Novartis heart-failure med Entresto cuts A1c, insulin starts in diabetics: analysis

A new analysis of data on Novartis' heart failure drug Entresto may trigger changes in the way the company analyzes blood-sugar numbers when in-process clinical trials wrap up.

WASHINGTON, D.C.—Novartis has been mining a pivotal study of Entresto, its heart-failure med, for more insights ever since it was first published in 2014. Now, a new analysis shows that Entresto beat an older med at reducing blood sugar levels in heart failure patients with diabetes.

By breaking out and analyzing data on 3,778 diabetic patients who participated in the Paradigm-HF trial, researchers found that those in the Entresto arm saw a 0.26% drop in HbA1c, a commonly used measure of blood sugar levels, compared with 0.16% among those taking enalapril, an older heart failure remedy. And 29% fewer diabetics in the Entresto arm needed to start insulin therapy during the course of the study, compared with those in the enalapril arm.

Entresto isn’t a diabetes drug, of course, and as much as Novartis would like to broaden use of the slow-starting med, it doesn’t envision trying to market Entresto for blood sugar control. Instead, the new data suggest that cardiologists need to keep an eye on blood sugar levels in diabetic Entresto patients, in case their diabetes meds need adjusting, according to the study’s lead author Scott Solomon, M.D., director of noninvasive cardiology at Brigham and Women’s Hospital and a Harvard Medical School professor.

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That could be a hefty percentage of patients: Overall, 40% of heart failure sufferers have diabetes, Solomon said. Plus, this group of patients is more likely to suffer complications. “We know these patients are at high risk,” Solomon said in an interview.

Novartis is looking to build up new data that can potentially broaden the use of Entresto, which hit the market to great fanfare in 2015 but since has struggled to gain traction. Payers, skeptical of the new, pricier drug in a field dominated by generics, have been slow to open up reimbursement, despite the outcomes data produced by the Paradigm-HF trial.

Hurdles raised by payers—including high co-pays and prior authorization requirements—hobbled Entresto last year; the drug brought in $170 million, a number far short of what the drugmaker had hoped when it launched. Novartis CEO Joe Jimenez has championed pay-for-performance contracts with payers, and the company has managed to set up some of those deals with prominent insurers such as Aetna and Cigna, but so far it's not been enough to significantly accelerate script growth.

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However, the company has persuaded payers to lower their hurdles a bit this year, with 48% of commercially insured patients now able to fill their Entresto scripts without prior authorization, compared with 26% last year, and preferred formulary status in 88% of those plans, Novartis Pharmaceuticals CEO Paul Hudson said during the company’s Q4 earnings call.

In addition to easing those barriers, Novartis is moving Entresto into new international markets; despite the U.S. market's rep as the world's biggest, the drug's uptake in Europe has been stronger, a fact that Novartis execs attribute to single-payer systems able to realize longer-term cost savings from the drug's ability to hold off expensive hospitalizations.

Plus, it’s been beefing up its U.S. commercial team, with more than double the coverage now than it had at the beginning of 2017, Hudson said. The Entresto salesforce is now working not only with cardiologists but primary care docs, too.

“[W]e’re at a steady state for covering the heart failure potential,” he said. “We’ll cover roughly 70% of all the heart failure potential patients” as of the end of February. And now, Novartis is expecting Entresto to more than double sales by year’s end, with $500 million for 2017

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Expanding Entresto’s target population is important to the drug’s long-term growth, so last year, the company expanded its development program to bring its total of planned or active trials to 40. Among those studies is Paragon-HF, testing Entresto in patients with preserved ejection fraction; right now, the drug is approved for heart failure patients with reduced ejection fraction, which is a measure of the percentage of blood pumped from the heart each time it contracts.

There’s also an outcomes trial, focusing on cardiovascular death and heart failure in patients who’ve suffered a heart attack, known as Paradise-MI. That study is expected to read out in 2020, with Paragon-HF results expected in 2019.

In light of this new analysis, presented at the American College of Cardiology meeting in Washington, D.C., on Saturday, Novartis may change the way it crunches the data from these follow-up Entresto studies, to look more closely at the drug’s glycemic effects in addition to its effects on heart failure, Solomon said.

Why would Entresto have an effect on blood sugar? Solomon said there are a few possibilities, though none proven. It might spur conversion of white fat to brown fat, which is more metabolically active. Also, sacubitril, one of Entresto's two active ingredients, could be indirectly boosting levels of glucagon-like peptide (GLP-1), a target of diabetes drugs such as Novo Nordisk's Victoza. 

Patients in the enalapril arm came into Paradigm-HF with HbA1c levels of 7.48, and saw a reduction to 7.30 after a year of therapy, Solomon said. Entresto patients began the study with average HbA1c levels of 7.41; after a year, that number had declined to 7.09. For comparison's sake, a recent trial of Novo's 1 mg dose of its experimental GLP-1 drug semaglutide reduced those levels by 1.5% from a baseline of 8.3%. The target level of HbA1c is less than 7%.