Novartis' Entresto, facing a big comeback in hard-to-treat heart failure patients, scores FDA nod after adcomm cakewalk
Hard-and-fast rules in drug development are hard to come by, but one has long been the standard for market approvals — you have to hit your primary endpoints in pivotal studies. But for Novartis’ heart failure med Entresto, what’s a Phase III miss between friends?
The FDA on Tuesday approved Entresto, a combination of neprilysin inhibitor sacubitril and angiotensin receptor II blocker valsartan, to treat heart failure patients with a preserved ejection fraction (HFpEF), making it the first drug on the market for that population.
The drug’s new label covers a combined indication called chronic heart failure — both HFpEF and reduced ejection fraction (HFrEF) — with a “below normal” left-ventricle ejection fraction, a variable condition the agency leaves open for physician’s judgement. Either way, Novartis thinks its drug could be useful for around 5 million of the more than 6 million heart failure patients at any one time in the US.
The agency primarily based its review on results from Novartis’ Phase III PARAGON-HF study, which, unlike most other successful pivotal trials, didn’t actually hit its primary endpoint of reducing the rate of total heart failures and death. Despite the flop, the FDA urged Novartis to pursue its application anyway, arguing the study’s design may have produced misleading results — the primary endpoint’s p-value was 0.06, by the way — and highlighting results from pre-specified follow-up analyses that pointed to significant benefits.
Dave Soergel, Novartis’ global head drug development for cardiovascular, renal and metabolism, told Endpoints News the FDA’s decision to consider the totality of evidence around Entresto’s application was “heartening” and shot down claims the approval undermined the standard 0.05 p-value that serves as an efficacy benchmark across the industry.
“If we had taken PARAGON alone to the agency, would we have gotten the same response? I doubt it. But we have thousands of patients in randomized clinical trials around the globe,” he said. “There isn’t really a magic to 0.05 and, in fact, there is regulatory precedent for supplemental indications based on clinical trials that didn’t hit that number. This isn’t breaking the mold; on the contrary, it’s taking a sophisticated and appropriate view of the totality of the data.”
In December, an FDA advisory committee nearly unanimously backed the agency’s investigators, handing down a 12-1 vote in Entresto’s favor. The approval could open a $5 billion market to Novartis, by some analysts’ lights, adding to its leading position in the treatment of heart failure patients with a reduced ejection fraction (HFrEF). That indication has competitors, though, including SGLT2 diabetes meds like AstraZeneca’s Farxiga and Eli Lilly and Boehringer Ingelheim’s Jardiance.
Victor Bulto, Novartis’ US pharma chief, didn’t want to talk sales projections on a call with Endpoints and noted that the Swiss drugmaker didn’t intend to expand its team to accommodate the roughly 2 million additional patients Entresto could cover. The prescribing physician pool, after all, wont change much.
“Most of the cardiologists are really familiar with Entresto and how to use it,” he said. Bulto also highlighted the roughly $30 billion burden heart failure puts on the US healthcare system each year. Thirty percent of that is tied to hospitalizations, he said, making a risk reduction there a potentially boon for payers and providers.
Entresto’s turnaround at the FDA is a surprise given the long reliance on pivotal Phase III studies as guideposts for an approval. Novartis admitted before the adcomm vote an approval for Entresto for HFpEF would be “unusual but not unprecedented.”
But the FDA has shown some willingness to consider drugs that don’t hit their checkpoints in the late-stage setting, sometimes to its detriment. The FDA, for instance, in November gave its backing to Biogen’s aducanumab, another candidate seeking a huge unmet clinical need. Instead of supporting the FDA’s argument that a Phase III trial flop for adu was misleading, an FDA adcomm shot down the drug’s application with prejudice. The FDA’s final decision is scheduled for early June.