A close look at LCZ696: Novartis success comes fro

Novartis released results of new heart failure drug LCZ696 from PARADIGM-HF trial on the weekend[1]. LCZ696 was tested against enalapril, the standard therapy, in patients with heart failure. This new drug reduced cardiovascular death by 20% and heart failure hospitalization by 21%.

These data suggest that LCZ696 could replace angiotensin-converting enzyme (ACE) inhibitors that have been central to treating heart failure for more than 20 years. David Epstein, the head of Novartis Pharmaceuticals, described LCZ696 as the most exciting new drug ever. Analysts such as Seamus Fernandez, Damien Conover and Timothy Anderson hiked their forecast to $6-8 billion a year in peak sales.

LCZ696 is a combination of valsartan and sacubitril (AHU377) in a 1:1 mixture. Valsartan is an angiotensin II receptor antagonist while sacubitril is a prodrug of LBQ657 which inhibits neprilysin (NEP).

This isn’t the first time that a drug inhibits renin-angiotensin system and NEP at the same time. Bristol-Myers Squibb had a drug called omapatrilat which inhibits both NEP and ACE. Unfortunately, its development was discontinued due to the increased risk of angioedema, a deadly side effect that can cause patients to suffocate.

What interests me most is that Novartis succeeded in which Bristol-Myers Squibb had failed.

Angioedema is thought to be mediated by bradykinin which is degraded by ACE, APP, NEP and DPP-4[2]. Omapatrilat not only inhibits ACE, but also inhibits NEP and APP. Inhibition of all three enzymes may greatly increase bradykinin, resulting in angioedema.

Angioedema caused by angiotensin II receptor antagonists is much less than that for ACE inhibitors. Novartis’s new combination inhibits only NEP and APP, thereby producing beneficial cardiovascular effects without the side effect of angioedema.

There is no rose without thorn. As William Foster mentions, the natriuretic peptides are not the only substrates of NEP. NEP also degrades the amyloid beta peptide which is strongly linked to Alzheimer’s disease (AD). Inhibition of NEP might lead to an increased level of beta-amyloid and thus an increased risk of AD. Further monitoring for neurological dysfunction is warranted.

[1] N Engl J Med. 2014, doi: 10.1056/NEJMoa1409077.

[2] Br J Pharmacol. 2008, 153(5), 947-955.