Amgen’s ASGR1 Research: Gene X

Amgen has been pursuing a new opportunity to fight heart disease since the variant in ASGR1 was first observed.

In October 2014, Sean Harper, Amgen’s executive vice president for Research and Development, discussed high-level details of “Gene X,” as the mutation was initially called. “This rare variant gene is telling us something profound about the biology of atherosclerosis that we don’t completely understand yet,” said Harper. “We are developing an inhibitor against this gene in parallel with our efforts to elucidate the biology so that we can move this program forward.”

ASGR1: A Well-Studied but Still Mysterious Receptor

In May 2016, Amgen and deCODE reported the mutation in ASGR1(asialoglycoprotein receptor 1) in a paper published in the New England Journal of Medicine (NEJM).1 ASGR1 is the major subunit of the ASGP receptor (ASGPR) complex, which is found mainly in the liver. The paper described two mutations in ASGR1. The more common of the two is called the del12 variant, because it arose from a deletion of 12 base pairs in one of the non-coding regions of the gene, leading to a non-functioning, truncated protein.

Biologists have been investigating ASGPR for roughly 50 years3, using it as a model to study certain cellular functions. “It’s remarkable that this protein could have been studied for so long before the association with heart disease was discovered,” said Peter Coward, a principal scientist in Amgen’s Cardiometabolic Disorders group. “It was basically known as a scavenger receptor that cleared different proteins from the bloodstream. There’s a lot of scientific literature out there on ASGR1, but there’s still a lot we don’t know about its activity.”

The receptor has several attributes that are encouraging from a drug discovery standpoint. For starters, the target resides on the surface of liver cells. “With some of the targets that deCODE has identified, the genetic data are very strong but the target itself is tricky and hard to get at it,” said Coward. “It’s fortuitous that ASGR1 is an accessible target.”

The del12 mutation is different. The cardioprotective effect is one of the biggest we’ve seen with any gene variant.
Paul Nioi, Scientific Director, Amgen


Probing the Biology of the ASGR1 Mutation

There is also reason to hope that a medicine targeting this receptor might offer benefits that complement those provided by current cholesterol-lowering agents. “We have good genetic evidence that the mutation impacts something in addition to cholesterol,” said Paul Nioi, first author of the NEJM paper and a scientific director at Amgen. “When you look at variations in the genome that affect cholesterol levels and heart disease risk, you see a predictable linear relationship. The more a variant lowers bad cholesterol, the more it also lowers the risk of heart disease, and the more it increases bad cholesterol, the more it increases heart disease. But the del12 mutation is different. The cardioprotective effect is one of the biggest we’ve seen with any gene variant, and it’s hard to explain this large effect based solely on the gene’s impact on cholesterol levels.”1

A large Amgen team has been probing the biology of the mutation to fully understand cardiovascular benefits. Scientists are using research approaches like proteomics, a protein identification and analysis technology, to determine what biological pathways are impacted by the gene variant.

“We have an intense effort underway to understand how the ASGR1 gene leads to the cardiovascular benefit seen in del12 carriers,” said Simon Jackson, a scientific director who is leading the drug discovery project team.

“We’ve made great progress overall since the program was launched,” said Coward. “The team has had tremendous support inside Amgen right from the start, and it really shows in terms of the speed and breadth of work that we have already accomplished.”

Amgen’s acceleration of the ASGR1 program is an example of the company’s R&D strategy in action. The strategy calls for a “Pick the Winners” approach to guide resource decisions to ensure that highly promising programs move rapidly. The selection of winners is driven by solid evidence that a target has a large impact on disease. That evidence frequently comes from genetic insights, most often provided by scientists at deCODE.

The ASGR1 program is “a beautiful illustration of the unbiased nature of genetics,” said Nioi. “As scientists, we can come up with fancy hypotheses about treating diseases, but we would have no reason to look at a receptor like ASGR1in the context of heart disease. But all of a sudden, the genetics is telling us that something is going on here and revealing novel biology that is very exciting.”

“The program has generated a lot of enthusiasm and energy,” said Jackson. “It’s a basic biologist’s dream to have a project like this to work on and to be given the resources and mandate to discover a new biological pathway. We haven’t been able to solve it yet, but we’re getting there.”


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