Novartis’s Paragon falls short of perfection

Trying a different primary endpoint did not help Entresto in heart failure with preserved ejection fraction, but Novartis seemingly still sees a path forward.

Chalk up another flop in heart failure with preserved ejection fraction (HFpEF), this time for Novartis’s Entresto. The company had tried to avoid other groups’ misfortunes in this tricky indication by experimenting with a novel primary endpoint in the Paragon-HF trial, but in the end this came to naught.

Novartis still seems to hold out hope for Entresto in this use, with the company saying it would discuss its next steps with regulators; apparently, Paragon only “narrowly missed” showing a benefit with Entresto versus valsartan on cardiovascular death and heart failure hospitalisations.

Novartis added that the overall results suggested a clinically important benefit with Entresto in HFpEF. The group did not give any more details, but no doubt the data will be dissected at the upcoming European Society of Cardiology meeting in Paris, where Paragon is due to be presented on September 1.

Investors do not appear to share the company’s optimism. Novartis’s stock lost 1%, or $2bn in value, this morning.

Entresto, a combination of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, was approved in the US for heart failure with reduced ejection fraction (HFrEF) in 2015, where it finally breached the $1bn mark last year. Novartis had also predicted blockbuster sales in HFpEF, which affects around the same number of patients.

Jefferies analysts, meanwhile, had estimated that Entresto could bring in $2.5bn in HFpEF at its peak, but had only given the drug a 40% chance of success here.

No Paragon

Their caution turned out to be warranted. Getting a result was always going to be tough: there are no approved therapies for HFpEF, which is characterised by normal heart pump function, and various companies have tried and failed to address the disease.

HFpEF is generally milder and has lower mortality rates than HFrEF, which has made it harder to demonstrate a benefit with drugs.

Novartis had hoped to get around this by using a different primary endpoint than earlier HFpEF trials: while previous studies had evaluated time to cardiovascular death or first hospitalisation due to HF, Paragon looked at cardiovascular death and both first and recurrent hospitalisations (Upcoming events – Novartis and Miragen hope for heartening data, June 21, 2019).

The trial’s investigators had argued that this was a better measure of disease burden in HFpEF; Novartis’s hopes had been boosted by a post-hoc analysis of the failed Charm Preserve study of another angiotensin receptor blocker, candesartan, which suggested a benefit if recurrent hospitalisations were taken into account.

During last week's earnings call, Novartis executives said success in Paragon would depend on Entresto's impact on hospitalisations. At the time they stressed that they had not seen the data, but it seems possible that the drug might have shown a benefit on hospital admissions without having any effect on cardiovascular death.

However, unless regulators are feeling particularly forgiving, Entresto might “only” bring in peak sales of around $3bn, which is what Novartis has guided for HFrEF. This is not to be sneezed at, but a win in Paragon could have doubled this figure. Over to the FDA.

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