Promising Results for TLR4 Antagonist Therapy Combined with EVT for Ischemic Stroke

According to a recent presentation at the International Stroke Conference 2023, administering ApTOLL, a TLR4 antagonist, along with endovascular therapy (EVT) in individuals diagnosed with ischmemic stroke is safe and was associated with reduced mortality and disability in a clinical study. After 72 hours post-stroke, individuals assigned to take the highest dose of ApTOLL experienced significant reductions in both the estimated volume of damaged brain tissue (-29.31 mL, 90% CI -49.28 to -9.34) and National Institutes of Health Stroke Scale (NIHSS) scores (–3.94; 90% CI, –6.86 to –1.02). After 90 days, those who had received the higher dose of ApTOLL had a lower death rate when compared with those taking the placebo (5% vs 17%, respectively) and had reduced brain edema and hemorrhagic transformation as well as reduced disability according to modified Rankin Scale scores (mRS shift: common OR: 0.41, 90% CI 0.20--0.85).

The APRIL phase 1b/2a trial (NCT04734548,) was a prospective, multicenter, double-blind, randomized, placebo-controlled trial which enrolled 151 adults In France and Spain, aged 18 to 90, with confirmed large vessel occlusion who were candidates for reperfusion therapy. In phase 1b, 32 participants were assigned to 4 different doses of ApTOLL from which 2 optimal doses were selected based on safety criteria to be used in phase 2a. In phase 2a, 119 participants were randomly assigned to receive either 0.05 mg/kg of ApTOLL, 0.2 mg/kg of ApTOLL, or placebo within 6 hours of onset of stroke along with standard EVT and iv-tPA, if indicated.

“The results are promising because for the first time a medicine studied as a neuroprotectant demonstrated not only a biological benefit by reducing the volume of damaged brain tissue, but also a reduction in long term disability and risk of death,” stated study senior author Marc Ribó, M.D., interventional neurologist at Hospital Vall d’Hebron in Barcelona, Spain.

ApTOLL is a novel TLR4 antagonist currently being studied for use in a number of diseases where the inflammatory response is involved, including myocardial infarction and ischemic stroke.