Tirzepatide immunogenicity on pharmacokinetics, efficacy, and safety: analysis of data from Phase 3 studies.

Anti-drug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. To evaluate treatment-emergent (TE) ADA in tirzepatide-treated participants across seven Phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. ADA were assessed at baseline and throughout the study until endpoint, 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. ADA-evaluable tirzepatide-treated patients with type 2 diabetes (N=5025). Tirzepatide 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross react with native GIP (nGIP) and GLP-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. TE ADA developed in 51.1% of patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81920 among TE ADA+ patients. Neutralizing antibodies (NAb) against tirzepatide activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of TE ADA+ patients, respectively. Less than 1.0% of tirzepatide-treated TE ADA+ patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb had no impact on pharmacokinetics or efficacy of tirzepatide. More TE ADA+ tirzepatide-treated patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and non-severe, and most events occurred and/or resolved irrespective of TE ADA status or titer. Immunogenicity did not impact tirzepatide pharmacokinetics or efficacy. Majority hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.

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© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.