Novartis is sticking to its guns. Despite the overall failure of the Paragon trial of Entresto in heart failure with preserved ejection fraction (HFpEF), the company believes that it has shown enough to get the drug to market in this underserved population.
Full data presented at the European Society of Cardiology meeting in Paris today suggest that the company could be justified in pressing on, especially given that there are no approved therapies for HFpEF. But Paragon was still, strictly speaking, a flop, and much will now depend on how lenient regulators are feeling.
The 4,800-patient study, published simultaneously in the NEJM, compared Entresto with valsartan, one of its active ingredients, on a primary composite endpoint of cardiovascular death and total heart failure hospitalisations.
Novartis previously said the miss was narrow, and the data unveiled today show just how close it was: Entresto reduced these events by 13%, giving a p value of 0.059.
Much of the benefit was driven by a 15% reduction in heart failure hospitalisations; there was no difference in cardiovascular death. This is perhaps not surprising given that HFpEF is generally milder and has a lower mortality rate than heart failure with reduced ejection fraction (HFrEF), for which Entresto is already approved.
The lead investigator, Dr Scott Solomon of the Brigham and Women's Hospital, Boston, also highlighted a benefit with Entresto on several secondary endpoints, including New York Heart Association classification and renal function, but since the study failed its primary analysis these can only be treated as exploratory.
|Full data from Paragon-HF (NCT01920711)|
|CV death & HF hospitalisations||894 events||1,009 events||Rate ratio 0.87; p=0.059|
|CV death||204 deaths (8.5%)||212 deaths (8.9%)||Hazard ratio 0.95|
|HF hospitalisations||690 hospitalisations||797 hospitalisations||Rate ratio 0.85; p=0.056|
|Source: ESC presentation, NEJM paper.|
David Soergel, head of Novartis’s cardiovascular, renal and metabolic drug development, told Vantage on the sidelines of the ESC meeting that Novartis would now file Entresto for HFpEF, but would not give any details on timings.
He was adamant that the totality of the data would support Entresto’s approval. Ultimately this will be down to the regulators, but two doctors at an ESC press conference this morning, with no links to the Paragon trial, appeared sympathetic to the company’s stance.
Dr Gabriel Steg of the Hôpital Bichat in Paris questioned whether a trial should be considered an out-and-out failure for falling just short of statistical significance, saying: “Everything in [Paragon] points to a substantial potential benefit.”
Meanwhile, Dr Dheepak Bhatt of Brigham and Women's Hospital agreed with Novartis’s “totality of the evidence” argument.
Mid-range ejection fraction
Dr Bhatt was particularly positive about Entresto's potential use in one HFpEF population, patients with a “mid-range” baseline ejection fraction; in other words higher than the cut-off for HFrEF, 40%, but below the median for the Paragon population, 57%.
A prespecified subgroup analysis found a benefit here, with mid-range ejection fraction patients showing a 22% reduction in the primary endpoint with Entresto versus valsartan.
Women also fared well in Paragon, with female Entresto-treated patients experiencing a 27% decrease in events. However, none of the other 10 populations included in the subgroup analysis returned a positive result.
If the FDA knocks back Entresto in the overall HFpEF population, perhaps there is a path forward in the mid-range ejection fraction patients. Novartis’s Mr Soergel would not speculate on whether Novartis would be prepared to run another trial in this population specifically, if requested to do so by the FDA.
Entresto is in another ongoing HFpEF trial, Parallax, set to complete late this year. But this primarily looks at functional measures like the six-minute walk test, and will not hold as much sway with the agency as an outcomes study.
A close result and an unmet need should work in Novartis's favour. But the FDA has shown recently that it is willing to bare its teeth, so Entresto's approval in HFpEF is far from a foregone conclusion.