Entresto Study Misses Primary Endpoint

Novartis announced topline results from the global Phase III PARAGON-HF study, investigating the safety and efficacy of sacubitril/valsartan versus the active comparator valsartan in HFpEF patients. According to the company, "the trial narrowly missed statistical significance for its composite primary endpoint of reducing cardiovascular death and total heart failure hospitalizations. Safety and tolerability were consistent with previously reported sacubitril/valsartan data."

"Around half of all heart failure patients, some 13 million people worldwide, are estimated to suffer from HFpEF, and there is currently no approved treatment. We embarked upon the landmark Phase III PARAGON-HF trial to determine whether sacubitril/valsartan could have a meaningful impact on the treatment of HFpEF, as it does in the treatment of heart failure with reduced ejection fraction," said John McMurray, M.D., Professor of Medical Cardiology at University of Glasgow and PARAGON-HF Executive Committee Co-Chair.

"The totality of evidence from the trial suggests that treatment with sacubitril/valsartan may result in clinically important benefits in HFpEF. We will be discussing potential next steps with clinical experts and regulators while we prepare to present the full results at the ESC Congress 2019 in September," said John Tsai, M.D., Global Drug Development and Chief Medical Officer, Novartis, "We thank the patients, investigators and site personnel around the world for their support during the PARAGON-HF study."

There is currently no approved treatment for HFpEF. Sacubitril/valsartan (approved as Entresto® since 2015) is a first-choice treatment in heart failure with reduced ejection fraction (HFrEF), based on its superiority to the angiotensin-converting enzyme (ACE) inhibitor enalapril and its ability to significantly reduce CV death and HFrEF hospitalizations. Novartis continues to study sacubitril/valsartan in HFrEF, with new data on cardiac remodeling being presented at the ESC Congress 2019. Detailed PARAGON-HF results will also be reported at that time. Additional studies investigating sacubitril/valsartan on other relevant endpoints in HFpEF are ongoing.

PARAGON-HF is the largest clinical trial in heart failure with preserved ejection fraction (HFpEF) conducted to date. The Phase III randomized, double-blind, parallel group, active-controlled, 2-arm, event-driven trial compared the long-term efficacy and safety of sacubitril/valsartan versus valsartan in 4,822 patients with HFpEF. The patients in the study represented ambulatory patients with established HFpEF being treated for symptoms and comorbidities, approximately half of whom had a history of heart failure hospitalizations. The primary endpoint of the trial is the composite of total (first and recurrent) heart failure hospitalizations and cardiovascular death. PARAGON-HF is part of FortiHFy, the largest global clinical program in the heart failure disease area across the pharmaceutical industry to date. Established by Novartis, the FortiHFy program comprises more than 40 active or planned clinical studies designed to generate an array of additional data on symptom reduction, efficacy, quality of life benefits and real world evidence with sacubitril/valsartan, as well as to extend understanding of heart failure.

PARAGON-HF follows the only positive Phase II trial in HFpEF, PARAMOUNT-HF, which demonstrated that sacubitril/valsartan reduced NT-proBNP (a biomarker of cardiac strain) to a greater extent than valsartan at 12 weeks and was associated with improvement in NYHA class at 36 weeks. Additional studies investigating sacubitril/valsartan on other relevant endpoints in HFpEF are ongoing.

Heart failure (HF) is a progressive and serious condition, affecting approximately 26 million people worldwide, where the heart cannot pump enough blood to the body. There are two distinct types of heart failure: preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF).

HFpEF is a distinct type of heart failure where the heart muscle contracts normally but the ventricles do not relax as they should during ventricular filling (or when the ventricles relax). HFpEF can be associated with high hospitalization rates, poor quality of life and increased mortality, and it is emerging as the predominant form of HF. There is currently no approved treatment for HFpEF.

HFrEF is a certain type of long-lasting heart failure, also known as systolic HF. HFrEF means the heart does not contract with enough force, so less blood is pumped out. There are approved treatment options for people living with HFrEF.

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