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DALLAS -- A novel anti-inflammatory aptamer given within 6 hours of ischemic stroke onset for patients undergoing mechanical thrombectomy appeared safe, and even had a mortality advantage along with a signal for reduced morbidity.

In a phase Ib/IIa trial, the drug, dubbed ApTOLL, reduced 90-day mortality to 4.76% at the higher, 0.2-mg/kg dose tested in the trial, compared with 18.18% in the placebo group and 26.19% in the lower-dose ApTOLL group that got 0.05 mg/kg, according to Marc Ribó, MD, PhD, of Hospital Vall d'Hebron in Barcelona and chief medical officer for drug developer AptaTargets.

That significant difference (OR 0.225, 90% CI 0.060-0.845) didn't come with an increase in symptomatic intracranial hemorrhage (4.76% at the higher dose and 7.14% with the lower dose vs 7.27% with placebo), he reported at the American Stroke Association (ASA) International Stroke Conference.

Among secondary endpoints in the trial, infarct volume was similar at baseline across groups but significantly lower at 72 hours by FLAIR criteria in the ApTOLL 0.2 mg/kg group compared with placebo (P=0.0434). NIH Stroke Scale (NIHSS) score, likewise, was similar at baseline but lower at 72 hours in the lower-dose ApTOLL group (P=0.0127).

The likelihood of a shift to less disability on the modified Rankin Scale score was significant for the 0.2-mg/kg dose (OR 2.61, 90% CI 1.27-5.35), according to Ribó and colleagues.

"We are very excited, because for the first time a neuroprotection study for acute stroke patients showed positive results in the primary outcome, which was safety," Ribó told 乌鸦传媒視頻 in a conversation monitored by American Heart Association (AHA)/ASA media relations personnel.

Over the past several decades, "we have seen in so many failures in this field in neuroprotection for stroke; it was kind of disappointing," he noted.

But a new era in neuroprotection appears to be on the horizon, because mechanical thrombectomy turns the stroke into transient ischemia, he said. "Maybe failure before with other molecules was due to the fact that patients never reperfused. Therefore even if there was some kind of effect, since reperfusion never occurred, this effect was overcome by the absence of reperfusion."

While exciting to have a drug that might work, Mitchell Elkind, MD, MPhil, of Columbia University Irving Medical Center in New York City, pointed to the small, early-phase study design. "As we've seen before, we have to be cautious," noted Elkind, who also is AHA chief clinical science officer.

Nevertheless, he said the takeaway was positive. "Neuroprotection is not dead, and we just need to keep pushing. These things always take time. It took a while to prove that thrombectomy works, and now we all take it for granted. So I think there's hope on the horizon," stated Elkind, who was not involved in the study.

Ribó called for a larger pivotal trial, but agreed that neuroprotection "is very alive and kicking, and we're one step closer to use it routinely."

ApTOLL is comprised of a short segment of single-strand, synthetic DNA that acts like an antibody against the Toll-like receptor 4 (TLR4), which is involved in the innate immune response and part of the inflammatory cascade after ischemic stroke.

Receptors in this family have been investigated in cardiovascular medicine more broadly, Elkind noted. "Mutations in Toll-like receptors seem to influence risk of atherosclerosis and cardiovascular events, so I think this drug doesn't come out of nowhere. Hopefully, it will pan out in other studies."

This agent might be advantageous compared with prior anti-inflammatory agents tried for neuroprotection in ischemic stroke because of its shorter half-life, around 13 hours, which avoided an impact on infection or immunosuppression in the trial, suggested Macarena Hernández, PhD, AptaTargets chief scientific officer.

The APRIL trial included adults (average age 70) treated in 15 hospitals in France and Spain. A 32-patient dose-escalation phase showed safety and pointed to the better doses among those tested from 0.025 mg/kg to 0.2 mg/kg. Phase II added 42 patients randomly assigned to 0.05 mg/kg of ApTOLL, 42 assigned to 0.2 mg/kg of ApTOLL, and 55 randomized to placebo. The trial was done from July 2020 to April 2022, "during the worst months of the COVID-19 pandemic," Ribó noted.

Brain edema was numerically but not significantly less common with ApTOLL than placebo (2.4% low-dose and 4.8% high-dose vs 7.3%). Recurrent stroke or transient ischemic attack was numerically but not significantly more common in the ApTOLL groups (7.1%, 4.8%, and 3.7%, respectively).

Enrollment criteria included patients with large vessel occlusion who got endovascular thrombectomy within 6 hours after stroke onset, and who had a baseline modified Rankin Scale score no more than 2, along with CT perfusion predicted infarct core of 5-70 mL, and NIHSS score greater than 8 and no more than 25 (median 17-19 across groups).

The drug was administered as a 30-minute infusion, initiated before groin puncture, which would work for the typical patient flow, suggested Elkind: "It always takes a little while to get thrombectomy up and running."

This homogeneous group was selected as the group most likely to benefit, Ribó told 乌鸦传媒視頻. "The objective is to secure the indication in this, let's say, limited profile of patients, and from there progressively expand to other patients in the later time window, for posterior circulation, for example, or large vessel occlusions or large cores on admission -- other populations in which there might still be an effect, but it would not be so obvious initially."

The drug also is being investigated for prehospital use, given the good safety profile, he added.

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