First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers

• Published in: Molecular therapy. Nucleic acids 2022-06, Vol.28, p.124-135
• Main Authors: Hernández-Jiménez, Macarena, Martín-Vílchez, Samuel, Ochoa, Dolores, Mejía-Abril, Gina, Román, Manuel, Camargo-Mamani, Paola, Luquero-Bueno, Sergio, Jilma, Bernd, Moro, María A., Fernández, Gerónimo, Piñeiro, David, Ribó, Marc, González, Víctor M., Lizasoain, Ignacio, Abad-Santos, Francisco
• Format: Article
• Language: English
• Subjects: antagonist; aptamer; clinical trial; first-in-human; healthy subjects; inflammation; MT: oligonucleotides; MT: therapies and applications; Original; pharmacokinetics; safety; TLR4
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2022.03.005

ApTOLL is an aptamer that antagonizes Toll-like receptor 4 and improves functional outcomes in models of ischemic stroke and myocardial infarction. The aim of this study was to characterize the safety and pharmacokinetics of ApTOLL in healthy volunteers. A first-in-human dose-ascending, randomized, placebo-controlled phase I clinical trial to assess safety and pharmacokinetics of ApTOLL (30-min infusion intravenously) was performed in 46 healthy adult male volunteers. The study was divided into two parts: part A included seven single ascending dose levels, and part B had one multiple dose cohort. Safety and pharmacokinetic parameters were evaluated. No serious adverse events or biochemistry alterations were detected at any dose nor at any administration pattern studied. Maximum concentration was detected at the end of the infusion and mean half-life was 9.3 h. Interestingly, exposure increased in the first four levels receiving doses from 0.7 mg to 14 mg (AUC of 2,441.26 h∗ng/mL to 23,371.11 h∗ng/mL) but remained stable thereafter (mean of 23,184.61 h∗ng/mL after 70 mg). Consequently, the multiple dose study did not show any accumulation of ApTOLL. These results show an excellent safety and adequate pharmacokinetic profile that, together with the efficacy demonstrated in nonclinical studies, provide the basis to start clinical trials in patients. [Display omitted] In this study, Hernandez-Jimenez and colleagues conducted a first-in-human clinical trial to assess safety and pharmacokinetics of ApTOLL (a TLR4 antagonist) after single and multiple doses. Results in healthy subjects show that ApTOLL is safe, its mean half-life is 9.3 h, and there is no accumulation after multiple doses.