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Chronic intake of high-energy diets alters the physiological response to food and favors overconsumption. Feeding, especially of palatable food, leads to dopamine (DA) release in the Nucleus Accumbens (NAc, in the ventral striatum), prefrontal cortex (PFC) and dorsal striatum. The mesocortical (ventral tegmental area (VTA) projecting to NAc) DA system has been implicated in motivational drive and food seeking while the nigrostriatal DA (projections from the substantia nigra (SN) to the dorsal striatum) pathway plays a role in both food anticipatory behavior and reinforcement. In humans, hypersensitivity to food-associated reward may predispose to weight gain, however as obesity progresses deficit in reward signaling emerges. Individuals with obesity have reduced DRD2 availability in prefrontal brain regions compared to lean counterparts. 

Jiyoung S. Kim, Kevin C. Williams, Rebecca A. Kirkland, Ruth Schade, ... Claire B. de La Serre

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Current Issue

Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: effects on weight loss and safety in adults with overweight or obesity

Martin Haljeta Friedrichsen, Lars Endahl, Frederik Flindt Kreiner, Ronald Goldwater, ... Sune Boris Nygård

Objective

Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity.

Methods

Our focus was a 12-week, multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N=99) received NN1177 (on an escalating dose regimen of 200, 600, 1,300, 1,900, 2,800, 4,200 and 6,000 μg) or placebo. Two other trials also contributed to the findings reported in this article: a first human dose (FHD)/single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N=49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1,100 μg) or placebo, and a drug–drug interaction, open-label, single-sequence trial in which adults (N=45) received a 4,200-μg dose of NN1177, following administration of a Cooperstown 5+1 index cocktail. Safety, tolerability, pharmacokinetic and pharmacodynamic endpoints were assessed.

Results

For the FHD/SAD and MAD trials, baseline characteristics were generally balanced across treatment cohorts. The geometric mean half-life of NN1177 at steady state was estimated at between 77 and 111 hours, and clinically relevant weight loss was achieved (up to 12.6% at week 12; 4,200 μg in the MAD trial). Although NN1177 appeared tolerable across trials, several unexpected treatment-related safety signals were observed; increased heart rate, decreased reticulocyte count, increased markers of inflammation (fibrinogen and C-reactive protein), increased aspartate and alanine aminotransferase, impaired glucose tolerance and reduced blood levels of some amino acids.

Conclusion

Although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, the observed safety signals precluded further clinical development.

Keywords

Glucagon-like peptide-1

Glucose-dependent insulinotropic polypeptide

Obesity

NN1177

Articles in Press

Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: effects on weight loss and safety in adults with overweight or obesity

Martin Haljeta Friedrichsen, Lars Endahl, Frederik Flindt Kreiner, Ronald Goldwater, ... Sune Boris Nygård

Objective

Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity.

Methods

Our focus was a 12-week, multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N=99) received NN1177 (on an escalating dose regimen of 200, 600, 1,300, 1,900, 2,800, 4,200 and 6,000 μg) or placebo. Two other trials also contributed to the findings reported in this article: a first human dose (FHD)/single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N=49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1,100 μg) or placebo, and a drug–drug interaction, open-label, single-sequence trial in which adults (N=45) received a 4,200-μg dose of NN1177, following administration of a Cooperstown 5+1 index cocktail. Safety, tolerability, pharmacokinetic and pharmacodynamic endpoints were assessed.

Results

For the FHD/SAD and MAD trials, baseline characteristics were generally balanced across treatment cohorts. The geometric mean half-life of NN1177 at steady state was estimated at between 77 and 111 hours, and clinically relevant weight loss was achieved (up to 12.6% at week 12; 4,200 μg in the MAD trial). Although NN1177 appeared tolerable across trials, several unexpected treatment-related safety signals were observed; increased heart rate, decreased reticulocyte count, increased markers of inflammation (fibrinogen and C-reactive protein), increased aspartate and alanine aminotransferase, impaired glucose tolerance and reduced blood levels of some amino acids.

Conclusion

Although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, the observed safety signals precluded further clinical development.

Keywords

Glucagon-like peptide-1

Glucose-dependent insulinotropic polypeptide

Obesity

NN1177

2021 impact factor: 8.568

You are what you eat

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