When Novartis’ heart medication Entresto was approved last summer, many expected the launch to be among the Swiss drugmaker’s most successful product launches.
By the time the drug won FDA approval for treatment of chronic heart failure, analysts had predicted as much as $8 billion in peak annual revenue.
And to support it, Novartis gathered some convincing evidence for Entresto. In the largest clinical trial conducted for heart failure, treatment with the drug significantly reduced the risk of cardiovascular-related death or hospitalization from heart failure, compared to standard-of-care enalapril.
Several new developments have now raised hopes Entresto might shrug off its initial sluggishness and more quickly gain acceptance among physicians, payers, and patients.
Strong clinical foundation
Entresto, an oral, fixed-dose combination of sacubitril and valsartan, was intended to provide doctors with a first-line treatment option for patients with chronic heart failure with reduced ejection fraction (known by the easy acronym HFrEF).
What really solidified Novartis’ initial confidence in Entresto was the data collected from the 8,400-patient plus PARADIGM-HF trial.
That trial was stopped early after the benefits of Entresto became apparent. An interim analysis found Entresto significantly reduced cardiovascular death or heart-failure hospitalizations by 20%, and reduced all-cause mortality by 16%.
Chronic heart failure affects over five million Americans—half of whom are statistically likely to die within five years of their diagnosis. With such a wide prevalence, Novartis hoped Entresto could be a game-changer.
Lingering clinical concerns
Despite the strength of the evidence supporting use of Entresto , a constellation of factors substantially slowed initial post-launch uptake of Novartis, leading to much weaker-than-expected sales.
After diving deeper into the PARADIGM data, some cardiologists had lingering concerns that sacubitril might increase the risk of macular degeneration and Alzheimer’s disease in certain vulnerable populations. Other concerns included a possible increase in the risk of angioedema in some black patients.
In mid-May, however, Novartis announced plans for an ambitious clinical trial program aimed at broadening the evidence base for Entresto. Known as FortiHFY, the program is comprised of 40 clinical trials and is enrolling patients in more than 50 countries.
“The outcomes of these trials will increase our understanding of heart failure, the patient populations who may benefit from Entresto, and could potentially support future regulatory applications for additional indications,” said Vas Narasimhan, Novartis’ chief medical officer, at the time the trials were announced.
Negotiating with payers
Entresto launched last fall, just as payers were becoming more conservative in covering specialty drugs. With a $4,600-per-year price tag, the drug appeared expensive compared with the standard-of-care. Most other therapies already on the market have low-priced generic treatment options.
Six months after launch, Entresto still had not cracked many formularies, as payers now increasingly wait at least six months before covering new specialty drugs.
But in February, Novartis notched two successes, announcing it had struck pay-for-performance deals with Aetna and Cigna, two of the largest payers in the U.S. Under terms of the agreements, the price of Entresto will be tied to the reduction in the proportion of customers hospitalized with heart failure.
A month later, Novartis reported three-quarters of eligible patients would be covered if prescribed Entresto. However, many of the covered patients will still have to jump through a prior authorization hoop in order to get the drug.
Clinical practice boost
Three leading U.S. cardiology societies—the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America—last month gave Entresto its strongest recommendation (Class 1) as part of an update to clinical practice guidelines.
Unsurprisingly, Novartis sees the updated guidelines as a major positive factor supporting Entresto.
“We expect the strength of the recommendation from these leading experts to establish Entresto as a standard of care treatment,” said a Novartis spokesperson.
“This strong, clear guidance to prescribe Entresto will allow physicians to more readily identify patients who can benefit from this medicine.”
Will the guidelines increase uptake?
When the updated guidelines were released, there was the sense that this might convince on-the-fence physicians to prescribe Entresto.
But in fact, key opinion leaders in cardiology had been following the broader regulatory process leading up Entresto’s approval for some time. When the PARADIGM data was first presented, it became clear that a practice guidance update for treating HF was in order.
In this sense, the updated guidelines aren’t focused on just Entresto.
“Guidelines are about a global approach to treating patients, and are never written to champion a specific product or elicit a specific behavior,” said Clyde Yancy, former president of the American Heart Association, current Chief of Cardiology at Northwestern University’s Feinberg School of Medicine, and author of the guidelines.
“Ultimately the role of the guidelines is to demystify and deconstruct data from well-designed clinical trials and repurpose that information into user-friendly guidelines so that the practitioner can use them at the point of care.”
Yancy points out that practice guidelines are only useful if they are trusted by practitioners.
“There are a boatload of HF guidelines out there,” Yancy said. “However, very few of these guidelines have the built-in rigor and integrity associated with the ACC/AHA guidelines. Physicians know that they can trust the group of people who write the guidelines, and they respect and rely upon their opinions.”
A turning point?
Novartis will gain more data on Entresto through the FortiHFY program, aiming to strengthen its evidence base.
Recently, Bernstein analysts updated their forecasts for Entresto, predicting $2.7 billion in annual sales by 2020, although consensus estimates are pegged at $3.8 billion.
Despite the slow uptake, Novartis is still forecasting $200 million in sales for 2016 and an eventual $5 billion per year at peak.
Given its substantial investment and struggles elsewhere, Novartis needs a win. Its looking at Entresto, as well as its psoriasis drug Cosentyx to bolster against declining revenues from its blood cancer drug Gleevec in the near-future.
Entresto's expansive clinical program for Entresto, combined with increasing physician familiarity with the drug likely will boost sales over time, but Novartis will want to see an effect sooner rather than later.