Despite trial miss, Novartis still believes in Entresto for HFpEF

Novartis was expecting a lot from its PARAGON-HF trial of Entresto in heart failure with preserved ejection fraction (HFpEF) and isn’t letting a missed endpoint scupper the programme.

The company insists that the bulk of evidence for Entresto (sacubitril/valsartan) suggest “clinically important benefits” in this poorly-served form of heart failure which currently has no specifically approved therapies.

Novartis first revealed that PARAGON-HF had missed the mark last month, but this weekend was able to make its case for Entresto as it presented detailed results at the European Society of Cardiology (ESC) congress in Paris.

The data – which has also been published in the New England Journal of Medicine – showed that Entresto reduced heart failure hospitalisations and cardiovascular death by 13% compared to valsartan on its own, which missed being a statistically significant improvement by a hair’s breadth (p=0.059).

A large part of the benefit came from a 15% reduction of hospitalisations for heart failure (p=0.056), and there were improvements on secondary measures such as New York Heart Association (NYHA) functional class that also backed Entresto’s use in at least some patients.

The drug had a significant impact on the primary outcome in women, who accounted for a little over half of the patient population, and seemed to perform better in people with structural abnormalities in the left ventricles of their hearts and those at the lower end of the ejection fraction range (below 57%).

HFpEF is associated with high hospitalisation rates, poor quality of life and increased mortality and accounts for around half of all heart failure cases. It has become something of an epidemic as it is often seen in elderly patients and so is tracking the ageing of the global population.

Unfortunately while tremendous strides have been made in improving survival in heart failure with reduced ejection fraction (HFrEF) – including with Entresto which was approved for that form in 2015 – no pharmacological therapy has yet shown similar benefits in HFpEF.

Cardiologist think this is because the disease is highly heterogeneous, and can result from impairments in a range of parameters including diastolic integrity, the function of the vasculature and kidneys, and even the oxygen carrying capacity of the blood.

That dearth of treatments is why Novartis feels Entresto is worth pursuing as a therapy for HFpEF, and that view was echoed at ESC by a number of commentators who suggested a case could be made for its used in some patients.

The next challenge will be to take the data to regulatory agencies to see if there is a route to adding HFpEF as a claim on Entresto’s label.

“Novartis is committed to reimagining heart failure treatment, and our next step is to further explore these results from PARAGON-HF,” said the company’s head of cardiovascular, renal and metabolic drug development David Soergel.

“We also look forward to continuing conversations with clinical experts and regulators to determine next steps.”

After a slow start in the marketplace Entresto has started to take off for Novartis, breaking the $1 billion sales threshold last year and growing around 80% to $778 million in the first half of 2019.