously been successful in HFrEF—such as sacubitril/valsartan—have been studied in HFpEF (for example, in the PARAGON‐HF trial), although their effects have often been limited to particular subgroups (e.g., patients with LVEF in the lower “normal” range or by sex).

Limitations of Current Therapies
Despite these advances, the current therapeutic options for HFpEF have notable limitations. The heterogeneity of the syndrome—with its varying degrees of myocardial fibrosis, vascular stiffness, and comorbid conditions—means that no single therapy can address all facets of the disease. Most of the drugs currently used improve symptoms but do not reduce mortality significantly. Moreover, many therapies have been extrapolated from HFrEF data, and multiple trials of agents that are effective in HFrEF have failed to demonstrate benefit in HFpEF patients. The lack of consensus on the diagnostic criteria and phenotypic classification of HFpEF also complicates clinical trial design and therapeutic decision‐making. This variability in patient populations has forced the research community to consider a more individualised approach to treatment based on pathophysiological subtypes.

Drugs in Development for HFpEF

Key Drugs in Clinical Trials
A number of drugs are in development specifically targeting HFpEF, and many of these agents are being evaluated in large, well‐designed clinical trials. The evidence emerging from recent research – particularly from structured and reliable sources such as synapse – points to several promising therapeutic candidates:

1. SGLT2 Inhibitors (Empagliflozin and Dapagliflozin)
Empagliflozin, originally developed for type 2 diabetes mellitus, has been shown to reduce hospitalizations and improve outcomes in HFpEF patients, as demonstrated in the EMPEROR‐Preserved trial. In addition, there has been extensive patent activity around the use of dapagliflozin for HFpEF; several patents describe “Methods of treating HFpEF employing dapagliflozin.” These drugs work by modulating renal glucose handling and natriuresis, with a beneficial impact on diuresis, blood pressure, and systemic metabolism. Both drugs have robust clinical data supporting their use in populations with preserved ejection fraction, and additional data continue to emerge from ongoing studies.

2. Sacubitril/Valsartan (ARNI)
While approved for HFrEF, sacubitril/valsartan was studied in the PARAGON‐HF trial for HFpEF. Although the overall benefit was modest, subgroup analyses indicated possible efficacy in patients with lower ranges of preserved LVEF or in women. Additional research and post‐hoc analyses aim to better define the patient subgroups that may derive the most benefit, and further development is expected to optimize dosing and patient selection.

3. GSK2798745 (TRPV4 Blocker)
Novel non‐traditional targets are also being explored, such as the transient receptor potential vanilloid 4 (TRPV4) channel. The TRPV4 blocker, GSK2798745, has recently shown promising results in preclinical models by reducing cardiac stress and fibrosis. By modulating TRPV4, this agent aims to impact the myocardial and vascular stiffness that is central to HFpEF pathophysiology.

4. Pirfenidone (Antifibrotic Agent)
Pirfenidone, an antifibrotic drug approved for idiopathic pulmonary fibrosis, is in development for HFpEF due to its ability to attenuate profibrotic pathways and potentially reverse myocardial fibrosis. Early-phase studies are evaluating its efficacy in reducing extracellular matrix deposition in the heart, which is a hallmark of HFpEF. Its repurposing for cardiac fibrosis is a promising area of research.

5. Elamipretide (Mitochondrial Function Enhancer)
Abnormal energy metabolism in cardiomyocytes is increasingly recognized in HFpEF. Elamipretide is a mitochondrial-targeted peptide that improves electron transport chain function, increases ATP production, and reduces oxidative stress. Several early phase trials are assessing its role in improving myocardial energy efficiency and thereby ameliorating diastolic dysfunction. Its mechanism of action – directly targeting the cardiomyocyte’s energy production – represents a novel pathway distinct from conventional vasodilatory or neurohormonal blocking agents.

6. Novel Recombinant Fusion Proteins (e.g., JK07)
Another innovative modality in development for both HFrEF and HFpEF is recombinant fusion proteins such as JK07. JK07 is designed as a fusion of a human IgG1 monoclonal antibody with a fragment of neuregulin-1 (NRG-1), a growth factor that has shown regenerative potential in cardiac tissue. The approach aims to selectively stimulate beneficial pathways (such as ErbB4 signaling) while inhibiting pathways associated with adverse effects (such as ErbB3), which could lead to improved cardiac remodeling and function.

