- LCZ696 is an investigational heart failure drug developed by Novartis that is expected to win FDA approval later this year.
- French researchers have published an article in the European Heart Journal examining the relationship between LCZ696 and the potential for an increased risk of Alzheimer's disease (AD) as a consequence of one mode of action associated with the compound.
- LCZ696 is comprised of two main compounds—sacubitril and valsartan. As Forbes explains, sacubitril inhibits neprilysin, a mode of action which increases levels of cardio-beneficial neuropeptides, but also inhibits amyloid-beta degradation in the brain. Valsartan is vasoprotective, which is good for both the heart and the brain.
While it is true that neprilysin (NEP) inhibition increases beneficial levels of neuropeptide and vasodilators and have a cardioprotective effect, the same mode of action is also associated with increased risk of beta-amyloid accumulation—a hallmark of AD. Why? Because NEP is associated with beta-amyloid plague degradation. In fact, NEP is a target in several AD studies.
Now the other side: Valsartan is both cardioprotective and vasoprotective in the brain. Moreover, LCZ696 is intended to have targeted cardiovascular (CVD) effects. However, if LCZ696 can cross the blood-brain barrier—well, that can become a problem. What does the data say? PARADIGM-HF, a large-scale phase 3 trial of LCZ696, does not signal increased risk of cognitive dysfunction, though it should be noted that cognitive dysfunction was not an endpoint in the study.
All told, there is not enough evidence of risk of adverse events to outweigh the benefits of LCZ696 at this point, and most likely, the drug will be approved. Most important: Over time more data will become available during the post-marketing phase to better understand the long-term risks—and benefits—of LCZ696.