Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies

被引:4
|
作者
Mullins, Garrett R. [1 ]
Hodsdon, Michael E. [1 ]
Li, Ying Grace [1 ]
Anglin, Greg [1 ]
Urva, Shweta [1 ]
Schneck, Karen [1 ]
Bardos, Jennifer N. [1 ]
Martins, Ricardo Fonseca [1 ]
Brown, Katelyn [1 ]
Calderon, Boris [1 ,2 ]
机构
[1] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA
[2] Lilly Corp Ctr, Indianapolis, IN 46285 USA
来源
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2024年 / 109卷 / 02期
关键词
incretin therapy; immunogenicity; type; 2; diabetes; clinical trial; GLP-1 RECEPTOR AGONIST; ONCE-WEEKLY SEMAGLUTIDE; DOUBLE-BLIND; DUAL GIP; TYPE-2; METFORMIN; PLACEBO; 56-WEEK;
D O I
10.1210/clinem/dgad532
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:361 / 369
页数:9
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