Neuroprotective Effects of ApTOLL, TLR4 Receptor Angatonists to Treat Ischemic Stroke

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Investigators Macarena Hernandez, PhD, and Marc Ribo, MD, provided commentary on positive phase 2a findings assessing ApTOLL in combination with EVT in patients with ischemic stroke.

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

Marc Ribo, MD

At the 2023 International Stroke Conference (ISC), held February 8-10, in Dallas, Texas, investigators presented findings from a double-blind, randomized controlled, phase 1a/2b study assessing the investigational agent ApTOLL together with endovascular therapy (EVT) in patients with acute ischemic stroke. The trial focused on those with confirmed large vessel occlusion who were candidates for reperfusion therapies including EVT with or without intravenous recombinant tissue plasminogen activator.

In phase 1b of the study, 4 ascending doses of the therapy were assessed (0.025, 0.05, 0.1, and 0.2 mg/kg), in comparison with a placebo group, to identify the most optimal dosages for phase 2a. A safety monitoring board selected the 0.05 mg/kg and 0.02 mg/kg doses for phase 2a, which were then assessed in a cohort of 119 patients (0.05 mg/kg, n = 36; 0.2 mg/kg, n = 36; placebo, n = 47). After 90 days, the number of deaths was lowest in the 0.2 mg/kg ApTOLL group, with 4.76%, while investigators observed rates of 22.5% and 16.98% for the 0.05 mg/kg and placebo groups, respectively.1

Macarena Hernandez, PhD, professor, Neurovascular Research Unit, Complutense University

Macarena Hernandez, PhD

ApTOLL, a TOLL-like receptor 4 (TLR4) antagonist, continued to show other notable findings, including reduced brain edema and hemorrhagic transformation. At doses of 0.2 mg/kg, the therapy, which was administered within 6 hours of onset of stroke, reduced brain infarct volume (–29.31 cc, 90% CI, –49.28 to –9.34) and National Institutes of Health Stroke Scale score (–3.94; 90% CI, –6.86 to –1.02).

Following their presentation, investigators Macarena Hernandez, PhD, professor, Neurovascular Research Unit, Complutense University, and Marc Ribo, MD, interventional neurologist, University Hospital Vall d’Hebron, answered a few questions. The duo provided insight on why ApTOLL’s ability to impact several different aspects of the brain make it a promising therapy for ischemic stroke, as well as why the industry should continue to investigate agents that offer neuroprotective effects to patients.

NeurologyLive®: What about ApTOLL’s mechanism of action makes it a promising therapy for treating for treating acute ischemic stroke?

Macarena Hernandez, PhD: ApTOLL is a new entity of molecules, an oligonucleotide that acts that like an antibody. It’s able to bind specifically to one target and antagonize its action. In this specific case, ApTOLL binds to TLR4 receptor, and with this binding, inhibits its action. The TRL4 receptor is involved in deinflammatory response after ischemic stroke. With all this action, we aim to inhibit TLR4, inhibit inflammation, and thus reduce infarct volumes of patients and improving functional outcomes.

Considering that the higher dose significantly outperformed the low dose and the placebo, could there be potential opportunities for an even greater dose size in future investigations?

Marc Ribo, MD: After the results of the phase 2 trial, we're planning a confirmatory pivotal trial that will eventually lead to the indication for treatment by a regulatory agency. One of the questions we are asking ourselves is, should we go further and test an even higher dose? This is under debate, because we had very good results with the 0.2 mg/kg dose, but it is possible that it could be even better with higher dose. I don't currently have the answer for that.

Do you have any ideas as to how you’d conduct the phase 3 trial?

Marc Ribo, MD: This is still under debate these days. We are planning to start this trial hopefully in last quarter of this year. We are currently planning be the design but it’s probably going to be very similar to what we did with the phase 2 trial. But again, there might be some slight differences, like an additional dose, different inclusion criteria. But our plan is to finalize the protocol in the next week, and get ready to start the study in September, hopefully.

Among the results you observed what stood out the most?

Marc Ribo, MD: What we were very happy to see and discover is that there is a whole story behind this. We did not only observe a positive result in one specific endpoint. The fact is that we observed a reduction in the infarct volume on MRI, we observed a nice trend towards less hemorrhagic transformation, either symptomatic or asymptomatic, a reduced neurological deficit in the early phase at 72 hours, and less disability at 90 days. Finally, very important, we observed a reduction in the mortality. It's not only single pieces, but also like a whole continuum. That reinforces the theory that we are having a strong biological effect of the drug.

Is there anything in the stroke field that you feel is a significant unmet need?

Macarena Hernandez, PhD: We think now we are opening up new opportunities to develop neuroprotective drugs in combination with reperfusion therapy. We are adding to the current standard of care of patients. Of course, we think this is an opportunity to encourage all the research groups to start putting effort in developing these kinds of drugs.

Transcript edited for clarity. Click here for more coverage of ISC 2023.

REFERENCE
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.
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