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

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.

Keywords: clinical trial; immunogenicity; incretin therapy; type 2 diabetes.

Figure 1.

Flowchart of immunogenicity testing strategy. Tier 1 (screening), tier 2 (confirmatory and cross-reactive), tier 3 (titer), tier 4 (neutralizing antibodies), and in silico cross-reactive neutralizing antibodies are displayed in each bubble. ADA, antidrug antibodies; CP, cutpoint; GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide; NAb, neutralizing antibodies; nGIP, native GIP; nGLP, native GLP; R, receptor.

Figure 2.

Flow diagram for immunogenicity analysis of randomly assigned participants from SURPASS-1 to -5, -Japan-mono, and -Japan-combo studies. ADA, antidrug antibodies; TE, treatment-emergent.

Figure 3.

Tirzepatide clearance by ADA status. Tirzepatide apparent clearance (CL/F) was not affected by A, ADA status or B, ADA titer. ADA titer 1:327 680 shown in B was observed at week 78 and was the maximum reported titer in one patient who had been randomly assigned to the tirzepatide 5 mg group. This patient was not TE ADA evaluable as no baseline sample had been collected. The patient's first ADA sample was collected 19 minutes after the first dose of tirzepatide 2.5 mg and was reported as 1:163 840. The second ADA sample for this patient was collected at week 41 during treatment with tirzepatide 5 mg and was reported as 1:40 960. Although all 3 ADA titers collected from this patient during tirzepatide treatment were high, the maximum titer was only 1 dilution higher than the first ADA sample. This patient did not experience any hypersensitivity or injection site reaction and showed glycated hemoglobin A_1c-lowering similar to other tirzepatide-treated patients. ADA, antidrug antibodies; CL/F, apparent clearance.

Figure 4.

HbA_1c assessment by ADA and titer status. Change from baseline in HbA_1c was not affected by TE A, ADA status or B, ADA titer less than 1:5120 vs 1:5120 or greater. ADA, antidrug antibodies; HbA_1c, glycated hemoglobin A_1c; Count, number of patients; TE, treatment-emergent.