Regeneron Genetics Center® Publication in New England Journal of Medicine Identifies New Genetic Variant Providing Protection from Chronic Liver Disease
TARRYTOWN, N.Y., March 21, 2018 /PRNewswire/ -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced a publication in the New England Journal of Medicine identifying for the first time a variant in the HSD17B13 gene that is associated with reduced risk of, or protection from, various chronic liver diseases for which there are currently no approved therapeutics. By analyzing extensive genetic sequencing data linked with electronic health records, researchers from the Regeneron Genetics Center (RGC) discovered a potential new therapeutic target to reduce the risk of chronic liver disease and progression to more advanced stages of disease, such as nonalcoholic steatohepatitis (NASH).
Specifically, researchers concluded that individuals with two copies of the loss-of-function variant in the HSD17B13 gene, which encodes the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, had 73 percent lower risk of alcoholic cirrhosis and 49 percent lower risk of nonalcoholic cirrhosis than individuals with two functioning copies of the gene. These individuals also had 53 percent lower risk of alcoholic liver disease and 30 percent lower risk of nonalcoholic liver disease than people with functioning copies of the gene. The variant was also associated with a reduced risk of NASH, suggesting that loss of HSD17B13 function protects from progression to later, more clinically-impactful stages of liver disease.
Based on these findings, Regeneron today also announced a collaboration with Alnylam Pharmaceuticals, Inc. to discover RNAi therapeutics for this target.
"These findings further emphasize the importance of large-scale human genetics data in drug discovery, and represent yet another actionable breakthrough coming from the Regeneron Genetics Center," said George Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron. "Finding a new target for drug development has always been one of the hardest and most important things that we do in this business. Examples of previous human genetics successes include the breakthrough work by Hobbs and Cohen that led to the discovery of the PCSK9 target for heart disease, eventually leading to an important new class of medicines. Today's publication demonstrates how our Regeneron Genetics Center uses large-scale, automated approaches to greatly expedite and expand our target discovery capabilities, as we work to deliver new medicines to patients in need."
Chronic liver disease and cirrhosis are leading causes of morbidity and mortality in the United States, accounting for over 38,000 deaths in 2014.1 The most common precursors to cirrhosis are alcoholic liver disease, chronic hepatitis C and nonalcoholic fatty liver disease (NAFLD). About 3 to 12 percent of adults in the United States have NASH,2 a more severe type of NAFLD, and prevalence is increasing due to rising rates of obesity.3,4 There is a great need for new medicines that treat non-viral forms of chronic liver disease, as there are currently no approved drugs for these conditions.
"This genetic 'experiment of nature' has pinpointed a new target for the discovery of novel medicines that mimic the action of this variant and similarly reduce the risk of chronic liver diseases, leading causes of death in this country," said Aris Baras, M.D., Vice President at Regeneron and Head of the Regeneron Genetics Center. "This work would not have been possible without the entire Regeneron team, as well as our great collaborators at the Geisinger Health System, the University of Pennsylvania and the University of Texas Southwestern. These groups are not only providing world-class care to their patients today, but investing in long-term outcomes by supporting pioneering large-scale genetics research like this."
"The results of this study illustrate the power of human genetics to identify targets for pharmaceutical intervention, even for diseases that are not strictly genetic, and have few therapeutic options. The substantial protection against non-viral liver disease enjoyed by individuals with DNA sequence variations in HSD17B13 suggests that pharmacological inhibition of this enzyme may slow or prevent the progression of these disorders," said co-author Dr. Jonathan Cohen, Professor of Internal Medicine and with the Center for Human Nutrition and the Eugene McDermott Center for Human Growth and Development at UT Southwestern Medical Center.
Methodology and Additional Findings
The association between the HSD17B13 variant and chronic liver disease was originally made by studying the exome sequence data and corresponding electronic health records of more than 46,544 participants in the DiscovEHR study population from the MyCode® Community Health Initiative at the Geisinger Health System (GHS). RGC scientists identified genetic variants associated with two common measures of liver health - alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels - and then evaluated associations between the implicated genetic variants and prevalence and severity of chronic liver disease in these patients.
The ALT and AST association findings were replicated in analyses of three additional populations: 2,644 additional individuals from the DiscovEHR population who had undergone bariatric surgery, 1,357 individuals from the Dallas Heart Study and 8,526 individuals from the Penn Medicine Biobank. Since these cohorts are primarily made up of people of European ancestry, researchers also confirmed the chronic liver disease associations in more diverse populations: the findings were replicated in 517 people in the multi-ethnic Dallas Liver and Heart Studies and 439 Hispanic American children in the Dallas Pediatric Liver Study. Regeneron scientists then performed analyses of human liver tissue and conducted expansive target biology programs to confirm that the variant resulted in loss of HSD17B13 protein expression and enzymatic function.
To evaluate for other clinical effects of the loss-of-function HSD17B13 variant, RGC researchers scanned for associations with thousands of clinical diseases and measurements captured in electronic health records, finding that the only strong associations were with conditions related to chronic liver diseases. This real-world data indicates that genetic loss of HSD17B13 function may be specific to reduction of chronic liver disease risk, which would be a positive safety consideration for potential therapeutics against this target.