Filtering the complexities of liver disease

Genetic variant that is protective against chronic liver dysfunction identified by Regeneron, which follows up its findings with an Alnylam collaboration

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TARRYTOWN, N.Y. & CAMBRIDGE, Mass.—Chronic liver disease, and nonalcoholic steatohepatitis (NASH) in particular, got a double-dose of news output from Regeneron Pharmaceuticals Inc. on March 21, starting with word of a Regeneron Genetics Center publication in the New England Journal of Medicine identifying a new genetic variant that seems to provide protection from chronic liver disease. And then, in tandem, news of a collaboration—based on those new findings that tied the HSD17B13 gene to reduced risk of chronic liver diseases—with Alnylam Pharmaceuticals to discover new treatments for NASH.
For the NEJM paper, titled “A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease,” Regeneron researchers analyzed extensive genetic sequencing data linked with electronic health records and, in so doing, they found 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. This opens up a potential new therapeutic pathway to lessen risks of developing chronic liver disease, reducing how many people progress to more advanced stages of disease—such as NASH—or both.
Getting down to specifics, the researchers determined that people who possess 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 a 73-percent lower risk of alcoholic cirrhosis and 49-percent lower risk of nonalcoholic cirrhosis than individuals with two functioning copies of the gene. In addition, such people 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, which the researchers surmise to mean that loss of HSD17B13 function protects from progression to later, more clinically impactful stages of liver disease.
“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 Dr. George Yancopoulos, 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. [This] 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 more than 38,000 deaths in 2014. 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, a more severe type of NAFLD, and prevalence is increasing due to rising rates of obesity. Finding treatment targets for non-viral forms of chronic liver disease is even made more critical by the fact that 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,” commented Dr. Aris Baras, 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, a professor of internal medicine at UT Southwestern Medical Center, who is also associated with the university’s Eugene McDermott Center for Human Growth and Development.
Drilling down even more into the published research, Regeneron notes that 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. Regeneron 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. It is worth noting that the researchers recognized that those cohorts were primarily made up of people of European ancestry, and so they made a point of also confirming 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, Regeneron 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.
Right on the heels of NEJM publishing the paper detailing these findings, Regeneron and Alnylam announced a collaboration to identify RNA interference (RNAi) therapeutics for NASH, and possibly other related diseases as well. This discovery collaboration is tied directly to the promising research findings about the HSD17B13 gene variant, with the thinking being that RNAi therapeutics could be used to potentially mimic the naturally occurring loss-of-function genetic variation in HSD17B13 seen in people who are protected from NASH disease progression.
This would mark the second time that Regeneron and Alnylam have teamed up on genetic exploration. In January, Alnylam and various other leading life-sciences companies joined Regeneron’s pre-competitive consortium to sequence 500,000 individuals in the UK Biobank health resource and subsequently make the data publicly available to the global research community.
“At Alnylam, we are dedicated to advancing RNAi therapeutics as a new class of medicines for patients with few or no treatment alternatives,” said Dr. John Maraganore, CEO of Alnylam. “As we transition Alnylam toward commercialization in rare diseases, the prospect of collaborating with a scientific leader like Regeneron on innovative medicines for more prevalent diseases like NASH makes perfect strategic sense. We believe the exquisite specificity afforded by the RNAi mechanism of action and our industry-leading, proprietary GalNAc-conjugate approach for delivery to the liver is an unparalleled combination for developing an RNAi therapeutic toward genetically-validated targets in NASH.”
Under the discovery collaboration, Regeneron will contribute research on the hepatocyte-expressed, genetically validated HSD17B13 target, and Alnylam will leverage its RNAi therapeutics platform to identify compounds directed to this target. Regeneron and Alnylam intend to enter into a separate, 50/50 collaboration to further research, co-develop and commercialize any therapeutic product candidates that emerge from these discovery efforts.
“Our Regeneron Genetics Center is delivering new targets that will require new approaches beyond our biologics capabilities. Since we are committed to following the science, we are pleased to join together with an equally science-minded company with a novel RNAi therapeutic approach that appears well suited to impact this particular target,” said Regeneron’s Yancopoulos. “NASH is a major cause of death in this country, with no current treatment options. We’re eager to build on the exciting science delivered by the Regeneron team in the hopes of helping patients with debilitating and life-threatening chronic liver diseases.”

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