Novel TLR4 Antagonist ApTOLL Shows Promising Results In Combination Therapy For Ischemic Stroke

A recent study published in JAMA Neurology has revealed the potential of a new therapeutic approach for treating acute ischemic stroke. The study, conducted across multiple sites in Spain and France, investigated the safety and efficacy of a TLR4 antagonist called ApTOLL when used in combination with endovascular treatment (EVT).

Ischemic stroke, caused by a blockage in a blood vessel supplying the brain, is a leading cause of death and disability worldwide. Time is of the essence in stroke treatment, as the sooner interventions are initiated, the better the chances of recovery. Current treatments involve the restoration of blood flow to the affected area through EVT and, if applicable, intravenous thrombolysis.

The phase 1b/2a clinical trial, a double-blind, randomized, placebo-controlled study conducted by Macarena Hernández-Jiménez and team of researchers, enrolled patients aged 18 to 90 years who had experienced an ischemic stroke due to large vessel occlusion. Participants were required to present within 6 hours after the onset of stroke symptoms and meet specific inclusion criteria. In total, 4174 patients underwent EVT during the study period.

The trial consisted of two phases. In phase 1b, different doses of ApTOLL (0.025, 0.05, 0.1, or 0.2 mg/kg) or placebo were administered to 32 patients, with a focus on evaluating safety. Phase 2a further investigated two selected doses, 0.05 and 0.2 mg/kg, in 119 patients randomized to receive ApTOLL or placebo in combination with EVT and, if needed, intravenous thrombolysis.

The primary objective of the study was to assess the safety of ApTOLL based on specific outcomes, including death, symptomatic intracranial haemorrhage, malignant stroke, and recurrent stroke. Secondary efficacy measures included final infarct volume, neurological status assessed by the NIHSS score, and functional disability evaluated using the modified

Rankin Scale (mRS) score at 90 days.

● Results from the trial showed that the administration of ApTOLL at a dose of 0.2 mg/kg within 6 hours of stroke onset, alongside EVT, was well-tolerated and demonstrated a potential clinical benefit.

● Compared to the placebo group, patients receiving the higher dose of ApTOLL experienced a lower NIHSS score at 72 hours, indicating improved neurological status.

● They exhibited smaller final infarct volumes and lower levels of disability at the 90-day mark.

● The primary endpoint analysis revealed that the incidence of adverse events, including death, symptomatic intracranial haemorrhage, malignant stroke, and recurrent stroke, was reduced in patients treated with ApTOLL, 0.2 mg/kg, compared to the placebo group.

These preliminary findings offer promising insights into the potential of ApTOLL as an adjunctive therapy for acute ischemic stroke. However, larger pivotal trials are necessary to confirm and validate these results.

These promising results from the ApTOLL clinical trial represent a significant advancement in the field of stroke treatment. If subsequent studies validate these findings, ApTOLL could potentially revolutionise the management of acute ischemic stroke and contribute to improved patient outcomes worldwide.

Reference:

Hernández-Jiménez, M., Abad-Santos, F., Cotgreave, I., Gallego, J., Jilma, B., Flores, A., Jovin, T. G., Vivancos, J., Hernández-Pérez, M., Molina, C. A., Montaner, J., Casariego, J., Dalsgaard, M., Liebeskind, D. S., Cobo, E., Castellanos, M., Portela, P. C., Masjuán, J., Moniche, F., … Ribo, M. (2023). Safety and efficacy of ApTOLL in patients with ischemic stroke undergoing endovascular treatment: A phase 1/2 randomized clinical trial. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2023.1660.