Anti-Inflammatory Thrombolytic JX10 (TMS-007) in Late Presentation of Acute Ischemic Stroke

Abstract

Background: Contemporary thrombolytics in acute ischemic stroke are limited to administration within 4.5 hours of last known normal. JX10 (formerly TMS-007), a Stachybotrys microspora triprenyl phenol family member, may extend this therapeutic window.

Methods: In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation phase 2a study, JX10 or placebo was administered as a single intravenous infusion to Japanese patients with acute ischemic stroke who were unable to receive tissue-type plasminogen activator or thrombectomy within 12 hours of last known normal. Primary end point was incidence of symptomatic intracranial hemorrhage with a worsening National Institutes of Health Stroke Scale score of ≥4 points within 24 hours of drug administration (symptomatic intracranial hemorrhage incidence).

Results: Ninety patients received either placebo (n=38; female 26.3%) or JX10 at 1, 3, or 6 mg/kg (n=6, 18, 28; female 0%, 33.3%, and 42.9%, respectively). Median age (range) and baseline median (range) National Institutes of Health Stroke Scale scores were respectively 76.5 (42-87) and 8 (6-21) for the combined JX10 cohort (JX10 Cohorts) and 75.0 (34-85) and 8 (6-22) for placebo. Median (range) dosing time since last known normal was 9.5 (5.0-12.1) and 10.0 (3.7-12.0) hours for JX10 Cohorts and placebo, respectively. Symptomatic intracranial hemorrhage incidence was 0% (0/52 [95% CI, 0.0-5.6]) for JX10 Cohorts versus 2.6% (1/38 [95% CI, 0.1-13.8]) for placebo (P=0.42). Vessel patency at 24 hours (secondary end point) in patients with baseline arterial occlusive lesion score <3 (39/90) improved in 58.3% (14/24) of patients in JX10 Cohorts versus 26.7% (4/15) for placebo (odds ratio, 4.23 [95% CI, 0.99-18.07]). In JX10 Cohorts, a significantly higher proportion of patients had modified Rankin Scale scores of 0 to 1 on day 90 (secondary end point) versus placebo (JX10: 21/52, 40.4% versus placebo: 7/38, 18.4%; P=0.03).

Conclusions: JX10 was well tolerated and may expand the acute ischemic stroke therapeutic window as a novel thrombolytic agent.

Registration: URL: https://rctportal.niph.go.jp/en; Unique identifier: jRCT2080223786.

Keywords: Stachybotrys; fibrinolytic agents; infusions, intravenous; intracranial hemorrhages; ischemic stroke.

Figure 1.

Trial profile. PD indicates pharmacodynamic; PK, pharmacokinetic; and PP, per protocol.

Figure 2.

Modified Rankin Scale (mRS) outcome on day 90.

Figure 3.

Recanalization of the occluded cerebral vessels. A, Recanalization of occluded cerebral vessels (patients with arterial occlusive lesion [AOL] score <3 for ≥1 vessel territory at baseline). B, Thirty-seven-year-old male patient with occlusion of left insular part (M2 segment) of middle cerebral artery (M2), National Institutes of Health Stroke Scale (NIHSS) score 21 (severe), randomized to JX10 1 mg/kg cohort. Time to treatment: 10.5 hours poststroke. T2 fluid-attenuated inversion recovery magnetic resonance imageries (MRIs) at baseline and 24 hours show stable infarct in the left inferior M2 division. C, Seventy-eight-year-old male patient with occlusion of right cortical part (M3 segment) of middle cerebral artery, NIHSS score 9, randomized to JX10 3 mg/kg cohort. Time to treatment: 8.5 hours poststroke. Diffusion-weighted MRIs at baseline and 24 hours show stable infarction in right posterior frontal area. MRA indicates magnetic resonance angiography; mRS, modified Rankin Scale; and OR, odds ratio. *AOL score <3 for at least 1 vessel territory. †Any improvement in AOL score. ‡Logistic regression model with treatment and status of clinical imaging mismatch (binary variable based on the criteria of Nogueira et al [2018]) as a covariate.