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

Sep 10, 2023Molecular metabolism

Weight loss and safety of NNC9204-1177, a drug acting on glucagon and GLP-1 receptors, in adults with overweight or obesity from three early trials

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Abstract

Weight loss of up to 12.6% was observed at week 12 in participants receiving the glucagon/GLP-1 receptor co-agonist NN1177.

The geometric mean half-life of NN1177 at steady state was estimated to be between 77 and 111 hours.
NN1177 appeared tolerable across the trials, but several unexpected safety signals were noted.
Increased heart rate and decreased reticulocyte count were among the treatment-related safety signals observed.
Markers of inflammation, such as fibrinogen and C-reactive protein, increased in response to NN1177.
Impaired glucose tolerance and reduced blood levels of some amino acids were also reported.

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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, 1300, 1900, 2800, 4200 and 6000 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 1100 μg) or placebo, and a drug-drug interaction, open-label, single-sequence trial in which adults (N = 45) received a 4200-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 h, and clinically relevant weight loss was achieved (up to 12.6% at week 12; 4200 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.

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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

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