Novartis’ heart failure drug Entrestro (Sacubitril/valsartan) has narrowly missed its primary endpoint in a trial of patients with preserved ejection fraction (HFpEF).
The results came from the Paragon-HF phase 3 clinical trials. The trial failed to demonstrate statistical significance for its primary endpoint of reducing cardiovascular death and total heart failure hospitalisations.
The news is unfortunate for Novartis, as heart failure remains an area of high unmet need, affecting around 26 million people worldwide. The distinct type which the Paragon-HF trial had wanted to show benefit for was HFpEF, where the heart muscle contracts normally but the ventricles do not relax as is typical during ventricular filling.
HFpEF is associated with high hospitalisation rates, poor quality of life and increased mortality and is emerging as the predominant form of heart failure, with no currently approved treatment.
This failure of Entresto in the use of patients with HFpEF creates doubts over potentially billions of dollars of revenue, and is a hard knock for one of Novartis’ bigger growth prospects. The company’s shares fell 1.4% to 91.20 Swiss francs ($91.90) following the results. Entresto sales have been growing rapidly, and broke through the $1bn annual sales barrier last year.
Regulators would almost certainly reject any application for a label update based on this data – leaving the door open for rivals such as Eli Lilly and Boehringer to claim the first approval for HFpEF treatment.
John Tsai, global drug development and chief medical officer, Novartis
“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, global drug development and chief medical officer, Novartis.
Entresto was approved in 2015 for use as a first-choice treatment in heart failure with reduced ejection fraction (HFrEF), and Novartis is continuing to study its use in this area alongside the Paragon-HF trial for HFpEF.
Novartis has faced increasing competition in the heart failure therapy area of late, with Jardiance, Eli Lilly and Boehringer Ingelheim’s SGLT2 inhibitor, recently fast tracked by the FDA for review of its use in heart failure in adults with HFrEF and HFpEF respectively. The EMPEROR trial programme testing Jardiance for this use is expected to complete and produce initial results in 2020.
Another contender is Cyclerion Therapeutics’s praliciguat (IW-1973), an oral soluble guanylate cyclase (sGC) stimulator currently in phase 2 trials. In November last year it also gained FDA Fast Track Designation for praliciguat for the treatment of HFpEF.
Novartis will present new data on cardiac remodeling at the European Society of Cardiology (ESC) congress 2019, and more detailed resilts from the Paragon-HF trial will also be reported at that time.