Combination of Higher Dose ApTOLL and EVT Reduces Mortality and Disability in Ischemic Stroke


At the conclusion of the trial, treatment with 0.2 mg/kg of ApTOLL with EVT resulted in reduced brain edema and hemorrhagic transformation, as well as fewer deaths than placebo and 0.05 mg groups.

Marc Ribo, MD, interventional neurologist, University Hospital Vall d’Hebron

Marc Ribo, MD

Findings from a phase 2a study (NCT04734548) assessing ApTOLL in patients presenting with ischemic stroke showed that use of the TOLL-like receptor 4(TLR4) antagonist at doses of 0.2 mg/kg within 6 hours of onset in combination with endovascular treatment (EVT) was safe, and associated with reduced mortality and disability at 90 days.1

These findings, presented as late-breaker at the 2023 International Stroke Conference (ISC), held February 8-10, in Dallas, Texas, provided support for larger phase 3 trials to confirm the agent’s effect. In the final cohort of 119 patients, those on ApTOLL 0.2 mg/kg accounted for the lowest proportion of deaths at 90 days (4.76%), followed by the placebo group (16.98%), and the 0.05 ApTOLL group (22.5%).

"We are now opening an opportunity to develop neuroprotective drugs in combination with reperfusion therapy," lead investigator Macarena Hernandez, PhD, professor, Neurovascular Research Unit, Complutense University, told NeurologyLive®. "We are adding to the current standard of care of patients. Of course, we think this is an opportunity to encourage all research groups to start putting effort into developing these kinds of drugs."

In the original phase 1b portion of the trial, 32 patients aged 18 to 90 years with large vessel occlusion (LVO) were assigned to 4 ascending doses of ApTOLL at 0.025, 0.05, 0.1, and 0.2 mg/kg, There were 6 patients on study drug and 2 patients on placebo in each group to assess which dose performed better, thus moving it into the phase 2a portion of the trial. Patients had Alberta Stroke Program Early CT Score (ASPECTS) scores between 5 and 10, and estimated infarct core volume on CT-perfusion that was between 5 and 70 ml.

At the conclusion of phase 1b, investigators moved the 0.05 and 0.2 ApTOLL dose groups forward for further evaluation, this time in a larger sample size. In addition to performing better the primary outcome of death, those in the higher dose ApTOLL group showed reduced brain edema and hemorrhagic transformation at 90 days. At 72 hours poststroke, those on 0.2 ApTOLL showed reduced mean infarct volume (–29.31cc, 90% CI, –49.28 to –9.34), and National Institutes of Stroke Scale (NIHSS) severity score (–3.94; 90% CI, –6.86 to –1.02). Additonally, this group showed better outcomes on disability at 90 days, demonstrated by shift in modified Rankin Scale score (OR, 0.41; 90% CI, 0.20-0.85).

Regarding the numerous positive outcomes with the higher dose group, senior investigator Marc Ribo, MD, interventional neurologist, University Hospital Vall d’Hebron, told NeurologyLive®, "It’s not only single pieces, it’s like a whole continuum. That reinforces the theory that we are having a strong biological effect of the drug."

ApTOLL, a TLR4 antagonist, had shown preclinical neuroprotective effect in healthy volunteers. Hernandez added, "It [ApTOLL] is a new entity of molecules, an oligonucleotide, that acts like an antibody. It binds specifically to one target and will antagonize. In this specific case, it binds TLR4 receptor, and with this binding it inhibits its action. The TRL4 receptor is involved in deinflammatory response after ischemic stroke. With all this action, we aim to inhibit inflammation, reduce infarct volumes in patients, and improve functional outcomes."

The first-in-human dose-ascending trial of ApTOLL was published in early 2022, and included 46 healthy adult male volunteers. It consisted of 2 parts: part A, which included 7 single ascending dose levels, and part B, which had 1 multiple dose cohort. Following 30 min intravenous infusion, there were no serious adverse events or biochemistry alterations observed at any of the doses followed nor at any administration pattern studies.2

Click here for more coverage of ISC 2023.

1. Hernandez M, Cotgreave I, Gallego J, et al. A double-blind, placebo-controlled, randomized, phase 1b/2a clinical study of ApTOLL for the treatment of acute ischemic stroke. Presented at: 2023 International Stroke Conference; February 8-10; Dallas, TX. LB2.
2. Hernandez-Jimenez M, Martin-Vilchez S, Ochoa D, et al. First-in-human phase 1 clinical trial of a TLR4 binding DNA aptamer, ApTOLL: safety and pharmacokinetics in healthy volunteers. Mol Ther Nucleic Acids. 2022; 28:124-135. doi:10.1016/j.0tm.2022.03.005.
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