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March 20, 2017 no comments

Anti-PCSK9 Drugs: An Ingenious Solution For A Problem That’s Mostly Already Solved

Anti-PCSK9 Drugs


On Friday, for the first time, we saw the full data from the FOURIER clinical trial of Amgen’s cholesterol-lowering antibody, evolocumab (Repatha). Depending on who you listen to, it was either “the most important study in at least 20 years” or a damp squib. So what does FOURIER really tell us? And how will it change management of patients with cardiovascular disease?

First the background:


What is evolocumab?  It is an antibody against an enzyme called PCSK9. Since PCSK9 is a protease that breaks down the LDL receptor, itself the major clearance mechanism for cholesterol from the blood, blocking PCSK9 increases the level of LDL receptor and therefore dramatically reduces circulating cholesterol, and in particular the triglyceride-rich lipoproteins, such as LDL, that are implicated in causing cardiovascular disease.


Anti-PCSK9 antibodies are the jewel in the crown of modern genomic medicine, illustrating what many hope will be a paradigm for future drug discovery. People with naturally occurring mutations in the gene encoding PCSK9 have lower levels of LDL cholesterol and are protected from heart disease, strongly suggesting that an antibody against the PCSK9 protein should have the same beneficial effects–a story that remains the poster child for exploiting human genetics to understand the biology of common diseases (such as heart disease) in the same way it revolutionized the discovery of new treatments for rare diseases a decade earlier.


The first part of the story has already been proven–lots of trials in various groups have demonstrated powerful reductions in LDL cholesterol following treatment with anti-PCSK9 antibodies, with reductions of more than half routinely observed even among patients with stubbornly high cholesterol resistant to other lipid-lowering medications.


This was enough to convince the FDA to approve the drug, albeit with a limited label. But use of these expensive antibodies has been rather limited while clinicians and payers alike waited for proof they actually reduce heart attacks and strokes. FOURIER was designed to answer that question.


What was the design of FOURIER? It was a conventional clinical trial design, in which more than 27,000 people who had previously suffered a heart attack, but who had been unable to achieve optimal LDL cholesterol with dietary advice and existing medications (including statins), were randomized to receive either evolocumab or a placebo regularly for just over two years. The participants were then followed to see who suffered cardiovascular events (which ranged from hospitalization for a worsening of their angina symptoms through to death).


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