Novartis hopes Entresto can be a Paragon of label expansion

New data for heart failure pill could clear the way for use in less severely ill patients.

Entresto’s painfully sluggish launch has at last started to gain momentum, and expansion into a less severe form of heart failure could add some thrust to Novartis’s biggest growth driver.

The Paragon-HF trial in patients with preserved ejection fraction is due for an interim analysis sometime in the next few months, and if Entresto beats Diovan with a high level of statistical significance the trial could be halted for efficacy. Still, Novartis executives and investors expect the study to continue to a final readout in 2019; the company believes that the new indication could add $1bn in annual sales.

While expectations for an interim win in Paragon-HF are low, it should be remembered that Entresto’s first pivotal trial, in heart failure patients with reduced ejection fraction, was halted because it showed early superiority to Vasotec in keeping heart disease patients alive and out of hospital (Novartis gets surprise heart failure win as ACC data roll in, March 31, 2014).

Can lighting strike twice?

Still, Paragon will have to clear a pretty high bar to be stopped this year. The trial has randomised 4,800 patients to treatment with either Entresto or Diovan, comparing the two on a composite endpoint of cardiovascular death or heart failure hospitalisation. Secondary endpoints are all-cause mortality, change in New York Heart Association functional class, renal outcomes, and change in score on the Kansas City cardiomyopathy questionnaire.

Product Entresto
Company Novartis
Market cap $213bn
Product NPV $13.2bn
NPV as a % of market cap 6%
Event Phase III interim analysis
Timing 2H 2018

The interim analysis will take place after about two thirds of the expected 1,847 cardiovascular events have occurred, which is due by the end of 2018. To qualify for an even earlier halt Entresto will need to show superiority on both the primary endpoint and cardiovascular death at a one-sided statistical significance level of 0.001 or less.

Because Novartis does not believe that Entresto will show a benefit on cardiovascular death at the interim look it expects the trial to proceed to final analysis in 2019, where the pill will need to show superiority below a one-sided statistical significance level of 0.025.

Heart failure with preserved ejection fraction, defined in this trial as left ventricular ejection fraction of 45% or more, is responsible for about half of all heart failure cases, and is growing as a share of all heart failure cases

Finding treatments that prevent death or complications has been more difficult in this type of heart failure, in part because researchers do not completely understand its pathophysiology; this in turn means that there is heterogeneity in the population. This could be why Novartis has played down the potential for success of Paragon at the interim read, and why investors and analysts have been cautious about its chances even at the final analysis.

Another billion

Diovan, which is given in the control arm of Paragon, is in fact one drug that has been tested in this patient group, failing to show a benefit on exercise time versus placebo. 

The active ingredient in Diovan, the angiotensin II receptor antagonist valsartan, is one of two in Entresto. The other is sacubitril, a neprilysin inhibitor, so in many ways Paragon is a test of this mechanism of action in treating heart failure, and could give developers some insight into potential single-agent use of sacubitril.

In treating reduced ejection fraction patients Entresto recorded $507m in sales in 2017, its third year on the market. This is forecast to grow to $4.2bn by 2024, according to EvaluatePharma’s sellside consensus. It appears that this forecast includes the potential new indication – Novartis's chief executive, Vas Narasimhan, told Bernstein analysts that reduced ejection fraction use could make Entresto a $3bn drug, and the expansion to preserved ejection fraction patients would push sales to $4bn.

Entresto will do well without success in the preserved ejection fraction population, as US guidelines now recommend switching from an ACE inhibitor or ARB to reduce complications and death in these patients. Adding $1bn in sales is an opportunity too big to pass up, however, even if the odds of success in the new indication look longer.

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