Heart Failure With Preserved Ejection Fraction (HFpEF): Pipeline Overview

Despite the long list of clinical trial failures in HFpEF, several promising drugs are in Phase III trials

Despite heart failure with preserved ejection fraction (HFpEF) accounting for approximately half of all chronic heart failure (CHF) cases, and despite our improved understanding of the pathophysiology, pharmacological treatments with proven outcomes benefits in HFpEF have proved elusive thus far. Indeed, clinical trials of agents with proven efficacy in heart failure with reduced ejection fraction (HFrEF) have consistently fallen short in HFpEF studies. Current clinical guideline recommendations for the treatment of HFpEF are, therefore, based on consensus opinion rather than on evidence from randomized clinical trials, with drug treatment focusing on the management of comorbidities. Despite the long list of clinical trial failures in HFpEF patients, several promising drugs are currently in Phase III trials seeking to demonstrate outcomes benefit in this heterogeneous and highly prevalent subpopulation. Here, we provide a brief overview of the most exciting prospects in late-stage development.

Entresto (Novartis)

If encouraging results from Entresto’s Phase II clinical trial in HFpEF patients are further supported by equally positive results from the ongoing Phase III PARAGON-HF trial, Entresto could become the first evidence-based therapy in this indication. Results from the Phase III trial in 4,822 HFpEF patients are expected before the end of 2019. Being the first therapy with proven outcomes benefit in both HFrEF and HFpEF populations, combined with physician and payer familiarity from years of use in HFrEF patients, should help drive early uptake in HFpEF and help propel Entresto to multi-blockbuster status.

SGLT-2 Inhibitors

Jardiance (Boehringer Ingelheim/Eli Lilly) was the first SGLT-2 inhibitor to demonstrate improved CV outcomes in T2D patients. In the EMPA-REG OUTCOME trial, Jardiance not only significantly reduced CV mortality and morbidity in T2D patients, but also reduced heart failure (HF) hospitalizations, laying the foundation for further evaluation of the efficacy and safety of empagliflozin in HF patients. Eli Lilly and Boehringer Ingelheim have since initiated two Phase III HF trials, EMPEROR-Reduced and EMPEROR-Preserved, which are investigating the drug in HFrEF and HFpEF populations, respectively.

The DECLARE trial evaluated the effects of another SGLT-2 inhibitor, AstraZeneca’s Farxiga/Forxiga, on CV outcomes in patients with T2D. While it failed to demonstrate a reduction in MACE, it did show a statistically-significant reduction in the composite end point of hospitalization for HF or CV death. In February 2017, AstraZeneca initiated the Phase III Dapa-HF outcomes trial of dapagliflozin in HFrEF patients with and without T2D. Subsequently, in August 2018, the Phase III DELIVER trial to evaluate dapagliflozin in HFpEF patients with and without T2D was announced.

In 2018, Lexicon Pharmaceuticals and Sanofi initiated the Phase III SOLOIST-WHF trial of their SGLT-2 inhibitor, sotagliflozin, in patients with CHF and comorbid T2D who experience worsening HF. Sotagliflozin became the third SGLT-2 inhibitor to undergo development in this indication and is being investigated in T2D patients with both HFrEF and HFpEF in the same trial. The trial has two primary objectives; to demonstrate a reduction in CV mortality and morbidity with sotagliflozin compared to placebo in (i) HFrEF patients and (ii) all HF patients, irrespective of ejection fraction status.

The mechanism behind the improved HF outcomes with SGLT-2 inhibitors remains incompletely understood, but results suggest a class rather than a drug-specific effect. The completion dates for these three SGLT-2 inhibitor trials suggest a slight launch advantage for Jardiance. Despite Invokana (Johnson & Johnson) also demonstrating CV outcomes benefit in the Phase III CANVAS trial, no further development in CHF patients has been announced to date. We anticipate that use of the SGLT-2 inhibitors will largely be confined to later lines in HFpEF patients, most likely in those patients with comorbid T2D.

Other HFpEF Clinical Trials of Note

The Sweden-based SPIRRIT trial is a registry-randomized clinical trial initiated to test the hypothesis that spironolactone reduces all-cause mortality in HFpEF. This trial is looking to build on promising, but generally inconclusive data from previous studies, such as TOPCAT, which suggested spironolactone may be effective in the treatment of HFpEF.

 

Table 1: Late-Phase HFpEF Pipeline Overview

Study Drug & ComparatorTrial Name, Phase, & ClinicalTrials.gov IdentifierEstimated Enrollment & Primary Completion DateComments
Novartis’ Entresto (sacubitril / valsartan) versus

valsartan

·     PARAGON-HF

·     Phase III

·     NCT01920711

·     4,822

·     May 2019

CV outcomes trial in HFpEF patients (defined as left ventricular ejection fraction [LVEF] ≥ 45%).
Boehringer Ingelheim /Eli Lilly’s Jardiance (empagliflozin)

versus placebo

·     EMPEROR-Preserved

·     Phase III

·     NCT03057951

·     4,126

·     June 2020

CV outcomes trial in HFpEF patients (defined as LVEF > 40%) with and without T2D.
AstraZeneca’s Forxiga/Farxiga (dapagliflozin) versus placebo·     DELIVER

·     Phase III

·     NCT03619213

·     4,700

·     June 2021

CV outcomes trial in HFpEF patients (defined as LVEF > 40%) with and without T2D.
Lexicon Pharmaceuticals /Sanofi’s Sotagliflozin versus placebo·     SOLOIST-WHF

·     Phase III

·     NCT03521934

·     4,000

·     Jan 2021

CV outcomes trial in CHF patients with T2D, following admission for worsening HF. Primary outcomes will investigate efficacy in HFrEF patients (defined as LVEF < 50%), and in all CHF patients, irrespective of LVEF.
Spironolactone versus placebo·     SPIRRIT

·     Phase IV

·     NCT02901184

·     3,500

·     Dec 2021

Registry-randomized trial that will test the hypothesis that spironolactone reduces all-cause mortality in HFPEF (defined as LVEF ≥ 40%).

 

Relevant reports: 

Snapshot of Chronic Heart Failure Disease Management

Heart Failure | Landscape & Forecast | Disease Landscape & Forecast

Heart Failure | Access & Reimbursement | Detailed, Expanded Analysis (US): Chronic Heart Failure: Special Focus on Outcomes-Based Contracting

Heart Failure | Current Treatment | Detailed, Expanded Analysis - Chronic Heart Failure - Preserved Ejection Fraction - Treatment Algorithms - Claims Data Analysis - US

 

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Contributors: Conor Walsh - Principal Director, Cardiovascular, Metabolic, Renal, and Hematologic Disorders Team
Published on: 23 January, 2019