Neuroprotective Effects of ApTOLL, a TLR4 Receptor Angatonist for Treating Ischemic Stroke

and 2023 International Stroke Congress (ISC)held February 8-10 in Dallas, Texas. Published findings From a double-blind, randomized, controlled phase 1a/2b trial evaluating the investigational drug ApTOLL and endovascular therapy (EVT) in patients with acute ischemic stroke. This trial focused on patients with confirmed large vessel occlusion who were candidates for reperfusion therapy, including EVT, with or without intravenous recombinant tissue plasminogen activator.

In Phase 1b of the study, four escalating doses of treatment (0.025, 0.05, 0.1, and 0.2 mg/kg) were evaluated compared to placebo to identify the optimal dose for Phase 2a. I was. The Safety Monitoring Board selected doses of 0.05 mg/kg and 0.02 mg/kg for Phase 2a and subsequently evaluated 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 his ApTOLL group at 0.2 mg/kg, at 4.76%, and researchers observed rates of 22.5% and 16.98% in the 0.05 mg/kg and placebo groups, respectively.1

ApTOLL, a TOLL-like receptor 4 (TLR4) antagonist, continued to show other notable findings such as reduced cerebral edema and hemorrhagic transformation. At a dose of 0.2 mg/kg, administered within 6 hours of stroke onset, this therapy reduced stroke 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, the researchers, Macarena Hernandez, Ph.D., Professor, Neurovascular Research Unit, University of Complutense and Marc Ribo, M.D., Interventional Neurologist, Val de Blon University Hospital, answered a few questions. I was. The duo discusses why his ApTOLL’s ability to affect several different aspects of the brain makes it a promising treatment for ischemic stroke, and why the industry should continue to investigate agents that offer neuroprotection to patients. provided insight.

NeurologyLive®: Does ApTOLL’s mechanism of action make it a promising therapy for treating acute ischemic stroke?

Dr. Macarena Hernandez: ApTOLL is a novel entity of a molecule, an oligonucleotide that acts like an antibody. It can specifically bind to one target and antagonize its action. In this particular case, ApTOLL binds to her TLR4 receptor and this binding inhibits its action. The TRL4 receptor is involved in the deinflammatory response after ischemic stroke. All of these actions aim to inhibit TLR4 and reduce inflammation to reduce infarct volume and improve functional outcomes in patients.

Given that the high dose is significantly superior to the low dose and placebo, are there potential opportunities for even larger dose sizes in future investigations?

Mark Ribo, M.D.: Following the results of the Phase 2 trial, a confirmatory pivotal study is planned that will ultimately lead to regulatory indications for treatment. One of the questions we ask ourselves is should we go further and test even higher doses? I have had very good results with a dose of 0.2 mg/kg, so this is debatable, but higher doses may have even better results. is not.

Do you have any ideas on how to conduct the Phase 3 trial?

Mark Ribo, M.D.: This is still an ongoing debate. We hope to start this trial in the fourth quarter of this year. We’re planning a design now, and it will probably be very similar to what we did in the Phase 2 trial. But again, there may be some minor differences, such as additional doses, different inclusion criteria, etc. is to prepare to start

Which of the results you observed stood out the most?

Mark Ribo, M.D.: What we were very happy to see and discover is that there is a whole story to this, not just the positive results observed for one specific endpoint. Indeed, a positive trend was observed with reduced infarct volume on MRI, fewer symptomatic or asymptomatic hemorrhagic changes, reduced neurological deficits in the early phase at 72 hours, and less disability at 90 days. was observed. Finally, and very importantly, a reduction in mortality was observed. It’s not just a single piece, it’s like a whole continuum. This supports the theory that the drug has potent biological effects.

Do you feel there is a significant unmet need in the stroke field?

Dr. Macarena Hernandez: We believe that new opportunities are now opening up to develop neuroprotective agents in combination with reperfusion therapy. We are adding to the current standard of care for our patients. Of course, we believe that this will serve as an opportunity for each research group to focus on the development of such drugs.

Edited transcript for clarity. click here Find out more about ISC 2023 here.

reference
1. Hernandez M, Cotgreave I, Gallego J, et al. A double-blind, placebo-controlled, randomized, phase 1b/2a clinical trial of His ApTOLL for the treatment of acute ischemic stroke. Presentation location: 2023 International Stroke Congress. February 8-10. Dallas, Texas. LB2.