☆ 4.6 Article

APRIL: A double-blind, placebo-controlled, randomized, Phase Ib/IIa clinical study of ApTOLL for the treatment of acute ischemic stroke

FRONTIERS IN NEUROLOGY (2023)

Journal

FRONTIERS IN NEUROLOGY

Volume 14, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA

DOI: 10.3389/fneur.2023.1127585

Keywords

clinical trial; stroke; aptamer; inflammation; neuroprotection; ApTOLL; TLR4

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Abstract

In the reperfusion era, the combination of endovascular treatment (EVT) and neuroprotective drugs, such as ApTOLL, is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). ApTOLL, a Toll-like receptor 4 (TLR4) antagonist, has shown neuroprotective effects in preclinical models and has a favorable pharmacokinetic and safety profile. This clinical trial, called APRIL, aims to assess the tolerability, safety, pharmacokinetics, and biological effect of ApTOLL in AIS patients eligible for EVT.

In the reperfusion era, a new paradigm of treating patients with endovascular treatment (EVT) and neuroprotective drugs is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). In this context, ApTOLL, a Toll-like receptor 4 (TLR4) antagonist with proven neuroprotective effect in preclinical models of stroke and a very good pharmacokinetic and safety profile in healthy volunteers, is a promising first-in-class aptamer with the potential to address this huge unmet need. This protocol establishes the clinical trial procedures to conduct a Phase Ib/IIa clinical study (APRIL) to assess ApTOLL tolerability, safety, pharmacokinetics, and biological effect in patients with AIS who are eligible for EVT. This will be a multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to evaluate the administration of ApTOLL together with EVT in patients with AIS. The study population will be composed of men and non-pregnant women with confirmed AIS with a < 6h window from symptoms onset to ApTOLL/placebo administration. The trial is currently being conducted and is divided into two parts: Phase Ib and Phase IIa. In Phase Ib, 32 patients will be allocated to four dose ascending levels to select, based on safety criteria, the best two doses to be administered in the following Phase IIa in which 119 patients will be randomized to three arms of treatment (dose A, dose B, and placebo).

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Role of TLR4 in Neutrophil Dynamics and Functions: Contribution to Stroke Pathophysiology

Violeta Duran-Laforet, Carolina Pena-Martinez, Alicia Garcia-Culebras, Maria Isabel Cuartero, Eng H. Lo, Maria Angeles Moro, Ignacio Lizasoain

Summary: The absence of TLR4 in neutrophils leads to smaller infarct volumes after ischemic stroke. TLR4-lacking neutrophils remain in a steady youth status and show higher phagocytic activity, preferential engulfment by microglia, and reduced production of ROS in the initial stages of inflammation post-stroke. These findings suggest that targeting TLR4 in specific cell types, especially neutrophils, may be a potential strategy for neuroprotection.

FRONTIERS IN IMMUNOLOGY (2021)