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Pfizer Discusses Early Work on Cholesterol-Lowering Drug Targeting PCSK9

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By Turna Ray

BOSTON — Pfizer is evaluating a monoclonal antibody against the PCSK9 enzyme as a treatment for high cholesterol.

At a conference here hosted by the Partners Healthcare Center for Personalized Genetic Medicine, Mikael Dolsten, president of worldwide R&D at Pfizer, discussed a monoclonal antibody the company is evaluating as a treatment for lowering bad cholesterol. The drug is currently in Phase I studies as a single agent and as a combination treatment with statins in those who do not respond well to statins alone, as well as in those who cannot tolerate statins.

Early investigations of this monoclonal antibody against PCSK9 have shown it to "significantly" lower LDL in hypercholesterolemia patients. Phase I studies suggest that the treatment can reduce LDL and has a "very favorable" safety profile, Dolsten said.

In previously published studies, mutations in the PCSK9 gene have been linked to a rare form of autosomal-dominant familial hypercholesterolemia. Additionally, variants in PCSK9 have been shown to reduce cholesterol and increase the risk of heart attack and stroke.

Since this drug is in early-stage development, it is unclear if Pfizer plans to advance it with a companion test to identify best responders to the antibody. At the conference, Dolsten did not discuss the development of the drug with a companion test.

However, for the time being, it appears that Pfizer is investigating diagnostic strategies to learn about PCSK9 and its link to LDL reduction.

In the January issue of the Journal of Lipid Research, researchers from the Clinical Research Institute of Montreal, McGill University Health Center, and Harvard Medical School published a study in which they used a polyclonal antibody against PCSK9 to develop an enzyme-linked immunosorbent assay.

In the study, funded by Pfizer Canada's Jean Davignon Distinguished Cardiovascular and Metabolic Research Award and other grants, researchers used the ELISA to evaluate plasma PCSK9 levels in 254 normal and 200 hypercholesterolemic participants who were either untreated or treated with statins or statins plus ezetimibe (Merck's Zetia).

The researchers, led by Genevieve Dubuc of the Clinical Research Institute of Montreal, then sequenced PCSK9 from certain individuals and identified a new loss-of-function R434W variant associated with reduced LDL cholesterol and lower levels of circulating PCSK9.

"In hypercholesterolemic subjects, PCSK9 levels were higher than in controls and increased in proportion to the statin dose, combined or not with ezetimibe," Dubuc et al. reported. "In treated patients (n = 139), those with familial hypercholesterolemia … had higher PCSK9 values than non-familial hypercholesterolemia, but LDL-cholesterol reduction correlated positively with achieved plasma PCSK9 levels to a similar extent in both subsets."

Based on the fact that the assay was able to detect circulating PCSK9 in both familial hypercholesterolemia and non-familial hypercholesterolemia subjects, the researchers suggest that it "could be used to monitor response to therapy in a wide range of patients."

As Pfizer investigates the PCSK9 pathway in developing cholesterol-lowering drugs, it may face some competition. Several other firms are also developing hypercholesterolemia drugs that target PCSK9, Dolsten said at the conference.

For example, as reported by PGx Reporter sister publication Gene Silencing News, Alnylam has a siRNA targeting PCSK9 in development and plans to file an investigational new drug application in 2011 (GSN 11/11/10). In April, Santaris Pharma announced it is also developing a compound, SPC5001, to inhibit PCSK9 and lower LDL cholesterol.


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