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Large-Scale Genetic Study Identifies Variants That Protect Against Obesity

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Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced that scientists from the Regeneron Genetics Center® (RGC) have discovered rare genetic mutations in the GPR75 gene associated with protection against obesity. As reported in Science, almost 650,000 people were sequenced to find rare individuals with this genetic 'superpower,' providing new insights into the genetic basis of obesity. Potential therapeutics mimicking these genetic superpowers are being developed at Regeneron, utilizing its VelocImmune technologies and novel technologies from collaborators such as Alnylam Pharmaceuticals, Inc.

It is estimated that more than one billion people could be suffering from obesity (body mass index [BMI] of 30 or higher) by 2030.1,2 Working with research collaborators, RGC scientists found that individuals who have at least one inactive copy of the GPR75 gene have lower BMI and, on average, tend to weigh about 12 pounds less and face a 54% lower risk of obesity than those without the mutation. Protective 'loss of function' mutations were found in about one of every 3,000 people sequenced.

"Discovering protective genetic superpowers, such as in GPR75, provides hope in combating global health challenges as complex and prevalent as obesity," said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer at Regeneron. "Discovery of protective mutations – many of which have been made by the Regeneron Genetics Center in its eight-year history – will allow us to unlock the full potential of genetic medicine by instructing on where to deploy cutting-edge approaches like gene-editing, gene-silencing and viral vector technologies."

As part of the research that led to the finding, RGC scientists analyzed deidentified genetic and associated health data from 645,000 volunteers from the United KingdomU.S. and Mexico. The study, one of the Regeneron Genetics Center's largest to date, was conducted in collaboration with Geisinger Health SystemNew York Medical College, the Nuffield Department of Population Health at the University of Oxford and the National Autonomous University of Mexico (UNAM) using data from the Mexico City Prospective Study, Geisinger's MyCode Community Health Initiative and UK Biobank.

The Regeneron team, collaborating with the labs of Dr. Schwartzman and Dr. Garcia at New York Medical College, then validated the finding in mice that were genetically engineered using Regeneron's VelociGene technology to lack copies of the GPR75 gene. Such mice gained 44% less weight than mice without the mutation when both groups were fed a high-fat diet.

"This is a potentially game-changing discovery that could improve the lives and health of millions of people dealing with obesity, for whom lasting interventions have often been elusive," said Christopher D. Still, D.O., Director for the Geisinger Obesity Research Institute at Geisinger Medical Center. "While the behavioral and environmental ties to obesity are well understood, the discovery of GPR75 helps us put the puzzle pieces together to better understand the influence of genetics. Further studies and evaluation are needed to determine if reducing weight in this manner can also lower the risk of conditions commonly associated with high BMI, such as heart disease, diabetes, high blood pressure and fatty liver disease."

Building on Regeneron's strengths in genetics-driven drug discovery and development, Regeneron scientists are pursuing multiple therapeutic approaches to target GPR75, including through antibodies, small molecules and gene silencing.

"The discovery of GPR75 is already enabling Regeneron and our collaborators to identify potential ways to safely replicate the effect of this mutation through novel therapeutic approaches," said Aris Baras, M.D., Senior Vice President at Regeneron and Head of the Regeneron Genetics Center. "This is the latest in a long line of protective human genetics discoveries that have fueled new therapeutics programs at Regeneron. The pace is only quickening, as we uncover more and more about the human genome and work to rapidly translate those discoveries to the development of new medicines."