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WASHINGTON -- The first drug to demonstrate a mortality benefit when compared with enalapril for heart failure -- Entresto (sacubitril/valsartan), previously known as LCZ696 -- received FDA approval Tuesday.
The drug, developed by Novartis, has been hailed as a game-changer by cardiologists who have previously been frustrated by disappointing results for other drugs for this condition.
A handful of older drugs, including the ACE inhibitor enalapril, demonstrated a mortality benefit in progressive heart failure among patients with reduced left ventricular ejection fraction who were receiving standard therapy, but that benefit was in comparison to placebo plus standard therapy.
For more than a decade - since the 2005 approval of for treatment of heart failure in black patients -- there were no "new" heart failure medications approved by the FDA. That drought ended last April when the FDA approved Amgen's ivabradine (Corlanor), but that drug reduced the risk of hospitalization with no improvement in mortality.
In addition to reducing heart failure deaths, Entresto, like Corlanor, is associated with reduced heart failure hospitalizations.
"This is terrific and very welcome news," Gregg Fonarow, MD, of UCLA David Geffen School of Medicine wrote in an email to 鶹ý.
Fonarow was one of many enthused cardiologists who responded to 鶹ý's request for comment on the Entresto approval, but none was happier than Milton Packer, MD, the researcher who led the PARADIGM-HF trial, which was the largest trial to date of heart failure patients with reduced left ventricular function.
It really has been a remarkable journey, Packer, chair of the Department of Clinical Sciences at UT Southwestern in Dallas, said in a telephone interview. In terms of benefits to patients, this is the biggest change in 20 years.
The FDA review was very straight forward and very rapid; the indications are very appropriate for patients and it is clear that the drug is intended as a replacement for ace inhibitors because t reduces mortality and hospitalizations better than optimal doses [of enalapril], Packer said.
In fact the journey was so fast and so smooth, that Packer admitted he was still more comfortable calling the drug LCZ696, which was its development code name and the name used during the pivotal trial.
But the speed demonstrated by the FDA was not unexpected since the drug did receive priority review and . Sacubitril is a neprilysin inhibitor that raises blood levels of natriuretic peptides; valsartan is an angiotensin receptor blocker sold as Diovan as an individual drug.
In the PARADIGM-HF trial the drug, which was tested at a dose of 200 mg twice daily versus enalapril 10 mg twice daily, was also superior in reducing death from any cause (711 patients versus 835, P<0.001). The study randomized 4,187 patients to LCZ696 and 4,212 to enalapril.
Moreover, patients in the LCZ696 arm were 21% less likely to be hospitalized for heart failure (P<0.001) and were less likely to report heart failure-related symptoms or disability (P=0.001).
The most common adverse effects in clinical trial participants being treated with Entresto were hypotension, hyperkalemia, and renal impairment -- all conditions that contribute to heart failure.
But Fonarow, who is director of the Ahmanson-UCLA Cardiomyopathy Center, added a few words of caution noting that "patients with lower systolic blood pressure and the medication has not been studied in patients with heart failure together with kidney failure. Also patients with elevated potassium levels cannot be treated with this medication."
Robert O. Bonow, MD, MS, also expressed enthusiasm but tempered it with caution about the drug's use in African Americans because there appears to be a increased risk of angioedema in that population. Bonow is a professor of cardiology at Northwestern University Feinberg School of Medicine and director of the Center for Cardiovascular Innovation at Northwestern.
In addition to reducing heart failure deaths, Entresto reduced heart failure hospitalizations.
"Heart failure is a leading cause of death and disability in adults," said Norman Stockbridge, MD, PhD, director of the Division of Cardiovascular and Renal Products in the FDA's Center for Drug Evaluation and Research, in an FDA statement. "Treatment can help people with heart failure live longer and enjoy more active lives."
Clyde Yancy, MD, MSc, a cardiologist well-known for his cautious approach to new therapies, had a one word reaction when told of the approval: "YEAH!"
Yancy, vice dean, diversity and Inclusion, and chief of the division of cardiology at Northwestern University Feinberg School of Medicine, said the approval was "the new day in heart failure that we anticipated when we first saw the PARADIGM-HF data. Rarely do we see a new therapy that is 'better than the standard.' This is it. I've already had patients send me e-mails requesting access. Clearly, not everyone is a candidate and there is much left for us to discover -- impact in special populations and especially costs -- but as a doctor who cares for those with a potentially devastating condition, we need this new tool. Our usual approach is to be hesitant and wait to see 'how it goes' first but for heart failure patients, hesitancy is not an option."
Former American Heart Association president Mariell Jessup, MD, said in an email that there "are two reasons the drug is a potential game changer: it represents a new class of drug which may have a meaningful impact on the trajectory of disease in many patients."
Jessup, a heart failure specialist and professor at the University of Pennsylvania Heart and Vascular Center, said the second reason "has already happened -- there is great excitement in the drug industry about the possibility of finding new therapeutic pathways in heart failure.
Packer said Jessup had it exactly right, noting that enthusiasm for development of cardiovascular drugs had waned over the last decade, but the Entresto experience had revitalized the field.
But Jessup added that price for the new drug -- no price has been set yet -- could be a problem if the drug is as pricey as some recently approved first-in-class therapeutics.
Price will be a factor-if the third party payors place some conditions on who can get the drug- clinicians will have to struggle to arrive at agreed upon criteria to use the drug.
Packer predicted that price would not be an issue, noting that the announced wholesale acquisition price is $12.50/day, which is the same as the Amgen drug and is pretty much the same as the NOACS (novel oral anticoagulants such as rivaroxaban (Xarelto), apixaban (Eliquis) and dabigatran (Pradaxa), except the benefits of LCZ696 are really more impressive.
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From the American Heart Association: