Neuroprotective agent linked to reduced death and disability in ischaemic stroke trial

aptoll isc 2023
Marc Ribó presenting at ISC 2023

ApTOLL, a neuroprotectant medication intended to shield the brain from tissue damage, has been linked to reduced death and disability when used alongside standard treatments to restore blood flow in ischaemic stroke patients. That is according to preliminary late-breaking data presented at the American Stroke Association’s (ASA) ongoing International Stroke Conference (ISC; 8–10 February 2023, Dallas, USA).

“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,” said study senior author and principal investigator Marc Ribó (Hospital Vall d’Hebron, Barcelona, Spain), who presented these findings at ISC 2023.

In the APRIL Phase 1b/2a trial—a double-blind, placebo-controlled, randomised study—researchers investigated the neuroprotective medication ApTOLL, which is a TOLL-like receptor 4 (TLR4) antagonist involved in immune responses that also responds to tissue damage.

Previous studies in animals have found that ApTOLL reduced inflammation and protected brain tissue from damage. Additionally, a first-in-human study in healthy adults did not find safety issues associated with ApTOLL.

In the recent APRIL trial, Ribó and colleagues set out to assess whether this intravenous neuroprotective agent could improve outcomes among stroke patients who also received standard treatment. From July 2021 to April 2022, more than 150 adults diagnosed with acute ischaemic stroke (average age=70 years) treated in 15 hospitals across France and Spain were randomly assigned to receive either 0.05mg/kg of ApTOLL, 0.2mg/kg of ApTOLL, or a placebo.

Within six hours of symptom onset, all participants received a mechanical thrombectomy procedure to restore blood flow to the brain. Study participants may also have received an intravenous tissue plasminogen activator (IV-tPA), if needed, to help dissolve the clot causing their stroke.

The primary endpoint was to assess ApTOLL’s safety based on four variables—death, symptomatic intracranial haemorrhage, malignant stroke, and recurrent stroke—while the secondary, efficacy-related endpoints included the final infarct volume after 72 hours; US National Institutes of Health Stroke Scale (NIHSS) score at 72 hours; and modified Rankin Scale (mRS) score at 90 days.

Key findings from the APRIL trial include:

  • The higher ApTOLL dose showed a neuroprotective effect while the lower dose did not show any effect compared to placebo
  • Ninety days after treatment, death rates among participants who received the higher dose of ApTOLL were more than four times lower compared to those who received placebo (4% vs 18%, respectively)
  • Imaging tests given 72 hours after treatment showed that the size of damaged brain tissue—the final infarct volume—was reduced by 40% among the participants who received the higher dose of ApTOLL compared to the placebo group
  • High-dose ApTOLL also achieved statistical significance in improving NIHSS scores at 72 hours
  • Sixty-four percent of participants who received the higher dose of ApTOLL were free of disability (mRS 0–2) at 90 days, compared to 47% of those in the placebo group

“ApTOLL did not show any interactions with the drugs that are administered for ischaemic stroke, meaning that it could be administered to most patients”, Ribó added.

“If the results are confirmed with larger studies, it will mean that we can effectively treat patients with neuroprotectants, in addition to current standard treatments to restore blood flow,” said co-lead author Macarena Hernández-Jiménez, chief scientific officer at AptaTargets—the company developing ApTOLL—who presented these data alongside Ribó at ISC. “Both kinds of treatments may be combined, and neuroprotectants will buy time, reducing brain damage until blood flow is restored.”

As per a press release from AptaTargets, these findings represent the first time a TLR4 antagonist neuroprotectant has achieved positive efficacy endpoints in an acute ischaemic stroke trial. ApTOLL has also shown promising preclinical results in haemorrhagic stroke and multiple sclerosis, the company claims.

While APRIL researchers have highlighted its small number of participants as a potential limitation of the trial, larger studies are currently in the planning stages—including two new Phase 2a trials: the RaceToll trial, where ApTOLL is administered to patients with suspected stroke in ambulances, and the ApSTEMI trial assessing the effects of ApTOLL in acute myocardial infarction.


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