Regeneron and Alnylam have developed an siRNA therapeutic candidate targeting CIDEB that could enter clinical stages of development in the next year

Unprecedented size of Regeneron Genetics Center human sequence database – representing approximately two million individuals and growing – enables discovery of protective gene variants too rare to be previously identified

Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced today that scientists from the Regeneron Genetics Center^® (RGC) have uncovered rare genetic loss-of-function mutations in the CIDEB gene that are associated with substantial protection from liver disease, including serious diseases such as nonalcoholic steatohepatitis (NASH) and cirrhosis. The new discovery has been published today in The New England Journal of Medicine. 

"The unprecedented protective effect that these CIDEB genetic variants have against liver disease provides us with one of our most exciting targets and potential therapeutic approaches for a notoriously hard-to-treat disease where there are currently no approved treatments," said Aris Baras, M.D., Senior Vice President and Head of the Regeneron Genetics Center at Regeneron. "RGC has repeatedly demonstrated the value of large-scale genetic sequencing in identifying novel and important targets for many serious diseases and this is yet another example of how we are fueling our pipeline through genetics discovery. Our growing dataset enables us to discover more rare and more powerful protective variants with the ultimate goal of improving human health."

In the largest sequencing study to date on the genetic basis of liver health, RGC sequenced the exomes of more than 540,000 individuals across five ancestry groups and multiple cohorts, including the UK Biobank and the Geisinger Health System MyCode cohort. By analyzing this genetic data in conjunction with deidentified health records, RGC researchers found that individuals who carry loss-of-function mutations in one of two copies of the CIDEB gene had an approximately 53% reduction in the risk of nonalcoholic liver disease and approximately 54% reduction in the risk of nonalcoholic cirrhosis. The study also found that CIDEB mutations had greater protective associations in individuals with obesity or type 2 diabetes, who are traditionally at higher risk for NASH, compared to individuals without these conditions.

Therapeutics that effectively mimic these protective mutations by blocking CIDEB expression or function could, therefore, potentially help prevent or treat NASH and other forms of liver disease. Based on these findings, Regeneron has already initiated a new therapeutic program to target CIDEB utilizing collaborator Alnylam Pharmaceuticals, Inc.'s RNA interference technology which can effectively silence genes in the liver. Regeneron and Alnylam already have two other investigational gene silencing treatments for NASH identified via human genetics, targeting the PNPLA3 and the HSD17B13 genes. The HSD17B13 program, which is in early-phase human clinical trials, was initiated based on a previous RGC discovery of protective associations for mutations in the HSD17B13 gene.

"RGC's discovery of CIDEB mutations, with one of the most powerful protections from liver disease seen to date, is a milestone in our understanding of the genetic basis of this disease," said Luca A. Lotta, M.D., Ph.D., Vice President and Head of Cardiometabolic and Musculoskeletal Disease Genetics at Regeneron. "By catalyzing multiple therapeutic development programs targeting distinct genetic mechanisms of liver disease, the RGC's insights are helping Regeneron develop a diversified slate of genetically-validated targets for NASH, including HSD17B13, PNPLA3 and now CIDEB."

The CIDEB discovery represents the latest example of rare protective gene variants that were identified through the unprecedented size of the RGC large-scale database, that includes genomic data from approximately two million volunteers. Other recently published examples include the discovery of rare gene variants in the GPR75 gene that provide protection against obesity. The CIDEB and GPR75 protective genetics findings suggest that the rarer the genetic discovery, the stronger the effect on disease protection – providing promise for novel therapeutic applications.