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12:58 PM
Sep 21, 2017
 |  BC Innovations  |  Targets & Mechanisms

Appetite for GFRAL

Why pharmas think GFRAL could be the next obesity target

Simultaneous publications from Eli Lilly and Co., Johnson & Johnson and Novo Nordisk A/S identifying GFRAL as the receptor of the anti-obesity hormone GDF15 will undoubtedly accelerate therapeutic translation of the pathway. The race is now on to reach the clinic.

The three pharmas had been competing for years to find the receptor for GDF15, an endocrine player suspected to be an important signaling molecule in the gut-brain axis. The axis is a collection of signaling pathways through which the enteric and central nervous systems communicate to control appetite, blood glucose and insulin sensitivity.

The results paint a picture in which GDF15 is released from various digestive tissues into circulation, travels to the brain and stimulates GFRAL receptors on a particular set of neurons that suppress food intake by producing a feeling of satiety.

All three companies told BioCentury they are interested in developing a therapeutic based on the pathway.

“It’s a race, but it’s always encouraging to find other labs in the world that are able to replicate the data you’re putting out,” said Mads Tang-Christensen, corporate VP and therapeutic area head obesity at Novo Nordisk.

For Novo Nordisk, which told BioCentury in March that it aims to lead the obesity space by creating therapies with substantial improvements over existing ones, the findings add a new mechanism to the company’s already fairly deep and growing pipeline.

While Lilly has no clinical-stage obesity compounds, GFRAL activation would dovetail with its extensive diabetes pipeline. For J&J the strategy would represent a move beyond SGLT2 inhibition.

The receptor could also offer opportunities for combination therapies. As GFRAL’s mechanism appears to be specific to appetite control, drugging it should complement marketed and clinical-stage therapies that modulate body mass by other mechanisms, such as increasing energy expenditure, glucose secretion and lipid excretion, and slowing gastric emptying. It might also offer a partner to up-and-coming preclinical strategies based on emerging areas of biology, in particular the browning of adipose tissue and bacterial signals from the microbiome.

Table: Biocentury Product Profile

ProductGDF15 analog or GFRAL activator
ConceptActivation of GFRAL receptors on hindbrain neurons suppresses appetite
CompetitionOther appetite suppressors; compounds that inhibit gastric emptying; compounds that decrease lipid digestion
DifferentiationFewer off-target toxicities due GFRAL’s highly restricted expression pattern and specificity for the brain’s satiety pathway
RisksUnknown off-target effects from activating other functions of the hindbrain neurons
Development statusPreclinical
PatentsOne patent issued and others filed (Novo Nordisk A/S); patent status undisclosed (Eli Lilly and Co.; Johnson & Johnson)
Company; lead investigatorNovo Nordisk A/S; Mads Tang-Christensen,Eli Lilly and Co.; Xinle Wu,Johnson & Johnson; Shamina Rangwala
Thinking about food

Although gut-brain signaling has been extensively studied in the obesity...

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