As pharma's NASH failures pile up, Regeneron thinks it found the target that matters

The race to be the first FDA-approved treatment for nonalcoholic steatohepatitis (NASH) has proven perilous, with pharma after pharma facing clinical defeat. As a result, opportunities to find new potential therapeutic avenues are in abundance.

New York-based Regeneron is one of the companies looking to pave new ground in the disease area, releasing new research last week showing how specific genetic mutations are associated with reductions in liver disease, including NASH. Published in The New England Journal of Medicine, scientists honed in on variations of the CIDEB gene, which is highly expressed in liver cells. 

The findings came to light via a genetic analysis conducted by the Regeneron Genetics Center of more than 540,000 people, touted as the largest ever focused on liver health. To arrive at these correlations, the scientists launched a multistep process of linking genetic clues with disease likelihood. First, they estimated the burden of associations between rare alleles, a term for versions of a DNA sequence, and alanine aminotransferase, a biomarker of liver disease. Those estimations were then corroborated by assessing the association between the alleles and aspartate aminotransferase. Lastly, the coding differences were linked to liver disease using electronic health records. 

Through this analysis, four genes—APOB, ABCB4, SLC30A10 and TM6SF2—were shown to be linked with liver disease. In contrast, tweaks to the CIDEB gene appeared to have a protective effect against liver disease. The association with protection was even stronger against NASH specifically, showing that people who had loss-of-function mutations in one of two copies of CIDEB had a 53% risk reduction for NASH.  One important qualifier of the results is that they suffer from a persistent lack of diversity seen in other genetic sequencing studies; the researchers flagged that 96% of genes sequenced were from volunteers of European ancestry. 

The researchers also challenged human hepatoma cell lines with oleate, a type of fatty acid, to see how inhibiting the gene impacted the cells. When CIDEB expression was knocked down using siRNA, lipid buildup was prevented, they noted 

Luca Lotta, M.D., Ph.D., head of cardiometabolic and musculoskeletal disease genetics at Regeneron, called the findings a “milestone” in the understanding of the genetic foundation of the disease, which is now informing the company’s own pipeline. The drugmaker already has one phase 1 drug aimed at NASH—HSD17B13—that’s being developed in collaboration with Alnylam. 

The findings come as company after company faces the clinical pitfalls of NASH. Pfizer most recently joined the list of pharmas to call it quits on another NASH project, joining the likes of Bristol Myers Squibb, Intercept and Metacrine. But Aris Baras, M.D., head of Regeneron’s genetic center, is optimistic that may change.

"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," he said in a statement.