Novartis now looks almost certain to pocket an important first-in-class approval for blockbuster heart drug Entresto, despite trial data that, at least on the surface, spelled failure for the drug.
An FDA advisory panel voted 12-1 for Entresto’s use in heart failure patients with preserved ejection fraction (HFpEF), a group whose hearts are compromised but haven’t yet lost as much power as those now approved for Entresto treatment.
The committee backing clears the path to a green light, especially given that FDA reviewers have already sung the drug’s praises in documents prepared for the meeting. But the details of that approval—namely, just how sick those patients have to be to qualify for Entresto—remains a question, Jefferies analyst Peter Welford pointed out in a note to clients.
If approved, Entresto could become the first therapy cleared for HFpEF, and, according to Welford, hike its annual sales by $1 billion at peak. The FDA is slated to decide in the first quarter of next year.
The panel vote was a clear win for the Swiss pharma, given that the drug narrowly missed its primary goal of reducing cardiovascular-related deaths and hospitalizations among HFpEF patients in its phase 3 Paragon-HF trial.
In their internal review, FDA staffers picked apart that failure to find more positive signs. For instance, they said the p-value of the data, at 0.06, was “only slightly above the 0.05 target” to hit statistical significance.
And, in an assessment that could shape Entresto’s new indication, they noted a clearer benefit for patients with lower ejection fractions. These are patients who look more like Entresto’s existing target, those with reduced ejection fraction (rEF), which is defined as 40% or less. The Paragon-HF study enrolled those with level of at least 45%.
The advisory committee almost unanimously agreed that Entresto deserves to expand beyond patients with rEF, but they were “unconvinced by the evidence for Entresto in the broad HFpEF population,” Welford noted. The experts argued that heart failure is more of a continuum than a dichotomy of HFrEF and HFpEF.
Several committee members suggested limiting the approval to patients with ejection fraction of less than 57%. That group responded more strongly to Entresto in clinical trials, according to a pooled analysis from the Paragon-HF and HFrEF’s Paradigm-HF trials.
Some said the label could specify “mildly reduced” ejection fraction, Welford noted. Another proposal would hew to the American Society of Echocardiography’s definition of normal ejection fraction—53% to 73%—suggesting a go-ahead for patients below that range.
The one “no” voter pointed to the lack of a reference drug in patients with pEF. The voter also raised concerns about one potential side effect of Entresto—low blood pressure—and how it might play out in the new patient group.
Now the ball is back in the FDA’s court, with a decision set for the first quarter of 2021. Welford currently projects peak Entresto sales of $5.1 billion, and an HFpEF indication could add up to $1 billion, he said.
Novartis is also running the Paradise-MI trial, pitting Entresto against ACE inhibitor ramipril in patients who've had a heart attack to see whether its drug can prevent another heart episode.