#4 PCSK9 Inhibitors for Cholesterol Reduction

Overview

Cholesterol, a soft, waxy substance present in cells throughout the body, serves many important functions. However, elevated levels of certain forms of cholesterol are some of the primary drivers in the development of coronary heart disease.
 
The bloodstream carries cholesterol throughout the body via special carriers called lipoproteins. The two major lipoproteins are low-density lipoprotein cholesterol—LDL-C—and high-density lipoprotein cholesterol—HDL-C. LDL has been dubbed “bad’ because it tends to collect in the arteries, promoting a lethal disease called atherosclerosis that can lead to heart attack and stroke.
 
Many Americans do not manage their cholesterol very well through diet, daily exercise, and/or medication. This has led, in part, to the current epidemic of heart disease in the United States, and is a major reason why heart disease is by far America’s number-one killer, with more than 600,000 deaths annually. 
 
We have effective statin medications that can dramatically change blood cholesterol levels. Statins, first introduced in 1987, are particularly effective drugs because they work directly to block HMG Co-A reductase, a key enzyme the liver needs to manufacture cholesterol.
Blockade of this enzyme results in depletion of cholesterol in the liver and an increase in the liver’s ability to remove cholesterol from the circulating blood. As a result, cholesterol levels drop and the lipid profile improves. 
 
Although more than 50 million Americans are potential candidates for statin therapy, and even though more than 200 million prescriptions are written annually for the drugs, there are some people who still don’t get enough reduction in their LDL levels or else continue having cardiovascular events, even though taking full doses of the statins.
 
A rare genetic mutation called autosomal dominant hypercholesterolemia, which causes high LDL cholesterol levels, eventually led to a search for a new target for cholesterol lowering. Some people with an underactive copy of the PCSK9 gene, which regulates the body’s LDL receptors, were found to have LDL levels of 15, instead of well over 100. They also had low levels of cardiovascular disease.
 
And this led to the hunt for a drug that could mimic the dramatic effects of this mutation and regulate how much artery-clogging LDL the liver can filter out of the body.
 
There are now the PCSK9 inhibitors, a new class of cholesterol-lowering drugs that are self-injected once or twice a month. The medications work on the cholesterol receptor in the liver by a mechanism that is similar to statins, yet completely unique. The drugs not only reduce LDL cholesterol levels dramatically, but also take them to super low levels never seen before.
 
Study results with these complex monoclonal antibodies have reported promising data, with LDL cholesterol levels plummeting by as much as half to two-thirds in patients taking the medication versus those taking placebo. And when a PCSK9 was taken along with a statin, LDL levels were reduced by 75 percent.
 
There are now several PCSK9 drugs currently in various stages of development. In 2015, the Food and Drug Administration is expected to approve the first of these drugs for its ability to significantly lower LDL cholesterol and help patients achieve their treatment goals.

 

Where Are They Now

This new class of cholesterol-reducing drug was approved by the FDA Advisory Board in June 2015, and official FDA approval has since been granted to specific inhibitors. Alirocumab was approved in July of 2015 and evolocumab in August of 2015.  A third drug, bococizumab, is currently in phase III trials. More positive results from trials of the drug alirocumab were released in 2017, though recent reports have highlighted several obstacles to prescribing PCSK9 inhibitors. However, doctors are ready to prescribe this drug to 17% of their patients with dangerously high LDL levels, potentially creating a $3 billion market.

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