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

Macarena Hernández-Jiménez, Samuel Martín-Vílchez, Dolores Ochoa, Gina Mejía-Abril, Manuel Román, Paola Camargo-Mamani, Sergio Luquero-Bueno, Bernd Jilma, María A Moro, Gerónimo Fernández, David Piñeiro, Marc Ribó, Víctor M González, Ignacio Lizasoain, Francisco Abad-Santos, Macarena Hernández-Jiménez, Samuel Martín-Vílchez, Dolores Ochoa, Gina Mejía-Abril, Manuel Román, Paola Camargo-Mamani, Sergio Luquero-Bueno, Bernd Jilma, María A Moro, Gerónimo Fernández, David Piñeiro, Marc Ribó, Víctor M González, Ignacio Lizasoain, Francisco Abad-Santos

Abstract

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.

Keywords: MT: oligonucleotides; MT: therapies and applications; TLR4; antagonist; aptamer; clinical trial; first-in-human; healthy subjects; inflammation; pharmacokinetics; safety.

Conflict of interest statement

M.H.J. and D.P.R. are employees of aptaTargets S.L. V.M.G. is researcher from FIBio-HRC. G.F. is employee of Aptus Biotech S.L. M.Ri. receives payment from Philips as Co-principal investigator of the WE TRUST study and he has a consulting agreement with Medtronic, Stryker, Cerenovus, CVAid, Methinks, Anaconda Biomed, and aptaTargets S.L. B.J. served as consultant to aptaTargets S.L. F.A.S. and D.O. have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, aptaTargets, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. The information disclosed in this article is protected by the international patent application WO2015197706 and its extensions to different countries; and by the international patent WO2020/230108.

© 2022 The Authors.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Subject disposition in the ApTOLL-FIH-01 clinical trial (for details see materials and methods section)
Figure 2
Figure 2
ApTOLL plasma concentrations versus time after administration of different dose levels in part A of ApTOLL-FIH-01 clinical trial (A–G) Plots of same color correspond to one subject enrolled in every single level of part A of the study. (A) Level 1 = 0.7 mg; (B) Level 2 = 2.1 mg; (C) Level 3 = 7 mg; (D) Level 4 = 14 mg; (E) Level 5 = 21 mg; (F) Level 6 = 42 mg; and (G) Level 7 = 70 mg. In every dose level, the concentration is shown in a lineal scale (left graphs) and in semilogarithmic scale (right graphs).
Figure 3
Figure 3
ApTOLL concentration versus time in the part B of ApTOLL-FIH-01 clinical trial (A and B) Plots of same color correspond to one subject enrolled in the part B of the study. 21 mg of ApTOLL was administered intravenously every 8 h during 24 h. The concentration is shown in lineal scale (A) and semilogarithmic scale (B).

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