NGM386 and NGM395
NGM386 and NGM395, also known as MK-4820 and MK-3606, respectively, are proprietary, engineered variants of the hormone GDF15 that we are developing with Merck as once-daily and once weekly, or less frequent, subcutaneous injections for the treatment of obesity. GDF15 is a human hormone expressed by tissues involved in core metabolic functions, and has been shown to induce changes in food intake, energy expenditure and body weight loss in rodent models.
Our research suggests that GDF15 is elevated in peripheral tissues following cellular insults, such as oxidative, metabolic or hypoxic stress, and may serve as a messenger hormone to communicate with the brain stem and orchestrate adaptive metabolic changes to cope with the energy demand of cells under various stress conditions. Among these adaptations are reduced food intake and a change in the fuel flux that favors the burning of free fatty acids through lipolysis, instead of burning carbohydrates. We discovered that GDF15 acts directly on GFRAL, a receptor located exclusively in the area postrema, or AP, and nucleus tractus solitarius, or NTS, of the brain stem. The AP is a circumventricular organ that is outside the blood-brain barrier, which means that it can readily sense any changes in the bloodstream. This discovery provided a mechanistic basis for the regulation by GDF15 of whole body metabolism through a distinct neural circuitry. Additional information about NGM’s pioneering work on the biology of GDF15 and its cognate receptor GFRAL can be found here.
In 2015, we granted Merck a worldwide license to further research, develop and commercialize NGM386, NGM395 and other GDF15 agonists pursuant to our collaboration agreement.