Entresto set for big sales hike after FDA panel endorsement

Novartis’ Entresto is on course to become the first drug to be approved in the US for a form of heart failure that is notoriously hard to treat effectively, despite missing the mark in a phase 3 trial.

An FDA advisory committee 12 to 1 in favour of approving Entresto (sacubitril/valsartan) for heart failure with preserved ejection fraction (HFpEF), which accounts for around half of all heart failure cases but proves highly resistant to drug treatment. In HFpEF, the heart muscles pump normally but the organ is too stiff to fill properly.

Entresto is already approved to treat heart failure with reduced ejection fraction (HFrEF), caused by the heart muscles not pumping effectively, and has revitalised the treatment of patients with this form since its launch in 2015.

After a slow start, it has grown to become a $1.7 billion product last year, and that represented a surge from around $1 billion in 2018 revenues.

Analysts have predicted that approval in HFpEF – which affects around 3 million people in the US alone – could more than double Entresto’s sales, perhaps driving them as a high as $5 billion a year. There’s also plenty of upside in HFrEF as three out of four eligible patients are still not being treated with the drug, according to Novartis.

The prospect of adding HFpEF to Entresto’s label looked shaky last year however, when the drug missed its primary objective in the phase 3 PARAGON-HF trial.

The 4,822-patient study missed statistical significance for a composite primary endpoint of reducing cardiovascular death and total heart failure hospitalisations by 13% compared with valsartan alone, but only by a whisker, and Novartis has been upbeat since about the chances of approval.

The published data from the study suggested that the drug performed better in women, people with structural abnormalities in the left ventricles of their hearts, and those with very low ejection fractions – the amount of blood pushed out of the heart each beat.

The positive vote by FDA advisors came after the FDA reviewer acknowledged the narrow miss for statistical significance and pointed to the pressing need for a drug treatment for HFpEF.

The agency’s own expert said that “various pre-specified and post-hoc analyses suggest that sacubitril/valsartan compared to valsartan reduces HF events” in HFpEF, and of course Entresto’s long track record of safety stands in its favour.

While the FDA doesn’t have to follow its advisory committee’s advice it generally does, and Novartis is now eyeing approval of Entresto in HFpEF in the first quarter of 2021.

The main question now is exactly how the FDA will word the label if it approves the drug, with panellists debating the use of ejection fractions percentages to guide treatment with little agreement.

PARAGON-HF in included patients with left ventricular ejection fraction (LVEF) of 45% or more, but earlier studies have suggested the drug can have a benefit in people with scores below 40%.