NGM, Partners Seek Next Diabetes Drug Targets Among GI Tract Hormones

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bariatric surgery in animals to search for regulatory agents that either promote diabetes or help resolve it, Rieflin says. Once found, those agents can become targets for experimental drugs—either to bolster the effect of beneficial compounds or to thwart those that destabilize blood sugar levels.

Since surgery alone seems to spur changes that can help Type 2 diabetes patients get their blood sugar under control, some researchers have been conducting clinical trials assessing it as a routine treatment that might be superior to existing medications. But Rieflin says surgery involves risks on the operating table, as well as side effects such as the reduced absorption of vitamins and other nutrients. On top of that, the widespread use of expensive surgeries as treatments for Type 2 diabetes would bankrupt the health care system, Rieflin argues. About 25.8 million people have diagnosed or undiagnosed diabetes in the United States, according to the Centers for Disease Control and Prevention. Among adults with diabetes, as many as 95 percent have Type 2 diabetes.

Some drug makers have already developed diabetes drugs based on knowledge of hormones produced by cells in the gut as food passes through it. So-called incretin hormones such as GLP-1 (glucagon-like peptide-1) prompt the pancreas to produce insulin, which keeps blood sugar levels steady in healthy people. Amylin’s drug exenatide (Byetta), approved for certain patients with Type 2 diabetes in 2005, was the first drug designed to mimic the effects of GLP-1. Newer drugs in this class are Novo Nordisk’s liraglutide (Victoza) and Merck’s sitagliptin (Januvia.) Rieflin says NGM aims to discover drug candidates that could complement the drugs that mimic incretin, which he expects will continue playing a significant role in diabetes treatment.

In the complex regulatory network that controls blood sugar, he says, it’s not likely that a single compound is responsible for the entire benefit of bariatric surgery. NGM has identified a number of molecules of interest by focusing on a form of surgery called a Duodenal-Jejunal Bypass (DJB), which prevents food from flowing from the lower stomach directly into the duodenum—the first segment of the small intestine.This surgery improves blood sugar control without causing weight loss.

“It separates the two effects,” Rieflin says.

NGM scientists track the changes in gene expression before and after the food is re-routed to bypass the duodenum, which retains its nerves and blood supply. Several theories could explain the benefits of the surgery, Rieflin says. The duodenum may produce a harmful agent in response to food, or it may produce a molecule that promotes stable blood sugar when it is starved of food. Looking at it another way, food that has not passed through the duodenum may induce the release of beneficial compounds in the remaining sections of the small intestine.

In its partnership with Janssen, NGM is studying a set of protein factors with the goal of reproducing the benefits of bariatric surgery in diabetes patients. The company’s agreement with MedImmune is based on NGM’s work in isolating the rare enteroendocrine cells (EEC) from the GI tract. These cells produce almost all the known GI hormones, including GLP-1, according to NGM. But they also may produce hormones important to glucose control that have not yet been identified. NGM has discovered new types of enteroendocrine cells as well, Rieflin says.

Rieflin says he can’t reveal how NGM’s research platform led to discoveries that form the basis of NGM’s collaboration with Daiichi Sankyo. The partners agreed to work together to develop factors that could regenerate the insulin-producing beta-cells of the pancreas—a potential boon for patients with either Type 1 or Type 2 diabetes. Diabetes stems in part from a decline in beta-cell functioning.

The partnerships have provided upfront payments and financial support for NGM’s research, though the startup isn’t giving out exact numbers. Rieflin says the drug companies relieve NGM of the task of taking drug candidates through clinical trials, and allow the startup to concentrate on its core strengths in basic scientific discovery.

Rieflin sees significant opportunities for NGM to originate one or more successful products that could earn a share of the total $175 billion US market in medical care for diabetes.

“It’s a very big sandbox to play in,” he says.

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