1. Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies.
- Author
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Mullins GR, Hodsdon ME, Li YG, Anglin G, Urva S, Schneck K, Bardos JN, Martins RF, Brown K, and Calderon B
- Subjects
- Humans, Injection Site Reaction, Gastric Inhibitory Polypeptide therapeutic use, Antibodies, Neutralizing, Glucagon-Like Peptide 1 therapeutic use, Hypoglycemic Agents adverse effects, Glucagon-Like Peptide-1 Receptor, Diabetes Mellitus, Type 2 drug therapy, Glucagon-Like Peptide-2 Receptor
- Abstract
Context: Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy., Objective: This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety., Methods: ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1., Results: TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer., Conclusion: Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2024
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