Entresto for Heart Failure – a Cautionary Note

In July 2015, the FDA approved the new drug Entresto (Novartis) for the treatment of heart failure.

Enthusiasm for this new drug is high among heart failure experts, and for good reason. In a large clinical trial (PARADIGM-HF), Entresto significantly outperformed enalapril, which currently is a mainstay of therapy for patients with heart failure.

Entresto is the first of the ARNI class of drugs. These drugs combine an ARB inhibitor (in this case, valsartan), with a neprilysin inhibitor (sacubitril). Neprilysin inhibition is the new feature of the ARNI drugs.

When the enzyme neprilysin is inhibited in heart failure patients, blood levels of natriuretic peptides increase. Because natriuretic peptides can be beneficial in heart failure, researchers postulated that drugs like Entresto could improve the outcome of patients with this condition. The results of the PARADIGM-HF study show that the researchers were right.

While Entresto appeared to be both effective and safe in the PARADIGM-HF trial, there are still a few things we do not know about long-term neprilysin inhibition.

Neprilysin has many actions in addition to reducing the levels of natriuretic peptides, and some of those actions appear to be beneficial. So inhibiting neprilysin may not be a universally good thing to do.

In particular, neprilysin reduces the accumulation of undesirable proteins in the body, including the proteins associated with Alzheimer’s disease and amyloidosis, and even prostate cancer. In fact, researchers are actively looking for drugs that can increase the activity of neprilysin, in the hopes that it might help treat or prevent conditions like these. So, despite the fact that few significant side effects were reported with Entresto in the PARADIGM-HF trial, there still may be a possibility of significant long-term consequences with a drug that inhibits neprilysin.

In none of my research on Entresto was I able to find even a mention (either by the researchers or by Novartis) of the potentially negative consequences of chronic neprilysin inhibition. So I contacted Novartis to ask whether the company has evidence, one way or the other, that using Entresto might affect the risk of diseases like Alzheimer’s, amyloidosis, or prostate cancer.

After a few days during which the company consulted its experts, I received this reply from Novartis. Here it is in full:

"Neprilysin is involved in a number of processes within the body including breaking down a variety of endogenous vasoactive peptides, which - by targeting neprilysin - Entresto helps enhance, leading to beneficial effects in heart failure patients. Neprilysin is one of many enzymes involved in breaking down amyloid beta proteins. Data from the PARADIGM-HF development program, with more than 10,000 patients studied, does not indicate any adverse effects related to amyloidosis, Alzheimer's or prostate cancer with Entresto. It's important to note that patients with heart failure have a 50% mortality rate at 5 years despite treatment with best current therapies, a death rate higher than most cancers. Entresto reduces mortality, prevents hospitalizations and makes people with HF-REF feel better."

I was struck by a few things about this response. First, the company was not ready with an immediate reply to (what I feel) is a pretty obvious and important question.

Further, the company is not denying the risk that neprilysin inhibition might worsen other kinds of serious diseases. The fact that their studies showed no evidence of such worsening is comforting, but we should note that studies with Entresto have all been of relatively short duration and that it’s not clear that patients treated with Entresto were particularly monitored for amyloidosis, Alzheimer’s or prostate cancer.

Finally, the company suggests that heart failure is such a bad condition that even if their drug did cause or worsen these diseases, the risk would be worth taking. This, obviously, is a matter of personal judgment. Whether a patient regards a risk as being worthwhile depends on his/her own assessment of the risks vs. the benefits. This is a difficult assessment to make, of course, if not all the risks are called out. 

Entresto appears to be a compelling drug for patients with heart failure, and it undoubtedly will be heavily used. It undoubtedly will help many patients with heart failure to live longer and with fewer symptoms.

But specifically because Entresto has the makings of a blockbuster drug, and therefore large numbers of patients will be exposed to neprilysin inhibition for the first time, it will be particularly important for Novartis (and the FDA) to conduct careful post-marketing studies, so that any “unexpected” side effects can be recognized and characterized as quickly as possible.