Regeneron Pharmaceuticals and Alnylam Pharmaceuticals said they will partner to discover RNA interference (RNAi) therapeutics for nonalcoholic steatohepatitis (NASH) and potentially other related diseases, through a collaboration whose value was not disclosed.
The companies are basing their discovery collaboration on a variant in the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene, which is associated with reduced risk of chronic liver diseases—a variant identified in a study (“Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease”) published today in The New England Journal of Medicine.
The study used coupled sequencing and health/medical data that Regeneron has curated through its more than three-year-old collaboration with Geisinger Health System. Since 2014, Regeneron and Geisinger have teamed up through their DiscovEHR partnership to combine genotypic and phenotypic data by creating databases of paired exome sequences and de-identified electronic health records of the health system's patients.
In the just-published study, researchers from Regeneron, Geisinger, and two other institutions used exome sequence data and electronic health records from 46,544 participants in DiscovEHR to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
The researchers replicated the variants in three additional cohorts totaling 12,527 participants, then evaluated those variants for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts totaling 37,173 participants, as well as with histopathological severity of liver disease in 2391 human liver samples.
A splice variant (rs72613567:TA) in the gene was associated with reduced levels of ALT and AST. Among DiscovEHR study participants, the variant was associated with reduced risks of:
- Alcoholic liver disease, by 42% among heterozygotes and 53% among homozygotes
- Nonalcoholic liver disease, by 17% among heterozygotes and 30% among homozygotes
- Alcoholic cirrhosis, by 42% among heterozygotes and 73% among homozygotes
- Nonalcoholic cirrhosis, by 26% among heterozygotes and 49% among homozygotes.
The variant was also associated with reduced risk of NASH, but not steatosis, in human liver samples, according to the study.
Looking to Mimic Loss of Function
By pursuing an RNAi approach, Regeneron and Alnylam reason, they can potentially mimic the naturally occurring loss-of-function genetic variation in HSD17B13 seen in people with NASH who show protection from disease progression.
Under the discovery collaboration, Regeneron has agreed to contribute research on the hepatocyte-expressed, genetically validated HSD17B13 target. Alnylam has agreed to apply its RNAi therapeutics platform to identify compounds directed to the target, and is looking to deliver RNAi therapeutics to the liver through its GalNAc conjugate, a small carbohydrate moiety attached on the end of a small interfering RNA (siRNA), targeting it for uptake by the hepatocytes and allowing for subcutaneous administration.
Regeneron and Alnylam said they intend to enter into a separate, 50-50 collaboration to further research, codevelop, and commercialize any therapeutic product candidates that emerge from their discovery efforts.
“Our Regeneron Genetics Center is delivering new targets that will require new approaches beyond our biologics capabilities,” George D. Yancopoulos, M.D., Ph.D., Regeneron’s president and CSO, said in a statement. “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.”
Alnylam CEO John Maraganore, M.D., Ph.D., added that the collaboration meshed with a shift in company strategy as its rare-disease treatments approach commercialization—led by the hereditary transthyretin-related amyloidosis (hATTR) candidate patisiran, for which Alnylam has filed an New Drug Application (NDA) with the FDA and a Marketing Authorisation Application with the European Medicines Agency. The company expects to launch patisiran in the U.S. and Europe later this year.
“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,” Dr. Maraganore stated. “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.”
The collaboration is Alnylam’s second with Regeneron. In January, Alnylam was one of five biopharmas that contributed $10 million each to join Regeneron in launching a $50 million-plus consortium aimed at speeding up exome sequencing of all 500,000 people within the UK Biobank.
The consortium aims to generate sequencing data from the volunteer participants, coupled with their detailed and de-identified medical and health records to create a resource designed to link human genetic variations to human biology and disease.
Earlier this month, Alnylam chief medical officer Pushkal Garg, M.D., discussed with GEN the company’s second lead program, incorporating an RNAi approach to fighting a liver disease. The Phase III RNAi candidate givosiran is being developed for acute hepatic porphyrias (AHPs), which result from defects in the heme synthesis pathway in the liver that culminate in a buildup of the neurotoxic metabolite aminolevulinic acid (ALA).
Through givosiran, Alnylam is using RNAi to block an enzyme higher up in the pathway, preventing buildup of ALA. That approach, according to the company, has led to an approximately 80% reduction in attacks.