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
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 r...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
|
| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823001357 |
| _version_ | 1797454374868353024 |
|---|---|
| author | Martin Haljeta Friedrichsen Lars Endahl Frederik Flindt Kreiner Ronald Goldwater Martin Kankam Søren Toubro Sune Boris Nygård |
| author_facet | Martin Haljeta Friedrichsen Lars Endahl Frederik Flindt Kreiner Ronald Goldwater Martin Kankam Søren Toubro Sune Boris Nygård |
| author_sort | Martin Haljeta Friedrichsen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:36:19Z |
| format | Article |
| id | doaj.art-b2b05f65c82543e7ad21889e4403b00b |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-09T15:36:19Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-b2b05f65c82543e7ad21889e4403b00b2023-11-26T05:12:26ZengElsevierMolecular Metabolism2212-87782023-12-0178101801Results 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 obesityMartin Haljeta Friedrichsen0Lars Endahl1Frederik Flindt Kreiner2Ronald Goldwater3Martin Kankam4Søren Toubro5Sune Boris Nygård6Novo Nordisk A/S, Søborg, Denmark; Corresponding author. Novo Nordisk A/S, Vandtårnsvej 108, Suborn, DK-2860, Denmark.Novo Nordisk A/S, Søborg, DenmarkNovo Nordisk A/S, Søborg, DenmarkParexel International, Baltimore, MD, USAAltasciences Clinical Kansas, Overland Park, KS, USANovo Nordisk A/S, Søborg, DenmarkNovo Nordisk A/S, Søborg, DenmarkObjective: 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.http://www.sciencedirect.com/science/article/pii/S2212877823001357Glucagon-like peptide-1Glucose-dependent insulinotropic polypeptideObesityNN1177 |
| spellingShingle | Martin Haljeta Friedrichsen Lars Endahl Frederik Flindt Kreiner Ronald Goldwater Martin Kankam Søren Toubro Sune Boris Nygård 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 Molecular Metabolism Glucagon-like peptide-1 Glucose-dependent insulinotropic polypeptide Obesity NN1177 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Glucagon-like peptide-1 Glucose-dependent insulinotropic polypeptide Obesity NN1177 |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823001357 |
| work_keys_str_mv | AT martinhaljetafriedrichsen resultsfromthreephase1trialsofnnc92041177aglucagonglp1receptorcoagonisteffectsonweightlossandsafetyinadultswithoverweightorobesity AT larsendahl resultsfromthreephase1trialsofnnc92041177aglucagonglp1receptorcoagonisteffectsonweightlossandsafetyinadultswithoverweightorobesity AT frederikflindtkreiner resultsfromthreephase1trialsofnnc92041177aglucagonglp1receptorcoagonisteffectsonweightlossandsafetyinadultswithoverweightorobesity AT ronaldgoldwater resultsfromthreephase1trialsofnnc92041177aglucagonglp1receptorcoagonisteffectsonweightlossandsafetyinadultswithoverweightorobesity AT martinkankam resultsfromthreephase1trialsofnnc92041177aglucagonglp1receptorcoagonisteffectsonweightlossandsafetyinadultswithoverweightorobesity AT sørentoubro resultsfromthreephase1trialsofnnc92041177aglucagonglp1receptorcoagonisteffectsonweightlossandsafetyinadultswithoverweightorobesity AT suneborisnygard resultsfromthreephase1trialsofnnc92041177aglucagonglp1receptorcoagonisteffectsonweightlossandsafetyinadultswithoverweightorobesity |