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In a picture perfect game of drug development, Novartis heartily delivered this week with LCZ696. Also propelling the world of cardiovascular disease treatments into high gear is a promising cholesterol therapeutic by Sanofi and Regeneron called alirocumab.

Last week, Novartis released a heart failure drug called LCZ696, along with the data behind their highly successful Phase III trial. Novartis is hopeful, with sights set on an FDA approval by year’s end.

Sanofi and Regeneron presented results that support further development of a whole new class of therapeutics for high cholesterol, thanks to alirocumab.

It is a double dose of good news for hearts everywhere. Let’s examine the science behind these new angles of attack against cardiovascular disease, which is currently the leading cause of death in the world.

TERM OF THE WEEK: HEART FAILURE

Heart failure, also known as chronic heart failure or congestive heart failure, is the inability of an individual’s heart to pump and/or fill with blood adequate to the demands of the body. The causes of heart failure are complex and varied but risk factors can include high blood pressure, diabetes, coronary artery disease—the narrowing of blood vessels brought on by cholesterol-containing plaque—and previous damage caused by heart attacks.

BEATING HEART FAILURE

An independent review panel ended the Phase III trial of Novartis’ heart failure drug LCZ696 last spring. The reasoning was that the experimental drug performs so much better than the standard of care it is unethical to continue testing. How does this wonder drug work?

LCZ696 is a combination drug: Valsartan and Sacubitril. They work together to lower blood pressure, which lowers the strain on the heart and lessens the accumulation of fluid in the tissues, such as the lungs—a key symptom of heart failure.

Valsartan is an angiotensin II receptor inhibitor; it stops angiotensin II. Why is stopping angiotensin II important?

Angiotensin II is a small hormone. When it attaches to the angiotensin receptor, it causes a cascade of reactions to occur. That cascade ultimately causes blood vessels to constrict, which causes blood pressure to increase. Think about it like this: it takes more pressure to move fluid through a narrow tube than through a wide one. Angiotensin II also promotes the release of a second hormone, aldosterone, which increases sodium retention by the kidney and further drives up blood pressure.

By blocking the angiotensin receptor, angiotensin II has nowhere to land, no reaction cascade, no blood vessel constriction and blood pressure is lowered.

Sacubitril is a neprilysin inhibitor; it stops the enzyme neprilysin. Why is stopping neprilysin important?

Neprilysin breaks down a hormone called natriuretic peptide. By stopping neprilysin, we increase levels of natriuretic peptide. Natriuretic peptide gets rid of sodium and dilates blood vessels; therefore, blood pressure is lowered.

By combining an angiotensin II receptor inhibitor and a neprilysin inhibitor, the effect is enhanced, allowing LCZ696 to get to the heart of the matter.

EASILY CONFUSED: HDL AND LDL CHOLESTEROL

Lipoproteins are divided into two categories for the sake of profiling cholesterol levels: high-density lipoproteins (HDL) and low-density lipoproteins (LDL). A lipoprotein is a protein with fat molecules attached for use as a transport system.

HDL is called good cholesterol because it transports the lipid component in a compact fashion without losing or dropping the fat molecule when traveling in the arteries. HDL can even scoop up and expunge the LDL, or bad cholesterol. LDL is more fluffy and detaches easily, wreaking havoc by oxidizing or subsequently attaching to arterial walls.

BEATING BAD CHOLESTEROL

Creating a buzz around a new pathway for fighting bad cholesterol is Sanofi/Regeneron’s alirocumab and its strong clinical trials data. What is the story? First, a little background.

Low-density lipoprotein receptors (LDLR) are found on various cell surfaces, like liver cells, and they help the body get rid of excess cholesterol. The LDL particles bind to the low-density lipoprotein receptor, and the LDL is subsequently taken up by the liver cell. The LDL is broken down inside the cell and cholesterol is released to be used within the cell. The receptor, or LDLR, is recycled back to the cell surface, where it can bind to and remove more LDL.

We also have another player, PCSK9, potentially interrupting this process. PCSK9 binds to the low-density lipoprotein receptor and both are taken in by the liver cell; however, PCSK9 and the low-density lipoprotein receptor are degraded—sort of like a murder-suicide. This results in fewer receptors present at the cell surface, impeding the process of removing LDL and breaking down cholesterol within the cell.

Alirocumab, a monoclonal antibody, binds to and inhibits PCSK9. In a way, it protects the low-density lipoprotein receptor so it can uptake LDL without interference. It helps the LDLR to continue the cell’s process of breaking down cholesterol without the threat of PCSK9.

More data is needed to clearly demonstrate the long-term safety and efficacy data of alirocumab, but these results have generated much excitement as a validation of PCSK9 as a cardiovascular drug target. Preliminary results suggest that alirocumab cuts heart attack and stroke rates in half.

Look for Merck and Amgen to jump on the bandwagon because both companies are also working on the development of monoclonal antibody inhibitors of PCSK9.

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