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.
| Autor: | Friedrichsen MH; Novo Nordisk A/S, Søborg, Denmark. Electronic address: mfrc@novonordisk.com., Endahl L; Novo Nordisk A/S, Søborg, Denmark., Kreiner FF; Novo Nordisk A/S, Søborg, Denmark., Goldwater R; Parexel International, Baltimore, MD, USA., Kankam M; Altasciences Clinical Kansas, Overland Park, KS, USA., Toubro S; Novo Nordisk A/S, Søborg, Denmark., Nygård SB; Novo Nordisk A/S, Søborg, Denmark. |
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| Jazyk: | angličtina |
| Zdroj: | Molecular metabolism [Mol Metab] 2023 Dec; Vol. 78, pp. 101801. Date of Electronic Publication: 2023 Sep 09. |
| DOI: | 10.1016/j.molmet.2023.101801 |
| Abstrakt: | 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. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martin Friedrichsen, Lars Endahl, Frederik Kreiner, Søren Toubro and Sune Nygård are employees of Novo Nordisk A/S. Martin Friedrichsen, Lars Endahl and Frederik Kreiner are shareholders in Novo Nordisk A/S. Martin Kankam has received funding from Diffusion Pharmaceutical Inc., Grifols, Urovant Sciences, ViroDefense, Merck, PhaseBio Pharmaceuticals, Inc., Idorsia Pharmaceuticals Ltd, DynPort Vaccine company/FDA/NIH, and Aerovate Therapeutics. Ronald Goldwater is an employee of Parexel International. (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.) |
| Databáze: | MEDLINE |
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