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

Hernández-Jiménez, Macarena; Martı́n-Vı́lchez, 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; Lizasoaín, Ignacio; Abad‐Santos, Francisco

doi:10.1016/j.omtn.2022.03.005

Cited by 32 publications

(36 citation statements)

References 42 publications

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“…Hence, the specific antagonism of TLR4 by ApTOLL but not its complete depletion may produce a remarkable clinical improvement, related to the modulation of an excessively strong immune response, preventing tissue damage. Interestingly, the therapeutic use of TLR4 humans is currently being studied in clinical trials in acute ischemic stroke (NCT04734548) and COVID-19 (NCT05293236) patients and has recently demonstrated good safety and pharmacokinetic properties in healthy volunteers [27].…”

Section: Discussionmentioning

confidence: 99%

“…Together, our current findings suggest a new therapeutic approach for the treatment of inflammatory and demyelinating diseases like MS. The molecular nature of the aptamer, ApTOLL, specifically blocking TLR4 exerting a clear anti-inflammatory effect as well as an indirect/direct neuroprotective and remyelinating effect confers advantages over other compounds, and also has a good safety profile, as demonstrated in the First-in-Human study [27]. This opens the door to future clinical studies with this aptamer in MS human trials.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the therapeutic use of TLR4 humans is currently being studied in clinical trials in acute ischemic stroke (NCT04734548) and COVID-19 (NCT05293236) patients and has recently demonstrated good safety and pharmacokinetic properties in healthy volunteers [27].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, ApTOLL has been successfully tested in preclinical models of diseases like ischemic stroke and myocardial infarction, producing an excellent protective effect [14, 60]. In clinical studies, ApTOLL has demonstrated a very good safety profile in a completed First-in-Human clinical trial [27] and it is currently undergoing a Phase Ib/IIa trial (APRIL trial) to determine its safety and biological effect in acute ischemic stroke patients.…”

Section: Introductionmentioning

confidence: 99%

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ApTOLL, a new therapeutic aptamer for cytoprotection and (re)myelination after Multiple Sclerosis

Fernández-Gómez

Marchena

Piñeiro³

et al. 2023

Preprint

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ApTOLL is an aptamer specifically designed to antagonize toll-like receptor 4 (TLR4), which is involved in the innate immunity that promotes inflammatory responses in several diseases, including multiple sclerosis (MS). MS is a chronic, immune, demyelinating and neurodegenerative disease of the central nervous system that represents the second most important cause of neurological disability in young adults. The drugs currently available to treat this disease are immunomodulators and, to date, there are no therapeutic remyelinating drugs available to manage MS. In this study, we show that TLR4 is located in post-mortem cortical lesions of MS patients and as a result, we evaluated the effect of its inhibition by ApTOLL in two different animal models of MS, that of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model. ApTOLL administration ameliorated the clinical symptomatology of the affected mice, which was associated with better preservation and restoration of myelin and oligodendrocytes in the demyelinated lesions of these animals. This revealed not only an immunomodulatory but also a remyelinating effect of the treatment with ApTOLL which was corroborated on purified cultures of rodent and adult human oligodendrocyte precursor cells (OPCs). In summary, the molecular nature of ApTOLL and its mechanism of action strongly supports its further study and use in novel strategies to treat MS and eventually, other demyelinating diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ApTOLL, a new therapeutic aptamer for cytoprotection and (re)myelination after Multiple Sclerosis

Fernández-Gómez

Marchena

Piñeiro³

et al. 2023

Preprint

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“…Drug compounds can simply be conjugated to aptamers via covalent or noncovalent bonding for targeted therapy. Most researchers have discussed the coupling of chemotherapeutic DNA structures to aptamers in their articles, and DOX is one of the most widely used drugs in this context [ 55 ]. Different DNA nanocarriers have been combined with therapeutic molecules that have unique properties.…”

Section: Dna-based Materialsmentioning

confidence: 99%

DNA-Based Nanomaterials as Drug Delivery Platforms for Increasing the Effect of Drugs in Tumors

Shishparenok

Furman

Zhdanov

2023

Cancers

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DNA nanotechnology has significantly advanced and might be used in biomedical applications, drug delivery, and cancer treatment during the past few decades. DNA nanomaterials are widely used in biomedical research involving biosensing, bioimaging, and drug delivery since they are remarkably addressable and biocompatible. Gradually, modified nucleic acids have begun to be employed to construct multifunctional DNA nanostructures with a variety of architectural designs. Aptamers are single-stranded nucleic acids (both DNAs and RNAs) capable of self-pairing to acquire secondary structure and of specifically binding with the target. Diagnosis and tumor therapy are prospective fields in which aptamers can be applied. Many DNA nanomaterials with three-dimensional structures have been studied as drug delivery systems for different anticancer medications or gene therapy agents. Different chemical alterations can be employed to construct a wide range of modified DNA nanostructures. Chemically altered DNA-based nanomaterials are useful for drug delivery because of their improved stability and inclusion of functional groups. In this work, the most common oligonucleotide nanomaterials were reviewed as modern drug delivery systems in tumor cells.

