AMGN Amgen Inc

By Ron Winslow and Jonathan D. Rockoff 

Researchers from Amgen Inc.'s deCode genetics unit said they have discovered a rare genetic variation that is associated with a 34% lower-than-average risk of heart disease, potentially opening up a new front in the battle against the world's leading killer.

Carriers of the variant, in a gene called ASGR1, had substantially lower levels of harmful cholesterol, which researchers said likely accounted for a portion of the lower heart risk.

Amgen is now working on several potential agents designed to mimic the effect of this genetic trait in hopes of converting discovery of a rare mutation into a drug that could have broad impact against a common disease. It expects to begin testing one of the candidates in people within two years.

The variant was found in one of about 120 people in the study and was associated with an additional year of life. A second much rarer variant of the same gene was also linked to lower harmful cholesterol.

Despite its link with lower cholesterol, the gene isn't associated with other known cholesterol-related mechanisms, fueling hope that an effective drug might further reduce risk of heart disease beyond reductions achieved with cholesterol-lowering drugs called statins.

"We have a mutation in a gene that is in a different pathway than the one people usually look at in cardiovascular disease," said Kari Stefansson, deCode's chief executive. He is senior author of a report on the discovery published online Wednesday by the New England Journal of Medicine.

DeCode, based in Reykjavik, Iceland, has accumulated a huge database of genomic and health data of Icelanders. Researchers discovered the role of the genetic anomaly by analyzing the data and then replicating the results by extending the analysis to 300,000 people in the U.S., United Kingdom and other countries.

The finding underscores the power of a new, big data approach to drug discovery: using computers to analyze huge genomic databases to identify potential drug targets.

Amgen is among several drug companies betting that big data can help make sense of the flood of data from genetic sequencing and electronic health records in a high-tech effort to find the molecular roots of disease.

Biogen Inc., Roche Holding AG's Genentech unit and Regeneron Pharmaceuticals Inc. are also poring over the vast data sets to uncover rare genetic changes that appear to have a big health impact.

Discovery of a potential drug target like ASGR1 "is exactly what we had in mind" when the company acquired deCode in 2012, said Sean Harper, Amgen's chief of research and development.

The genetic hitch in ASGR1 is what scientists call a loss-of-function variant, which essentially means the gene isn't active in people who have the mutation. Amgen's experimental compounds are designed to block the effects of a normal ASGR1 gene to achieve a similar effect.

"It turns out in drug development it's a lot easier to inactivate proteins than activate them," said Dr. Harper. "If you want to inactivate a drug target, there generally are more ways to do that and your probability of success is higher."

Whether blocking the impact of a normal gene will have troublesome side effects won't be known until it is tested in people, researchers said. But Dr. Stefansson said people with the variant didn't have any apparent health problems and they had a slightly longer lifespan on average, based on the findings.

A normal ASGR1 gene is present in a large segment of the general population, making it an attractive drug target.

Much genetics research is focused on disease-causing genes. The new research underscores the value finding mutations that protect people against illness, said Eric Topol, a cardiologist and director, Scripps Translational Science Institute, La Jolla, Calif., who wasn't involved in the research. "This is quite an important paper," he said.

With the expectation that millions of people will have their genome sequenced over the next decade, Dr. Topol said, it is likely many more rare genetic variants that protect against heart disease and other medical conditions will be discovered.

The research was funded by the National Institutes of Health and other organizations.

Write to Ron Winslow at ron.winslow@wsj.com and Jonathan D. Rockoff at Jonathan.Rockoff@wsj.com

(END) Dow Jones Newswires

May 18, 2016 17:29 ET (21:29 GMT)

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