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Identifying Gut Proteins To Tackle Metabolic Disorders

Historians of science love to tell about “eureka moments”—simple observations leading to major insight. Greek mathematician Archimedes allegedly exclaimed the original “Eureka!”—meaning “I have found it!”—upon witnessing the volume of water displaced by his body in the bathtub equaled the volume of the body part he had submerged. Medicine’s most famous eureka moment is probably the discovery of penicillin in 1928 when microbiologist Alexander Fleming observed the absence of bacteria developing on his growth plates in areas where the mold Penicillium rubens happened to be sprouting.

The roots of NGM Biopharmaceuticals (South San Francisco, CA) are based on a eureka moment as well—the simple observation that many recipients of gastric bypass surgery begin to see almost immediate improvement in blood glucose levels before the occurrence of weight loss, and in some cases even without significant dietary changes. In this issue, we’ll find out how the science of gastric bypass surgery is being used to discover new drugs in the metabolic space.

Bypassing Normal Digestive Routes

Gastric bypass surgery is pretty much “stomach stapling” and then a change-up in the route of digestion. A portion of an obese patient’s stomach is made physically smaller, and therefore only capable of holding about a cup or so of food at a time. Then the new, smaller stomach is disconnected from the upper part of the small intestine and reconnected lower down, thereby reducing absorption of food through the small intestine. Less food and less absorption of food lead to weight loss.

The initial understanding of surgery results implied positive outcomes came from weight loss (averaging 60% of excess weight). However, the significant improvement in blood glucose levels seen in many patients immediately following the surgery—before weight loss occurs—remained unexplained.

It appeared that rerouting the digestive tract altered some basic physiology. Various hormones are released in response to digestion, signaling satiety and regulating the pace at which the stomach empties. Could one of these hormones be altered just by rerouting the stomach? This question formed the basis of NGM Biopharmaceuticals, a company founded on identifying potential therapeutic proteins produced in the gastrointestinal (GI) tract.

Replicating A Stomach Hormone

One of the first GI tract proteins with potential metabolic benefits identified was fibroblast growth factor 19 (FGF19). FGF19 is a hormone whose primary function is to regulate bile synthesis, but FGF19 also impacts glucose and lipid metabolism by interacting with receptors on the surface of fat cells. In fact, patients with metabolic syndrome, non-alcoholic fatty liver disease, or insulin resistance all have reduced levels of FGF19—which is restored to normal levels after gastric bypass surgery and before weight loss. This suggests lowered levels of FGF19 may be contributing to some of the observed metabolic problems of obese patients, and increasing those levels may confer benefit.

NGM Bio’s drug candidate NGM282 is an engineered version of FGF19. NGM282’s gene sequence is modified, so it does not promote liver cell growth but still interacts with the signaling pathways regulating bile synthesis and normalizing glucose and lipid metabolism.

The exact mechanism by which FGF19/NGM282 works is not fully understood. It is known that both proteins interact with receptors on the surface of liver and fat cells, and likely influence signal transduction pathways. Recent research also suggests that FGF19 (and by extension, NGM282) also interact with neuronal pathways that regulate metabolism.

Challenging Cholestatic Liver Disease, NASH & Diabetes

NGM282 is currently in Phase II clinical trials for cholestatic liver disease, an inflammatory liver disease caused by the build-up of bile in the liver. NGM282 appears to modulate the production of bile acid, resulting in reduced liver inflammation. The drug is also in Phase II for Type 2 diabetes due to its ability to lower blood glucose levels. Look for Phase II trials for nonalcoholic steatohepatitis (NASH) in the near future.

Another Gastric Pathway?

FGF19 is not the only hormone released in the gut (stomach, pancreas, and small intestine) that plays a critical role in glucose and fat metabolism. More than twenty exist to control appetite, glucose absorption, and insulin release. These complex interactions help to explain why understanding and managing metabolic disorders continue to be a challenging medical problem.

One of the best characterized gut hormones is glucagon-like peptide 1 (GLP-1). Secreted by cells of the large intestine, GLP-1 increases insulin secretion and insulin sensitivity, inhibits stomach emptying, and decreases glucagon secretion. Since insulin release causes muscle, fat, and liver cells to absorb blood glucose, and glucagon stimulates the liver to release stored glucose, increasing insulin while decreasing glucagon will reduce blood glucose levels.

There are several Type 2 diabetes drug on the market acting as GLP-1 analogs, or peptides (amino acids sequences composed of 50 or fewer amino acids). These drugs mimic the effect of GLP-1 and lower blood glucose levels—examples include Amylin Pharmaceutical’s (San Diego, CA) Byetta and Lilly’s (Indianapolis, IN) Trulicity.

The rise in metabolic disorders has ballooned, so let the eureka moments continue!

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