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Attention is turning this year to heart failure with preserved injection fraction.
For years, heart failure was the unsolvable problem of healthcare. Patients with heart failure cannot adequately pump blood through the body, causing fatigue, persistent cough, weakness or other symptoms. They have long hospital stays. When they are discharged, they often return. Most have other health problems, diabetes being among the most common. Half of patients with heart failure will die within five years of showing symptoms.
Heart failure is so costly — the tab reached $30.7 billion in 2012 — that it got special mention in the Patient Protection and Affordable Care Act, which tried to compel the delivery system to stop the revolving hospital door by imposing readmission penalties. Meanwhile, drug manufacturers have been searching for better treatments, partly because any products they come up with will enjoy a growing market. Heart failure is a disease of old age, and tens of millions of baby boomers are now in their 60s and beyond.
Even so, a 2014 heart failure breakthrough received a lukewarm reception. Results from the pivotal PARADIGM-HF trial showed that patients taking Novartis’ Entresto (sacubitril/valsartan) had a 20% lower risk of death from cardiovascular causes than those taking enalapril, an ACE inhibitor. But sales fell short of expectations, and heart failure lost some luster as a therapeutic area. “If a ‘blockbuster’ therapy with demonstrable mortality reduction benefit was seldom prescribed for patients who would benefit, how could future investments be justified?” wrote Tariq Ahmad, M.D., M.P.H., FACC, and Nihar R. Desai, M.D., M.P.H., of the Yale School of Medicine, in JACC: Heart Failure.
But in 2020, Novartis’ patience with Entresto paid off. Third- quarter results showed U.S. sales had climbed 45% for the year. Marie-France Tschudin, president of Novartis Pharmaceuticals, told investors that in a pandemic, “Entresto delivers on its value proposition of keeping patients out of the hospital. This, of course, is especially important right now.”
Two types of heart failure
Patients in the PARADIGM-HF trial had heart failure with reduced ejection fraction, also called systolic heart failure, which occurs when the heart’s left ventricle becomes enlarged and fails to push blood out into the circulatory system properly. At the time the Entresto results were reported, other treatments for this type of heart failure were already available. It took time for Entresto to be embraced as a first choice, but Tschudin said this is finally happening.
Keeping patients out of the hospital is the goal of other heart failure treatments under development, including Amgen’s omecamtiv mecarbil, which targets a protein that powers the pumping function. Omecamtiv mecarbil, for reduced ejection fraction, is among a new wave of drugs being studied that addresses cardiac damage without causing adverse events. Another is Merck and Bayer’s vericiguat, which has a different mechansism of action.
Some patients, however, have heart failure with preserved ejection fraction: The left ventricle has enough pumping power but the heart is stiff, so the chamber doesn’t fill up with enough blood. This year, it looks like heart failure with preserved ejection fraction is where the action will be as far as drug development, approval and marketing.
Novartis got a head start by filing an application with the FDA in June 2020 to market Entresto as a treatment for heart failure with preserved ejection fraction. Novartis’ strategy for Entresto seemed to pay off on Dec. 15 when an FDA advisory committee voted 12-1 to be the first drug approved for heart failure with preserved ejection fraction. An FDA staff recommendation, and the positive committee vote, came despite trial results that fell short of reaching statistical significance. The advisory panel debate highlighted some of the problems with dividing heart failure into reduced and preserved ejection fraction.
By the end of the discussion, Norman Stockbridge, M.D., Ph.D., director of the FDA’s Office of Cardiology, Hematology, Endocrinology and Nephrology, said that coming up with a meaningful label may require a different way of describing “the heart failure spectrum.” Steven Nissen, M.D., of Cleveland Clinic, discussed a label that would include reducing heart failure hospitalization. Cynthia Chauhan, M.S.W., the panel’s consumer representative, called for a new trial that would have greater representation of minorities and patients with common comorbidities. Novartis’ David Soergel, global head of cardiovascular, renal and metabolic drug development, said the need for diversity is recognized within the company and across the industry.
Both the FDA staff and the panel weighed the fact that results from the phase 3 PARAGON-HF trial supporting the preserved ejection fraction indication did not reach statistical significance for reducing morbidity and mortality. But Novartis’ supplemental new drug application included data from PARADIGM-HF and made the case that the “totality of the evidence” supported approval with ejection fraction in the “overlap HFrEF (heart failure with reduced ejection fraction) and the lower end of HFpEF (heart failure with preserved ejection fraction).”
Novartis is studying Entresto for yet another indication in the phase 3 PARAGLIDE-HF trial. This trial looks at whether the drug works in patients with preserved ejection fraction with acute decompensated heart failure — a sudden worsening of heart failure — after stabilization during hospitalization. This indication could have important implications for insurers because of the penalties for hospital readmissions. But results from this trial aren’t expected until early 2022. The next day the committee made a similar recommendation for the blood pressure medication spironoclatone but by a narrower vote of 8-4. Spironoclatone is currently approved to treat heart failure with reduced ejection fraction.
Hot on Novartis’ heels are the SGLT2 inhibitors, which started as diabetes drugs but have crossed over and are fast becoming heart failure drugs too. AstraZeneca’s Farxiga (dapagliflozin) is approved as a treatment for heart failure with reduced ejection fraction, and Eli Lilly and Boehringer Ingelheim’s SGLT2 inhibitor Jardiance (empagliflozin), may join Farxiga based on strong results presented at European Society of Cardiology Congress 2020. Results of trials assessing both of them as treatments for heart failure with preserved ejection fraction are expected to be reported this year.
Most likely, the effective treatment of heart failure — for both reduced and preserved ejection fraction — will not be a single drug but a combination of drugs. Ahmad and Desai endorsed “quad therapy” for heart failure with reduced ejection fraction, arguing that a cocktail of Entresto, Farxiga, a beta blocker and a mineralocorticoid receptor blocker would be greater than the sum of its parts.
Burkert Pieske, M.D., a German heart disease researcher, says the same is true in preserved ejection fraction: “I do believe in the future, a combination therapy of Entresto and an SGLT2 inhibitor and, in addition, a (mineralocorticoid receptor) antagonist — as an anti-fibrotic and blood pressure lowering agent — could be the ideal combination.”
The only thing to do now, he says, is wait for the data.