PDF: JX10 TMS-007
(2024)Objective
JX10 (TMS-007) vs placebo — to evaluate safety and efficacy of a novel anti-inflammatory thrombolytic with dual action (plasminogen conformational change + soluble epoxide hydrolase inhibition) in Japanese AIS patients unable to receive tPA or thrombectomy within 12 hours of symptom onset.
Study Summary
• 90-day mRS 0-1 achieved in 40.4% JX10 vs 18.4% placebo (aOR 3.34, 95% CI 1.11-10.07; p=0.03).
• Vessel recanalization at 24 h in patients with occlusion: 58.3% JX10 vs 26.7% placebo (OR 4.23, 95% CI 0.99-18.07).
• Median treatment time 9.5 hours after last known normal — well beyond the 4.5-hour tPA window.
• No significant changes in plasma fibrinogen, α2-antiplasmin, or dihydroxyeicosatrienoic acid — suggesting localized rather than systemic fibrinolysis.
• AEs comparable to placebo; novel dual-action thrombolytic positioned for phase 2b/3 evaluation.
Intervention
Single IV infusion of JX10 (formerly TMS-007) at 1, 3, or 6 mg/kg (maximum 360 mg) or placebo, within 12 hours of last known normal, in a dose-escalation design. Cohort 1 randomized 2:1 JX10:placebo at 1 mg/kg; Cohort 2 2:1 at 3 mg/kg; Cohort 3 1:1 at 6 mg/kg.
Inclusion Criteria
Japanese males 20-88 or postmenopausal females 60-88 with AIS on MRI/angiography (± CT), NIHSS 6-23, DWI-ASPECTS ≥5, unable to receive tPA or thrombectomy per treating physician, able to start treatment within 12 hours of last known normal.
Study Design
Arms: Placebo vs JX10 1 mg/kg vs JX10 3 mg/kg vs JX10 6 mg/kg (combined JX10 for efficacy)
Patients per Arm: Placebo 38; JX10 1 mg/kg 6; JX10 3 mg/kg 18; JX10 6 mg/kg 28 (JX10 combined 52)
Outcome
• mRS 0-1 at day 90: JX10 40.4% (21/52) vs placebo 18.4% (7/38); adjusted OR 3.34 (95% CI 1.11-10.07); p=0.03
• Vessel recanalization (AOL score <3 at baseline): 58.3% (14/24) JX10 vs 26.7% (4/15) placebo; OR 4.23 (95% CI 0.99-18.07)
• mRS 0-2 at day 90: JX10 53.8% (28/52) vs placebo 36.8% (14/38); OR 2.01 (95% CI 0.83-4.86); p=0.12
• Asymptomatic ICH: 11.5% JX10 vs 7.9% placebo; extracranial bleeding 21.2% vs 13.2%; no major bleeding in either arm
Clinical Question
In Japanese patients with acute ischemic stroke unable to receive tPA or endovascular thrombectomy and treated within 12 hours of last known normal, is JX10 (TMS-007) safe and efficacious — assessed by symptomatic intracranial hemorrhage within 24 hours, vessel recanalization, and 90-day functional outcome?
Bottom Line
In 90 Japanese AIS patients (52 JX10, 38 placebo) unable to receive tPA or thrombectomy and treated at median 9.5 hours after last known normal, JX10 caused no symptomatic intracranial hemorrhage (0/52 vs 1/38 placebo; p=0.42) and significantly increased 90-day mRS 0-1 to 40.4% vs 18.4% (adjusted OR 3.34, 95% CI 1.11-10.07; p=0.03). Vessel recanalization also improved numerically (58.3% vs 26.7%; OR 4.23, 95% CI 0.99-18.07). Phase 2a proof-of-concept for a novel BBB-sparing thrombolytic in the late window.
Major Points
- Multicenter phase 2a dose-escalation double-blind placebo-controlled RCT at 41 Japanese sites (Niizuma 2024)
- N=91 consented, 90 treated; 3 cohorts of 1, 3, 6 mg/kg; cohort 3 randomized 1:1, cohorts 1-2 randomized 2:1 (JX10:placebo)
- Enrolled Japanese AIS patients unable to receive tPA or EVT within 12 hours of last known normal
- NIHSS 6-23, DWI-ASPECTS ≥5 at screening; median treatment time 9.5 h (IQR 5-12.1) in JX10 cohorts
- Primary endpoint: sICH with ≥4-point NIHSS deterioration within 24 h — 0/52 JX10 vs 1/38 placebo (p=0.42)
- No major bleeding in either arm; asymptomatic ICH 11.5% vs 7.9% (low overall)
- 90-day mRS 0-1: 40.4% (21/52) JX10 vs 18.4% (7/38) placebo; adjusted OR 3.34 (95% CI 1.11-10.07); p=0.03 — SIGNIFICANT
- mRS 0-2 at 90 d: 53.8% vs 36.8%; OR 2.01 (95% CI 0.83-4.86); p=0.12 (trend)
- Vessel recanalization (AOL score <3 patients, n=39): 58.3% vs 26.7%; OR 4.23 (95% CI 0.99-18.07)
- Dual mechanism appears validated by absence of systemic fibrinolytic markers change (fibrinogen, α2-antiplasmin, DHET unchanged)
- Anti-inflammatory effect (via soluble epoxide hydrolase inhibition) may contribute to safety in extended window
- Phase 2a proof-of-concept supporting late-window use; further phase 2b/3 trials needed to confirm in larger, more diverse populations
Study Design
- Study Type
- Phase 2a multicenter randomized double-blind placebo-controlled dose-escalation trial (jRCT2080223786; formerly JapicCTI-183842)
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 90
- Follow-up
- 90 days primary efficacy; 14 days for neurological/safety
Primary Outcome
Definition: Incidence of symptomatic intracranial hemorrhage with ≥4-point NIHSS deterioration within 24 hours of JX10 administration
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 1/38 (2.6%, 95% CI 0.1-13.8) | 0/52 (0%, 95% CI 0.0-5.6) | - (Upper bound 5.6% for JX10) | p=0.42 (Fisher exact) |
Limitations & Criticisms
- Small sample size (N=90) and heterogeneous cohorts limit definitive efficacy conclusions; phase 2a should not drive practice
- Japanese-only population — generalizability to Western or more genetically/environmentally diverse AIS populations uncertain
- Predominantly male (66%), excluded women <60 y due to absence of reproductive toxicity data — significant selection bias
- Age >88 excluded, lacunar stroke capped at 50% of cohort 3 — restricts generalizability
- No direct comparison with tPA or tenecteplase — cannot claim superiority or non-inferiority to standard thrombolysis
- Baseline NIHSS upper limit 23 and DWI-ASPECTS ≥5 may have selected for patients with better prognosis, inflating mRS 0-1 rates
- PD markers (fibrinogen, α2-antiplasmin, DHET) showed no change — while this supports mechanistic safety, it also raises questions about whether the drug reached therapeutic tissue concentrations