7. Other Novel Agents and Strategies
In addition to the agents mentioned above, research is exploring a wide array of compounds that target varied aspects of HFpEF pathophysiology. These include:
- Agents that enhance cGMP signaling by targeting the NO-soluble guanylate cyclase pathway, potentially offering benefits by improving vasodilation and reducing myocardial stiffness.
- Anti-inflammatory agents and microRNA modulators that work by reducing systemic inflammation, a key contributor to HFpEF.
- Drugs designed to modify myocardial metabolism beyond the effects of SGLT2 inhibitors, with the goal of optimizing substrate utilization in the heart and reducing oxidative stress.

Collectively, these drugs represent a diverse portfolio in development that are being tested in various phases of clinical trials, from early phase studies to large, multicenter randomized trials. The work is guided by emerging advances in our understanding of the molecular markers and phenotypes of HFpEF, with systems biology and machine learning techniques integral to refining patient selection and therapeutic response.

Mechanisms of Action
The drugs in development for HFpEF are being designed to tackle the multiple facets of the syndrome through diverse mechanisms:

- Renal and Metabolic Modulation:
SGLT2 inhibitors (empagliflozin and dapagliflozin) not only reduce hyperglycemia but also induce natriuresis and reduce interstitial fluid overload. They exert beneficial effects on blood pressure, reduce inflammation, and improve endothelial function. The downstream effect includes improved myocardial relaxation and decreased cardiac fibrosis.

- Antifibrotic and Remodeling Modulation:
Sacubitril/valsartan and pirfenidone target myocardial remodeling by reducing profibrotic signaling and extracellular matrix deposition. Sacubitril/valsartan works by inhibiting neprilysin (thus increasing natriuretic peptides) combined with angiotensin receptor blockade, whereas pirfenidone directly interferes with fibrotic pathways.

- Energy Metabolism Enhancement:
Elamipretide directly targets mitochondrial dysfunction by binding to cardiolipin in the inner mitochondrial membrane, leading to more efficient electron transport and ATP generation. This helps correct the energy deficit in stressed cardiomyocytes seen in HFpEF.

- Ion Channel and Vascular Modulation:
TRPV4 blockers such as GSK2798745 work by reducing calcium influx and related downstream signaling that leads to myocardial stiffening and vascular dysfunction. This specific modulation of cardiac ion channels offers a novel avenue to reduce myocardial fibrosis and improve ventricular compliance.

- Growth Factor Pathway Modulation:
Recombinant fusion proteins like JK07 are engineered to harness neuregulin-1’s regenerative capacity by selectively activating ErbB4 receptors on cardiomyocytes. This targeted approach mimics natural repair processes in the heart, potentially reversing adverse remodeling and improving diastolic function without causing untoward side effects associated with broad growth factor administration.

- cGMP Pathway Enhancement:
Other agents under research are designed to boost the NO–cGMP signaling cascade, a key regulator of smooth muscle relaxation and myocardial compliance. By enhancing this pathway, these drugs aim to reduce vascular and myocardial stiffness—a critical contributor to HFpEF physiology.

Challenges and Future Directions in HFpEF Drug Development

Drug Development Challenges
Despite the diverse array of promising agents, several challenges persist in the development of drugs for HFpEF:

- Heterogeneity of the Patient Population:
HFpEF is not a single disease entity but rather a syndrome encompassing a wide range of phenotypes. The heterogeneity in underlying pathophysiology—ranging from predominant myocardial fibrosis to severe vascular stiffness or isolated metabolic derangements—complicates patient selection in clinical trials and may dilute observable drug effects in a mixed population.

- Diagnostic Ambiguity:
The lack of universally accepted diagnostic criteria (with different studies using slightly varying thresholds for natriuretic peptides, imaging markers, and echocardiographic parameters) hampers the ability to enroll a homogenous study population. This variability can lead to negative or inconclusive results in trials even when a drug is beneficial in a subset of patients.

- Endpoint Selection:
In HFpEF, reduction in symptomatic hospitalizations may be easier to demonstrate than a clear reduction in mortality, which remains high but may be influenced by non‐cardiac comorbidities. Therefore, selecting appropriate surrogate endpoints that reflect both quality of life and hard outcomes (such as death or major cardiovascular events) is challenging.

- Safety Concerns:
Since HFpEF patients are typically older with multiple comorbidities, drug safety profiles must be exceptionally favourable. Some of the novel agents that modulate growth factor pathways or intracellular metabolism raise concerns about off-target effects that require painstaking evaluation in early-phase studies.

- Integration of Comorbidities:
Many HFpEF patients suffer from obesity, diabetes, renal dysfunction, and hypertension, which may interact with the pharmacological actions of new drugs. Tailoring therapy to overcome these barriers without causing additional side effects is an ongoing challenge in drug development.

Future Research Directions and Innovations
Future research in HFpEF drug development is likely to focus on several avenues that aim to overcome these challenges:

- Advanced Phenotyping and Precision Medicine:
Utilizing high-throughput genomic, proteomic, and metabolomic techniques along with machine-learning algorithms can help further categorize HFpEF patients into distinct phenogroups. This precision medicine approach would enable targeted clinical trials where therapies are tested in a more homogeneous population with similar pathophysiological abnormalities.

- Biomarker-Driven Drug Development:
The integration of reliable biomarkers for inflammation, fibrosis, and myocardial stress can aid in both diagnosis and stratification of patients for clinical trials. Recent developments in circulating biomarkers, as discussed in several synapse papers, may help predict which patients are most likely to respond to specific therapies such as antifibrotic agents or SGLT2 inhibitors.

- Combination Therapies:
Given the multifactorial nature of HFpEF, future strategies may involve combination therapies that target different aspects of the disease simultaneously—for example, combining a metabolic modulator (like an SGLT2 inhibitor) with an antifibrotic agent (like pirfenidone) or a mitochondrial enhancer (like elamipretide). This multipronged approach might have a synergistic effect in improving clinical outcomes.

- Innovative Drug Delivery and Dosing Strategies:
Novel formulations – including sustained-release forms, targeted nanoparticle delivery systems, and even gene or cell-based therapies – might overcome issues of bioavailability and off-target effects. These innovations could enhance the efficacy of drugs while reducing side effects in a sensitive, elderly population.

- Improved Clinical Trial Methodologies:
Future trials may incorporate adaptive designs and focus on hard endpoints as well as patient-reported outcomes. Incorporating real-world evidence and leveraging digital health technologies for remote patient monitoring and adherence tracking may further improve the quality of data collected from HFpEF studies.

- Translational Research on Novel Targets:
Ongoing studies in basic research may identify new molecular targets such as key microRNAs that regulate fibrosis or novel kinases that modulate calcium handling and contractile function. Early-phase research on such targets, including the modulation of the TRPV4 channel and the NO–cGMP pathway, provides a promising direction for the development of next-generation HFpEF therapies.

Detailed Conclusion

In summary, the development of drugs for HFpEF represents one of the most challenging yet rapidly evolving areas in cardiovascular medicine. According to robust and structured synapse information, emerging therapies include SGLT2 inhibitors like empagliflozin and dapagliflozin, which have already demonstrated promising benefits in clinical trials such as EMPEROR‐Preserved and through multiple patents. Sacubitril/valsartan, although primarily effective in HFrEF, is also under continued investigation in HFpEF populations for specifically defined subgroups. In addition, novel molecules such as the TRPV4 blocker GSK2798745 are being evaluated in preclinical models to reduce myocardial stiffness through ion-channel modulation. Antifibrotic agents (pirfenidone) and mitochondrial enhancers (elamipretide) are other promising candidates targeting unique components of the HFpEF pathophysiologic spectrum, including myocardial fibrosis and deranged energy metabolism. Finally, innovative recombinant fusion proteins like JK07 are designed to harness the regenerative potential of neuregulin while mitigating adverse effects, representing an entirely new class of biologic therapy for heart failure.

However, all these promising agents must contend with major challenges in drug development, primarily driven by the heterogeneity of the HFpEF syndrome, diagnostic ambiguity, and the need for precise patient phenotyping. Future research directions are increasingly geared toward precision medicine approaches that integrate advanced biomarker discovery, genomic and proteomic profiling, and adaptive clinical trial designs to ensure that therapies are matched to the right patient subgroups. Combination therapies that address multiple facets of HFpEF simultaneously also represent a promising approach in which drugs with complementary mechanisms (such as metabolic modulation with SGLT2 inhibition combined with antifibrotic and mitochondrial protective strategies) may yield synergistic benefits.

From a general perspective, while current therapies for HFpEF provide some symptomatic relief, they fall short of significantly modifying the disease course or reducing mortality. From a specific perspective, the drugs in development address these areas by targeting not only the neurohormonal and hemodynamic alterations but also the underlying molecular and cellular aberrations driving fibrosis, inflammation, and energy metabolism defects. Returning to a general view, these multi‐angled strategies embody a paradigm shift in HFpEF management—from a one-size-fits-all model to a more stratified, patient-centered approach that promises to improve long-term outcomes and quality of life for this growing patient population.

In conclusion, the current pipeline of drugs in development for HFpEF is both diverse and promising. The emphasis on novel molecular targets, individualized therapy based on precise phenotyping, and innovative clinical trial designs signals a new era in the management of HFpEF. Although the path ahead is fraught with challenges, the integration of these innovative strategies offers hope that future therapeutics will not only relieve symptoms but also modify the disease trajectory, thereby reducing the enormous morbidity, mortality, and healthcare burden associated with HFpEF.