#ACC21: Novartis' Entresto takes its 2nd failure of the weekend at ACC, showing no benefit in most dire heart failure patients
Novartis’ Entresto started the ACC weekend off rough with a trial flop in heart attack patients, slowing the drug’s push into earlier patients. Now, an NIH-sponsored study is casting doubt on Entresto’s use in the most severe heart failure patients, another black mark on the increasingly controversial drug’s record.
Entresto, a combination of sacubitril and valsartan, could not beat out valsartan alone in an outcomes head-to-head for severe heart failure patients with a reduced ejection fraction (HFrEF), according to data presented Monday at the virtual American College of Cardiology meeting.
The LIFE study, funded by the NIH with participation from Novartis, found that in 355 patients with Class IV HFrEF, Entresto couldn’t top placebo in terms of heart failure severity as measured by the area under the curve for N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels after six months of treatment. The Class IV designation is reserved for patients with an ejection fraction measured below 35% as well as other physiological and functional markers of severe heart failure.
The data showed no difference in terms of clinical outcomes, researchers said, but on some follow-on endpoints valsartan alone actually outperformed Entresto, including on instances of hyperkalemia, or excess potassium levels.
“Although the trial did not have the statistical power to evaluate endpoints such as cardiovascular death and heart failure hospitalization, when you look at the totality of the data, everything was in favor of valsartan,” lead author Douglas Mann said in a statement.
The study looked at the most severe heart failure patients as a follow-up on Novartis’ pivotal PARADIGM-HF trial, which earned Entresto its first FDA nod in HFrEF back in 2015. At the time, Entresto was heralded as a breakthrough in heart failure, but since then its record has been less than sterling despite one major approval that came with controversy of its own.
Earlier this weekend, Novartis revealed full data from its PARADISE-MI study testing Entresto after a heart attack in preventing a composite endpoint of death and heart failure events. The drug missed badly on that primary mark, but Novartis still touted some positive secondary endpoints, potentially setting up an argument for the drug’s use in that setting.
Meanwhile, Entresto recently earned a come-from-behind approval in other heart failure patients — those with a preserved ejection fraction (HFpEF) — after missing the primary endpoint on its pivotal study in that population. Despite the “narrow miss” on p-value, as Novartis called it, Entresto earned the FDA’s backing to go ahead with a filing, arguing that prespecified analyses and supplementary data cast doubt on the pivotal study’s design and didn’t capture the full range of benefit for the drug.
With that approval, Entresto became the first drug approved for HFpEF, offering some hope to a patient population with poor outcomes and few options.