Once again Novartis’ cardio team looks to beat the odds using sketchy data and a familiar argument
Whenever a clinical trial team starts touting the “totality” of the data, you know they’re in trouble.
Bioregnum Opinion Column by John CarrollFor Novartis’ Entresto (sacubitril/valsartan) team, that’s the early go-to position on their latest round of pivotal data for the blockbuster — which the pharma giant believes has megablockbuster potential. We already knew that Novartis’ team plans to field the drug to regulators in search of a label extension — but now we have a better idea of the hurdles it faces.
And they are steep.
Entresto flat failed the primary endpoint in reducing the composite primary endpoint of total (first and recurrent) heart failure hospitalizations and cardiovascular death — hitting a 13% reduction among heart failure patients with preserved ejection fraction (HFpEF). The p-value was 0.059, which means they couldn’t prove their case for the drug.
Novartis’ position that this was a narrow miss rarely passes muster at the FDA.
Then they made a sketchy move, switching to a sub-population analysis which is sure to attract lots of skepticism among regulators — many of whom would have been involved in shutting down Novartis’ last play on that in cardio with canakinumab, where the team shot (and missed) at a particular sub-population where they felt the drug could succeed commercially.
Sticking with “individuals with a left ventricular ejection fraction equal to or below the median of 57%” in this new study, researchers teased out a 22% reduction on the endpoint. In women, it was 27.5%.
“While the reduction in the primary endpoint was not statistically significant, the totality of evidence from PARAGON-HF suggests potential overall benefit of sacubitril/valsartan compared with valsartan in HFpEF, particularly in patients with ejection fraction below normal. It also highlights the complexity of HFpEF and may suggest that some treatments have a more pronounced impact in certain patient groups, including women, who are more likely to suffer from this condition than men,” said Harvard’s Scott Solomon in a prepared statement.
While Novartis has been racking up an impressive slate of positive late-stage studies in a variety of fields, it hasn’t performed well in cardio — one of the toughest R&D sectors in the business, where regulators expect pristine data before opening up labels to large numbers of patients. And Novartis likes to push the envelope in cardio — though without much success.
Just 9 months ago they trotted out positive data underscoring Entresto’s ability to beat on key survival and re-hospitalization numbers in a head-to-head study with the cheap ACE inhibitor enalapril. But some experts in the field also questioned why they used a low dose of the cheap rival when significant numbers of patients typically are prescribed a higher dose.
Novartis, though, appears intent on testing regulators’ increased openness to something less than the gold standard, making this a new case study on just what standards the FDA plans to enforce. And if they do get by regulators, they will still face plenty of questions from payers, who had erected some stiff barriers to this drug after its first approval in 2015.
Initially a slow-moving product hampered by physicians reluctant to adopt a new med and payers who were none too happy with the price, Entresto is now comfortably hitting its blockbuster stride. But Novartis wants to add billions more in annual sales, and its latest trial failure won’t make that task any easier.
