PCSK9 monoclonal antibody REGN727- a new drug to lower LDL Cholesetrol?

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According to a new study, a monoclonal antibody (REGN727) to the protein PCSK9 can significantly reduce bad cholesterol.  PCSK9 (proprotein convertase subtilisin/kexin 9) is a serine protease.  LDL cholesterol levels in the blood increases when its receptors (LDL receptor) are degraded by binding to PCSK9.

The phase 1 study results were reported this week in the New England Journal of Medicine. The study was supported by Regeneron Pharmaceuticals and Sanofi.

The researchers conducted three phase 1 trials. The patients participated in the study included those receiving atorvastatin. In one of the studies REGN727 doses of 50, 100, or 150 mg were administered subcutaneously on days 1, 29, and 43.  They found that REGN727, the monoclonal antibody to PCSK9,  administration significantly lowered LDL cholesterol levels in all the studies. The bad cholesterol was reduced by as much as 65%.

Statins are a class of drugs commonly used to lower cholesterol levels. Statins work by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. The best-selling statin is atorvastatin, marketed as Lipitor.

The PCSK9 inhibitor used in this study is a monoclonal antibody.  A monoclonal antibody is an antibody with single specificity.  The antibody binds to PCSK9 and prevents the PCKK9mediated degradation of  the LDL receptor. 

However compared to statins, a monoclonal antibody therapy requires intravenous or subcutaneous administration of the drug, like insulin administration by diabetic patient.  Nevertheless the finding is a landmark in the treatment for high cholesterol.

The research was led by Dr. Evan Stein of the Metabolic and Atherosclerosis Research Center in Cincinnati. According to Stein, the experimental drug may lead to "even greater reductions in LDL-C than the most effective statins."   To quote from the ABC news: Dr. Robert Eckel, former president of the American Heart Association, said that if the drug indeed lives up to its promises, it could potentially benefit many patients he sees every day. "Despite the proven benefit of statins in reducing [cardiovascular] risk, additional LDL-C lowering therapies are needed for patients with several genetic disorders that cause high levels of LDL-C and those with statin intolerance." These patients, he added, make up 40 percent of the patients treated at his clinic.

The authors note that “in the end, evidence of long-term safety, along with data showing protection from coronary disease, will be needed to define the role of these agents in clinical practice. High-risk patients who have not reached their recommended cholesterol target and patients who cannot tolerate statins could benefit greatly. Patient selection will undoubtedly be influenced by cost–benefit considerations.”

Science Story Reference: 

Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol. Evan A. Stein et al. N Engl J Med 2012; 366:1108-1118March 22, 2012

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