Safety, Tolerability, and Pharmacokinetics of the Neuroprotectant 2-Iminobiotin in Patients With Large-Vessel Occlusion Ischemic Stroke Treated With Endovascular Thrombectomy

Abstract

Background: 2-Iminobiotin (2-IB) is a biotin analog with neuroprotective properties. It selectively inhibits neuronal and inducible nitric oxide synthase. The primary objective of this study was to assess the safety, tolerability, and pharmacokinetics of 2-IB in patients with ischemic stroke due to large-vessel occlusion treated with endovascular thrombectomy. The secondary objective was to investigate preliminary efficacy.

Methods: In this single-center, randomized, placebo-controlled phase 2a study, patients received continuous infusion of 2-IB or placebo for 24 hours. The primary outcome was safety and tolerability measured by vital parameters and pharmacokinetic parameters in the first 28 hours after treatment and serious adverse events up until 7 days. Secondary and additional outcomes included National Institutes of Health Stroke Scale score and infarct volume at 24 to 48 hours, mortality at 90 days, and (baseline-prognosis adjusted) modified Rankin Scale score at 90 days.

Results: In the modified intention-to-treat population, 40 patients were randomized, 20 per treatment group. Median age was 76 (interquartile range [IQR], 66-82) years and 40% were female. Baseline characteristics were similar between groups. Vital parameters during treatment did not differ between groups. In total, 17 serious adverse events occurred, 6 (30%) in 2-IB and 11 (55%) in placebo. Median 2-IB exposure (AUC_{avg_4 h}) was 320 (IQR, 243-395) ng h/mL. Median National Institutes of Health Stroke Scale score at 7 days was 3 (IQR, 1-11) in 2-IB and 3 (IQR, 0-16) in placebo. Median infarct volume at 24 to 48 hours was 12.5 (IQR, 8.4-60.5) mL versus 13.7 (IQR, 4.0-94.5) mL. Median modified Rankin Scale at 3 months was 3 (IQR, 1-3) in the 2-IB group versus 3 (2-6) in placebo-treated patients. Mortality was 15% (3/20) in 2-IB versus 40% (8/20) in placebo.

Conclusions: In patients with ischemic stroke with large-vessel occlusion treated with endovascular thrombectomy, 2-IB is safe and well tolerated. Pharmacokinetic parameters could be predicted well. The efficacy of 2-IB needs to be investigated further in a phase 2b/3 clinical trial.

Registration: URL: www.onderzoekmetmensen.nl; Unique identifier: NL-OMON51194.

Keywords: 2-iminobiotin; Netherlands; ischemic stroke; nitric oxide synthase; stroke.