The PCSK9 of NASH? Regeneron and Alnylam join forces to tackle a promising target for severe liver diseases

The Regeneron Genetics Center $REGN routinely sifts through a mountain of sequencing data. And every now and then, the researchers there will pan out a glittering finding that looks like it could rank right up there with PCSK9.

Here’s one.

John Maraganore

This evening, in a study published in the New England Journal of Medicine, they are pointing to one such discovery that they believe has some big implications for severe liver diseases, including the Holy Grail of NASH. And without a logical antibody strategy to put into play — given an intracellular target in the spotlight — they’ve enlisted an experienced crew at Alnylam to bring their RNAi gene silencing platform into the game to find the most efficient way to provide the key to countering a raft of ailments.

“We obviously saw the data and we were blown away,” says Alnylam $ALNY CEO John Maraganore, who’s now in wait-and-see mode as their lead drug patisiran rolls up to an August PDUFA date. “This target  — HSD17B13 — from a human genetics perspective it really is the  PCSK9 of NASH.”

Aris Baras

Regeneron prides itself on moving aggressively when they find something promising for clinical development. And in Alnylam, they feel they are working with close kin in that respect.

“These guys at Alnylam have a similar approach and track record,” says Aris Baras, head of the RGC. And he feels this target deserves speed and care, which inspired a 50/50 deal on research costs and any commercial potential that comes out of the preclinical alignment.

How fast can Alnylam move here? “We’re not giving guidance,” says Maraganore, but he says you shouldn’t be surprised if there’s a program in the clinic next year. (Yes, that is fast.)

The deal, he adds, calls for shared economics in development, with Alnylam doing the critical early development and Regeneron picking up the late-stage work. That will be their first RNAi study of their own, says Maraganore, but there’s no real mystery in how that works. And they’ll stay closely involved throughout.

The study of human genetics in these centers is beginning to have a real impact on R&D efficiency, says Baras. And this project in particular, he believes, highlights the promise of the field in quickly zeroing in on a viable drug program.

By setting up a large pile of genetic data on thousands of patients with liver disease and comparing it with sequencing data on a group of tens of thousands of healthy people, Baras tells me, the researchers at Regeneron’s genetics arm narrowed down possible genetic triggers for disease to a loss-of-function genetic variation in HSD17B13.

Fully shut down by the variation, the investigators found that eclipsing the gene reduced enzymatic activity:

— Cutting the risk of alcoholic cirrhosis by 73%.

— Lowering the risk of nonalcoholic cirrhosis by 49%.

— And cutting the risk of alcoholic liver disease by 53%, and nonalcoholic liver disease by 30%, with an associated reduction in risk of NASH.

Regeneron is also going after some small molecule programs in the process.

“We think this is big biology and there are different shots on goal with different modalities,” says Baras.

We’ll stay focused here at Endpoints on this one to see whether it lives up to the preclinical promise. Tradition suggests that any program that goes into the clinic will have at best around a 1 in 10 shot at an approval. Genetics aims to change those odds for the better.

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