New Heart Drug From Novartis: Will It Raise The Risk of Alzheimer’s Disease?

LCZ696 is a heart failure drug from Novartis that many observers think will gain FDA approval later this year and go on to become a blockbuster. Perhapsthe biggest obstacle to the drugs success is the fear that it might raise the risk of Alzheimers disease. Now a new article in a top cardiology journal lays out the detailed basis for this concern. The authors donot contend that the Alzheimers issue will likely ruin the drugs chances, but they do maintain that the problem needs to be carefully monitored.

I spoke with Milton Packer, the co-principal investigator of PARADIGM-HF, the mega trial that set off the mega excitement about the drug last year. He offers several persuasive arguments that Alzheimers disease wont bethe Achilles heel of LCZ696.

But first lets look at the paper, published in theEuropean Heart Journal, by a group of French researchers. The paper focuses on the potential impact of sacubitril, which is one of the two key ingredients of LCZ696. Sacubitril inhibits the action of neprilysin. The French authors focus on two conflicting roles for neprilysin.The cardiovascular benefitsare achieved because in the heart neprilysin inhibition leads to increased levels of neuropeptides and vasodilators that are beneficial in hypertension and heart failure. However, in the brain neprilysin appears to play a key role in degrading the beta amyloid plaque that is one of the hallmarks of Alzheimers disease. The French authors raise the possibility that the drug could accelerate the progression of Alzheimers disease, particularly in people at high risk forthe disease, though they confess that it is uncertain whether LCZ696 can penetrate the blood brain barrier, which would be necessary for this effect.

The French authors note that although nosignal for cognitive dysfunction was found in PARADIGM-HF, the trial did not rigorously assess this endpoint. This endpoint will be followed much more closely with serial cognitive tests in the next big LCZ696 trial, PARAGON-HF, in heart failure patients who have preserved ejection fraction. However, write the authors, it is unclear whether the duration of follow-up of this trial will be sufficient to exclude any deleterious effect of LCZ696 on cognitive function.

The French authorsacknowledge someimportant points that worksagainst their concern. The second component of LCZ696, the angiotensin-receptor blockervalsartan, may protect against Alzheimers because of its vasoprotective properties. It is possible, therefore, that any negative effect of sacubitril could be counterbalanced by a positive effect of valsartan. It is also possible that the long time frame for Alzheimers development could mean that any adverseeffect would be undetectable or clinically meaningless, given the advanced age of most heart failure patients.

Milton Packer Responds

The LCZ696 investigators are of course aware of these concerns. Animal studies,Packer told me, first raised the issue 10-20 years ago. Fortunately, he said, 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. (Remember that OVERTURE was the trial testinga similar agent, omapatrilat. It failed spectacularly, but not because of neurocognitive issues.)

Packer offered the same possible explanationas the French investigators for the observed decrease in dementia events. The reason might be related to the fact the dementia is multifactorial and has an important vascular component, and the vascular component would actually be expected to be improved by neprilysin inhibition, said Packer. And heres the important piece of news: In any case, Packer told me, there was no imbalance (not even a numerical imbalance) in dementia-related events with omapatrilat or LCZ696.

But theres one important caveat: this data has not been presented or published yet. Packer told me the PARADIGM investigators have placed a high priority on theneurocognitive paper but it is important to reserve judgement until the data undergoes outside scrutiny. (And, not to be coy about it, Milton Packer has not always received a lot of praisefor the timely publication of important papers.)

Packer also explained why PARAGON-HF will include a much more rigorousneurocognitive evaluationthan PARADIGM-HF:

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New Heart Drug From Novartis: Will It Raise The Risk of Alzheimer's Disease?