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Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment

et al. 2023

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ImportanceApTOLL is a TLR4 antagonist with proven preclinical neuroprotective effect and a safe profile in healthy volunteers.ObjectiveTo assess the safety and efficacy of ApTOLL in combination with endovascular treatment (EVT) for patients with ischemic stroke.Design, Setting, and ParticipantsThis phase 1b/2a, double-blind, randomized, placebo-controlled study was conducted at 15 sites in Spain and France from 2020 to 2022. Participants included patients aged 18 to 90 years who had ischemic stroke due to large vessel occlusion and were seen within 6 hours after stroke onset; other criteria were an Alberta Stroke Program Early CT Score of 6 to 10, estimated infarct core volume on baseline computed tomography perfusion of 5 to 70 mL, and the intention to undergo EVT. During the study period, 4174 patients underwent EVT.InterventionsIn phase 1b, 0.025, 0.05, 0.1, or 0.2 mg/kg of ApTOLL or placebo; in phase 2a, 0.05 or 0.2 mg/kg of ApTOLL or placebo; and in both phases, treatment with EVT and intravenous thrombolysis if indicated.Main Outcomes and MeasuresThe primary end point was the safety of ApTOLL based on death, symptomatic intracranial hemorrhage (sICH), malignant stroke, and recurrent stroke. Secondary efficacy end points included final infarct volume (via MRI at 72 hours), NIHSS score at 72 hours, and disability at 90 days (modified Rankin Scale [mRS] score).ResultsIn phase Ib, 32 patients were allocated evenly to the 4 dose groups. After phase 1b was completed with no safety concerns, 2 doses were selected for phase 2a; these 119 patients were randomized to receive ApTOLL, 0.05 mg/kg (n = 36); ApTOLL, 0.2 mg/kg (n = 36), or placebo (n = 47) in a 1:1:√2 ratio. The pooled population of 139 patients had a mean (SD) age of 70 (12) years, 81 patients (58%) were male, and 58 (42%) were female. The primary end point occurred in 16 of 55 patients (29%) receiving placebo (10 deaths [18.2%], 4 sICH [7.3%], 4 malignant strokes [7.3%], and 2 recurrent strokes [3.6%]); in 15 of 42 patients (36%) receiving ApTOLL, 0.05 mg/kg (11 deaths [26.2%], 3 sICH [7.2%], 2 malignant strokes [4.8%], and 2 recurrent strokes [4.8%]); and in 6 of 42 patients (14%) receiving ApTOLL, 0.2 mg/kg (2 deaths [4.8%], 2 sICH [4.8%], and 3 recurrent strokes [7.1%]). ApTOLL, 0.2 mg/kg, was associated with lower NIHSS score at 72 hours (mean difference log-transformed vs placebo, −45%; 95% CI, −67% to −10%), smaller final infarct volume (mean difference log-transformed vs placebo, −42%; 95% CI, −66% to 1%), and lower degrees of disability at 90 days (common odds ratio for a better outcome vs placebo, 2.44; 95% CI, 1.76 to 5.00).Conclusions and RelevanceIn acute ischemic stroke, 0.2 mg/kg of ApTOLL administered within 6 hours of onset in combination with EVT was safe and associated with a potential meaningful clinical effect, reducing mortality and disability at 90 days compared with placebo. These preliminary findings await confirmation from larger pivotal trials.Trial RegistrationClinicalTrials.gov Identifier: NCT04734548

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

Cited by 32 publications

References 42 publications

ApTOLL, a new therapeutic aptamer for cytoprotection and (re)myelination after Multiple Sclerosis

ApTOLL, a new therapeutic aptamer for cytoprotection and (re)myelination after Multiple Sclerosis

DNA-Based Nanomaterials as Drug Delivery Platforms for Increasing the Effect of Drugs in Tumors

Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment

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