Regeneron Discovers the Therapeutic Target for Non-Viral Chronic Liver Diseases. Alnylam is Assigned to Discover and Create the Targeted RNAi Therapeutic

Regeneron (REGN) and Alnylam (ALNY) announced a collaborative agreement aimed at identifying RNAi therapeutics for the chronic liver disease nonalcoholic steatohepatitis (NASH) and potentially other related diseases. The agreement is not the first between the two firms, but it would not have occurred if not for Regeneron’s identification of an important and unique therapeutic target that influences the liver debilitating and life-threatening nonviral hepatitis diseases, which affect thousands of people.

Indeed, finding a product that targets the new Regeneron discovered therapeutic target is expected to reduce the risk of chronic liver disease and its progression to more advanced stages of a disease, such as nonalcoholic steatohepatitis (NASH).

The story was published in The New England Journal of Medicine, detailing Regeneron identification for the first time of 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 that reduces the risk of chronic liver disease and progression to more advanced stages of a disease, such as NASH.

The researchers concluded that individuals who have 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 geneThe variant was also associated with a reduced risk of NASH.

These findings suggest that loss of HSD17B13 function protects from progression to later, more clinically-impactful stages of liver disease.Based on these findings, Regeneron announced its collaboration with Alnylam Pharmaceuticals (ALNY) to discover RNAi therapeutics for this target.

George Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron explained: “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. 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.”

Indeed, Regeneron’s Genetics Center Expanded Regeneron’s discovery capabilities. This time the discovery is a Therapeutic target. The therapeutic, Regeneron decided, will have to come at this time from Alnylam, which is the distinct leader of the RNAi drugs.

Precursors of Liver Cirrhosis

The most common precursors to liver 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, which is a more severe type of NAFLD, and its prevalence is increasing as a result of the increasing rates of obesity.

Comments & Explanation

Aris Baras, M.D., Vice President at Regeneron and Head of the Regeneron Genetics Center explained: “The 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, the leading causes of death in this country.” Dr. Baras added, “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.”

Co-author of the study, Dr. Jonathan Cohen, Professor of Internal Medicine with the Center for Human Nutrition and the Eugene McDermott Center for Human Growth and Development at UT Southwestern Medical Center said: “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.”

The Regeneron Alnylam Agreement

Regeneron Pharmaceuticals and Alnylam Pharmaceuticals announced a collaboration to take advantage of Regeneron’s discovery of a target for the treatment of non-viral chronic liver diseases to join  Alnylam for the discovery and development of RNAi treatment for nonalcoholic steatohepatitis (NASH) and potentially other related diseases.

Why Alnylam?

Alnylam, we reiterate is the leader of RNA interference (RNAi) therapeutics, which represent a novel approach to targeting and silencing genes involved in the causation of, human disease. This approach could potentially mimic the naturally occurring loss-of-function genetic variation in HSD17B13 seen in people who are naturally protected from NASH disease progression.

John Maraganore, Ph.D., Chief Executive Officer at Alnylam explains: “At Alnylam, we are dedicated to advancing RNAi therapeutics as a new class of medicines for patients with few or no treatment alternatives. 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, a proprietary GalNAc-conjugate approach for delivery to the liver is an unparalleled combination for developing an RNAi therapeutic toward genetically-validated targets in NASH.”

Terms of the Collaborative Agreement

Regeneron will contribute research: The research will deal with liver cells – expressed genetically-validated HSD17B13 target;

Alnylam will leverage its RNAi therapeutics platform: The aim is to identify compounds directed to the HSD17B13 target.

Regeneron and Alnylam intend to enter into a separate, fifty-fifty collaboration to further research, co-develop and commercialize any therapeutic product candidates that emerge from these discovery efforts.


George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron explains: “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. 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.”

Chronic liver disease and cirrhosis are leading causes of morbidity and mortality in the United States, accounting for over 38,000 deaths in 2014.

Prohost Observations

There is a tremendous need for new medicines that treat non-viral forms of chronic liver disease, as there are no approved drugs to treat these life-threatening conditions. With the many efforts made by biotechnology firms towards bringing treatments to the market, we suddenly see Regeneron’s Genetic Center discovers the most important piece of information required for treatments to target and solve the currently unsolved disease problems.

The gene target discovered by Regeneron will have an RNAi drug to be discovered by Alnylam.  The RNAi products will mimic the natural way the healthy capable body would have solved the unsolved NASH problem.

This kind of News we consider the best to expect from biotech companies. That’s why both Regeneron and Alnylam are among our picks and old members in the Prohost Portfolio.

We see this news as great for Regeneron’s discovery and for Alnylam’s involvement in saving the lives of people who have NASH or subjected to have this nasty chronic liver disease


Information That Some Would Like To Be Aware Of:

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).

Regeneron Genetic Center’s 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 individuals from the DiscovEHR population who had undergone bariatric surgery; 1,357 additional 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 the 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 indicate 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.

Regeneron Genetics Center (RGC)

The RGC is a genomics program that bridges early gene discovery and functional genomics, facilitating drug development. The goal is improving patients’ outcomes through identifying novel drug targetsclinical indications for development programs, and genomic biomarkers for pharmacogenomic applications. The RGC is tackling large-scale sequencing and analytical approaches and has established numerous collaborationswith leading human genetics researchers. The RGC utilizes fully-automated sample preparation and data processing, as well as cutting-edge cloud-based informatics. Through these efforts, the RGC is currently sequencing de-identified samples from patient volunteers at a rate of almost 250,000 unique exomes per year. Major collaborations include Geisinger Health System and the UK Biobank supporting their goal of sequencing 1,000,000 individuals linked to their comprehensive digital health records, plus many other major initiatives in disease specific-studies, founder populations, and family based-studies.

Omeros (OMER) has good news. We believe that much better news is on its way to this firm. Do not forget to read the Week in Review. We hope to post on Sunday, March 25, 2018.  

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