After a slow start, the heart failure drug Entresto has become one of Novartis’s biggest growth drivers. It is now set to become bigger still, with the FDA yesterday approving broader use that will encompass some patients with preserved ejection fractions.
Previously, there were no therapies for HFpEF, which affects around half of all heart failure patients. However, the drug’s new US label is vague, leaving much of the interpretation in the hands of doctors, and Novartis admitted today that ramp-up in the new population would be slow. Entresto could soon be challenged by generic competitors, meaning the company might not have long to make a mark in HFpEF.
These issues could help explain why Novartis stock fell 1% today despite the FDA nod, which on the face of it was a great result for the company – especially considering that Entresto’s pivotal trial in HFpEF, Paragon, missed its primary endpoint, albeit narrowly (ESC 2019 – Novartis sees reasons to push on post-Paragon, September 1, 2019).
However, as expected, this was not a broad approval, and Entresto’s use will be limited to HFpEF patients with a left ventricular ejection fraction (LVEF) below normal. Still, Novartis says Entresto can now be used to treat five million of the six million heart failure patients in the US.
The group estimates peak Entresto sales of $5bn, but reckons that only $1bn of this will come from the HFpEF population. During a conference call today executives explained their caution by saying uptake in the new use would take time, adding that Entresto’s incorporation into guidelines would be key here.
They also revealed that internal forecasts assumed no generic competition only until 2025, a scenario that would exacerbate the problem of slow uptake.
What is normal?
The executives dodged questions on the exact definition of a “below normal” LVEF – an important issue as Entresto’s label now notes that the drug’s benefits are most evident in patients who fall into this range.
However, the label does not give a specific cut-off for what is deemed below normal. Paragon, which enrolled patients with an ejection fraction of 45% or higher, found the most pronounced benefit in those with an ejection fraction below 57%, so this might be an appropriate cut-off.
Ultimately, the onus appears to be on doctors to decide. Novartis said LVEF was “quite variable”, a stance echoed by the new Entresto label, which highlights physicians’ own clinical judgement.
Entresto’s new indication adds to its original approval in 2015 for heart failure with reduced ejection fraction (HFrEF), defined as an LVEF of less than 40%.
There could be more to come: in the second quarter data are due from the Paradise-MI trial, evaluating whether Entresto reduces cardiac events in patients who have had a myocardial infarction. If successful, Novartis believes this could add another 800,000 patients per year in the US alone.
Novartis has patents extending until 2027, but is embroiled in litigation against generic manufacturers. All of these label-expansion efforts will come to nothing if generic versions of Entresto hit the market sooner than expected.