By Alice Park
July 24, 2015

On Friday, the U.S. Food and Drug Administration (FDA) approved the first new class of cholesterol-lowering drugs since the statins flooded the market beginning in the 1980s. Similar to the way statins work, by binding up cholesterol made in the liver so less of it circulates in the blood, this new class, called PCSK-9 inhibitors, takes advantage of genetic mutations that regulate the level of LDL receptors in the liver. Less PCSK9 leads to more LDL receptors that can soak up LDL and therefore leave less cholesterol in the blood.

The FDA approved alirocumab (Praluent), an injectable drug made by Sanofi and Regeneron, in people with familial hypercholesterolemia, a genetic condition in which cholesterol levels are high, or those with a history of heart disease who can’t reduce their LDL levels enough with existing statin drugs. (Another PCSK9 inhibitor, evolocumab (Repatha) developed by Amgen, received approval in Europe but won’t be evaluated by the U.S. FDA until the end of August.)

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While PCSK9 drugs help to lower cholesterol, the story of how these medications developed began in a French family with the opposite problem. Their members had exceptionally high levels of LDL and greater than average rates of heart disease. But unlike others with similar cholesterol problems, this family did not have the usual mutations in cholesterol-regulating genes. Instead, French researchers studying them in 2003 found they had aberrations in PCSK9, a gene that produces a protein found primarily in the liver, kidneys and intestines.

An ocean and half a continent away, Jonathan Cohen and Dr. Helen Hobbs at the University of Texas, Southwestern Medical Center in Dallas (coincidentally the same institute where scientists discovered LDL, or the heart-disease contributing cholesterol and earned the Nobel Prize for their work), read the description of PSCK9 and wondered whether those with lower levels of PCSK9 would show the opposite effect of the French family and actually enjoy decreases in levels of LDL in the blood.

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Cohen and Hobbs were involved in a large heart disease study involving nearly 15,000 participants, and decided to look for the PCSK9 mutations among their participants. They homed in on those with the highest and lowest levels of LDL cholesterol, and sequenced their genomes to see if any patterns emerged. Sure enough, they found 33 people whose LDL levels were about 40% lower than average and who shared mutations that effectively silenced PCSK9. Essentially, their LDL amounts were about the same as those who relied on statins to drop their cholesterol.

These PCSK9 mutations associated with the lowest LDL appeared predominantly in African-American participants. Those with one copy of the mutation in this gene showed an 88% lower risk of heart disease. Another mutation in the same PCSK9 gene that appeared more commonly in whites had the same effect, but to a lesser extent, dropping LDL by 15% and the risk of heart events by 47%.

“The results were quite compelling,” says Cohen, who published the findings along with his colleagues in the New England Journal of Medicine (NEJM) in 2006. “They told us that PCSK9 was likely an attractive therapeutic target.” Even more encouraging, in all of the people with the mutations and lower LDL levels, there didn’t seem to be any significant side effects. For all intents and purposes, these participants were healthy and had the added advantage of being at very low risk of heart disease.

To confirm this, Cohen searched for anyone in the study with two copies of the mutation, to see if having double the effect would trigger any adverse events. He found one woman, a 32 year old daughter of one of the participants, who had two different mutations in each of the PCSK9 copies she inherited from her mother and father. The result? An LDL of 14 and no other health problems. “If you measure the amount of PCSK9 in her blood, it’s basically absent, you can’t see any,” says Cohen. That contributed to an unprecedented low level of LDL cholesterol as well.

So far, he says, only one other individual has been described with two mutant copies of PCSK9, a 21 year old woman living in south Africa with an LDL of 20.

Those descriptions piqued the interest of researchers at Regeneron, a biotech company that specializes in turning genetic discoveries like this one into drugs. To confirm and better understand the effects of PCSK9, researchers there studied the effect of human versions of PCSK9 in mice, and then began trials of antibodies they developed that inhibit the function of this gene, much like the mutations do, in several thousand people.

Those results, published in the NEJM last April, showed that PCSK9 inhibitors can lower LDL cholesterol by an additional 60% on average beyond that achieved by statins. Those findings formed the basis of the companies’ application to the FDA for approval of these first-in-class drugs.

For now, the agency says the drugs should only be prescribed to people with familial hypercholesterolemia, or those who have failed to reduce their LDL levels sufficiently using statins. For many, the new drugs will be taken in combination with statins and a heart-healthy diet. But doctors say they anticipate many patients outside of these groups, who have family histories of heart disease or other risk factors, such as hypertension or diabetes, may start asking about the medications. For them, doctors will have to weigh how well they are doing on statins before considering adding a PCSK9 inhibitor.

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