February 9, 2015
By Mark Terry, BioSpace.com Breaking News Staff
A study published Jan. 30, 2015 in the European Heart Journal throws out some concerns about Novartis AG ' heart failure drug, LCZ696.
In August 2014, Novartis presented very promising data at the European Society of Cardiology (ESC) Congress 2014 regarding LCZ696. The drug is a twice-a-day tablet for heart failure that “acts in a unique multimodal way to enhance the protective neurohormonal system of the heart (NP system) while simultaneously suppressing the harmful system (the RAAS).”
The drug was part of the PARADIGM-HF study, which evaluated the efficacy of the drug compared to enalapril. Enalapril is marked as Vasotec in the U.S. and as Enaladex in other countries. Enalapril is an angiotensin-converting-enzyme (ACE) inhibitor used to treat hypertension, diabetic nephropathy and some types of chronic heart failure.
The data from the trial was positive enough that the trial was ended early in March 2014. The Data Monitoring Committee (DMC) unanimously recommended early closure because patients receiving the compound lived longer without hospitalization for heart failure than patients receiving enalapril.
In the study published in the European Heart Journal, a group of French researchers looked at one of the two key ingredients of LCZ696, sacubitril, and its potential impact. The compound, sacubitril, inhibits the action of neprilysin.
Neprilysin has two conflicting roles. In the heart, neprilysin inhibition causes increased levels of neuropeptides and vasodilators, which are beneficial to the cardiology system. In the brain, however, neprilysin apparently plays a role in degrading the beta amyloid plaques linked to Alzheimer’s disease. Because of this, the French researchers, led by Nicolas Vodovar, speculated that use of the drug could speed the progression of Alzheimer’s disease, especially in people at high risk for dementia and Alzheimer’s. They do, however, admit that it is unknown whether LCZ696 can pass the blood brain barrier.
In addition, the second key ingredient of LCZ696, valsartan, which is an angiotensin-receptor blocker, may have some Alzheimer’s preventive properties due to its vasoprotective properties.
Milton Packer, co-principal investigator of PARADIGM-HF, indicates that they were aware of these concerns, which were raised 10 to 20 years ago. “Fortunately,” Packer said in a statement, “we have actual data from long-term clinical trials (not only PARADIGM-HF but also OVERTURE), showing no increase (and actually a decrease) in dementia-related adverse events in patients receiving long-term treatment with neprilysin inhibitors.”
The data proving this has yet been published, although it is clear that Novartis intends to follow this issue closely. “This is not a time frame issue,” said Packer in a statement. “It is a competing risk-to-benefit issue. Simply put, if you are dead or suffering repeatedly hospitalizations for heart failure, you are probably not too worried about a small hypothetical effect on some dementia scale. No observational study will change the clear-cut decision for the patient.”
That said, researchers and healthcare practitioners want to be assured that they’re not buying a problem with their solution. “Our enthusiasm for a new treatment paradigm in heart failure,” said Clyde Yancy, division chief of Medicine-Cardiology at Northwestern University Feinberg School of Medicine in a statement, “and importantly the hope that so many patients have for improved outcomes should not be doused by what are at best theoretical considerations…. But we should be resolute in our surveillance to insure safety first when new therapies are introduced.”
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