In continuation on my update on drug discovery in the class of Monoclonal antibodies
Researchers have known for some time that when the protein PCSK9, (below structure) which stands for proprotein convertase subtilisin/kexin 9, binds to LDL receptors on the liver, it compromises the organ’s ability to filter the bad cholesterol from the blood.
Too much LDL cholesterol circulating in the blood can lead to the thickening of artery walls, making them less flexible and therefore impairing their function and increasing the risk of heart disease.
In a phase one clinical trial, which is designed to determine if a drug is safe, researchers found that using a monoclonal antibody (lab-produced protein) called REGN727, was not only safe, but effectively blocked PCSK9 and therefore signficantly reduced bad cholesterol in healthy patients as well as those also taking the popular cholesterol-lowering drug Lipitor.
“Wars for PCSK9 are far bigger than the statin wars,” said Dr. Evan A Stein, lead author of the study and researcher at the Metabolic and Atherosclerosis Research Center in Cincinnati, Ohio. “This is a hot research area and everybody is so close together.”
The REGN727 study included three trial arms. Two arms used 72 healthy volunteers who were either injected with a single dose of the drug in increasing amounts to test for side effects, which is the purpose of a phase one clinical trial. A third arm included 21 people with a family history of high cholesterol, and 30 people with nonfamilial high cholesterol. All of those subjects were also receiving treatment with the statin Lipitor.
A control group of subjects with nonfamilial high cholesterol was treated only with a special diet. None of the subjects who received REGN727 discontinued the study because of adverse effects, and the subjects who received REGN727 had a striking reduction of 60 to 65% in LDL cholesterol, according to Stein.
A PCSK9 inhibitor, Stein said, differs from statins “because it’s unlike any other drug. With statins you get toxicity – with these drugs we don’t see any side effects with the antibody.”
In an accompanying editorial, authors Dr. Stephen G. Young, and Loren G. Fong, Ph.D. write: “At this point, the status of PCSK9 therapeutics appears to be full speed ahead. Soon, we can expect more human trials in which investigators will dissect the properties of different PCSK9 antibodies and assess the effect of these agents.”
However, without long-term safety data and evidence that PCSK9 inhibitors truly help prevent heart disease, Young and Fong caution that it will remain unclear how important this class of drugs will be.
The cost of this drug will also play a role in determining which patients might use it, Fong and Young say. But they also note that “patients who cannot tolerate statins could benefit greatly.”
Researchers also claim that, the study methodology was thorough because it included people with high cholesterol as well as people with genetic familial high cholesterol, which is proven to be a result of impaired PCSK9 genetic function.
Researchers have known for some time that when the protein PCSK9, which stands for proprotein convertase subtilisin/kexin 9, binds to LDL receptors on the liver, it compromises the organ’s ability to filter the bad cholesterol from the blood.
Researchers conclude that, In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia.
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