First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers
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,...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253122000543 |
| _version_ | 1818357945621020672 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Macarena Hernández-Jiménez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T20:21:10Z |
| format | Article |
| id | doaj.art-1d6415b299c844c7bc5d3c6a71847c5b |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-13T20:21:10Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-1d6415b299c844c7bc5d3c6a71847c5b2022-12-21T23:32:40ZengElsevierMolecular Therapy: Nucleic Acids2162-25312022-06-0128124135First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteersMacarena Hernández-Jiménez0Samuel Martín-Vílchez1Dolores Ochoa2Gina Mejía-Abril3Manuel Román4Paola Camargo-Mamani5Sergio Luquero-Bueno6Bernd Jilma7María A. Moro8Gerónimo Fernández9David Piñeiro10Marc Ribó11Víctor M. González12Ignacio Lizasoain13Francisco Abad-Santos14AptaTargets S.L., Avda. Cardenal Herrera Oria 298, 28035 Madrid, Spain; Corresponding author AptaTargets S.L., Avda. Cardenal Herrera Oria 298, 28035 Madrid, Spain.Clinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, SpainClinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, SpainClinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, SpainClinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, SpainClinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, SpainClinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, SpainDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaCentro Nacional de Investigaciones Cardiovasculares Carlos III (F.S.P.), 28029 Madrid, Spain; Unidad de Investigación Neurovascular, Department of Pharmacology and Toxicology, Faculty of Medicine, Universidad Complutense, 28040 Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainAptus Biotech S.L., Avda. Cardenal Herrera Oria 298, 28034 Madrid, SpainAptaTargets S.L., Avda. Cardenal Herrera Oria 298, 28035 Madrid, SpainAptaTargets S.L., Avda. Cardenal Herrera Oria 298, 28035 Madrid, SpainAptus Biotech S.L., Avda. Cardenal Herrera Oria 298, 28034 Madrid, Spain; Grupo de Aptámeros, Departamento de Bioquímica-Investigación, IRYCIS-Hospital Ramón y Cajal, 28034 Madrid, SpainUnidad de Investigación Neurovascular, Department of Pharmacology and Toxicology, Faculty of Medicine, Universidad Complutense, 28040 Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainClinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, SpainApTOLL 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.http://www.sciencedirect.com/science/article/pii/S2162253122000543MT: oligonucleotidesMT: therapies and applicationsaptamerTLR4inflammationantagonist |
| spellingShingle | 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 First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers Molecular Therapy: Nucleic Acids MT: oligonucleotides MT: therapies and applications aptamer TLR4 inflammation antagonist |
| title | First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers |
| title_full | First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers |
| title_fullStr | First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers |
| title_full_unstemmed | First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers |
| title_short | First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers |
| title_sort | first in human phase i clinical trial of a tlr4 binding dna aptamer aptoll safety and pharmacokinetics in healthy volunteers |
| topic | MT: oligonucleotides MT: therapies and applications aptamer TLR4 inflammation antagonist |
| url | http://www.sciencedirect.com/science/article/pii/S2162253122000543 |
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