Immunogenicity does not affect pharmacokinetics, efficacy of tirzepatide

Treatment-emergent (TE) antidrug antibodies (ADA) do not show any influence on the pharmacokinetics or efficacy of tirzepatide (TZP), as shown in a study. Most of the hypersensitivity or injection site reactions in patients with TE ADA are either mild or moderate in severity.

“Immunogenicity was not associated with any effect on TZP pharmacokinetics or efficacy, and the majority of hypersensitivity or injection site reactions (ADA+) were mild to moderate in severity,” said the investigators, who assessed TE ADA in TZP-treated patients across seven phase III trials.

ADA were evaluated at baseline and until the study endpoint, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). ADA characterization samples were obtained at SURPASS trial sites. A total of 5,025 ADA-evaluable, TZP-treated patients with type 2 diabetes were included. Interventions consisted of TZP 5, 10, 15 mg.

The investigators detected and characterized ADA for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize TZP activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1.

Of the patients, 51.1 percent developed TE ADA, with similar proportions across TZP dose groups. Maximum ADA titres ranged from 1:20 to 1:81,920 among those with TE ADA. [J Clin Endocrinol Metab 2024;109:361-369]

Investigators observed neutralizing antibodies (NAb) against TXP activity on GIP and GLP-1 receptors in 1.9 percent and 2.1 percents of patients, respectively. They also found that <1.0 percent of participants had cross-reactive NAb against nGIP or nGLP-1.

TE ADA status, ADA titre, and Nab status showed no impact on TZP pharmacokinetics and efficacy. Hypersensitivity or injection site reactions occurred more frequently among TE ADA+ than TE ADA‒ patients. The majority of these reactions were neither serious nor severe, and most events occurred or resolved regardless of TE ADA status or titre.

Of note, evaluable patients were classified as TE ADA+ if they had either of the following: (1) baseline status of ADA not present and at least one postbaseline status of ADA present with titre two or more times the minimum required dilution of the ADA assay, or (2) baseline and postbaseline status of ADA present, with the postbaseline titre being greater than or equal to fourfold than the baseline titre.

On the other hand, patients who did not meet the TE ADA+ criteria were classified as TE ADA‒.

Immunogenicity

“Immunogenicity to therapeutic proteins has the potential to affect the drug's pharmacokinetics, efficacy, and/or safety,” according to the investigators. [https://www.fda.gov/media/85017/download]

“The data show that the development of anti-TZP antibodies had no effect on the drug's pharmacokinetics or efficacy,” they added.

“Although there was a numerical imbalance seen in hypersensitivity and injection site reactions, these events resolved irrespective of TE ADA status and titre, and were mostly mild in severity and most patients continued on treatment,” the investigators said.