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Background: Patients with AIS and disabling symptoms often have limited treatment options, particularly when reperfusion therapies are not feasible. LT3001 (Odatroltide), a novel molecule that enhances endogenous fibrinolysis and scavenges free radicals, was evaluated in two Phase 2 trials with distinct selection strategies: LT3001-202 (NCT05686642; China, clinical diagnosis) and LT3001-205 (NCT05403866; US, EU, Taiwan, imaging-assisted selection). Methods: Two independent, randomized, placebo-controlled Phase 2 trials in AIS within 24 hours of onset were analyzed separately. Disabling symptoms were defined as NIHSS item #5 (arm motor) >2 or item #6 (leg motor) >2 at baseline. The primary efficacy endpoint was the proportion of patients achieving a mRS score at day 90. Analyses focused on the predefined moderate stroke (NIHSS 6–12) subgroup, with further evaluation in LAA-enriched patients (LT3001-202) and in mismatch-positive patients (LT3001-205). Results: In LT3001-202 (n=297; 0.05 mg/kg=99, 0.025 mg/kg=96, placebo=102), moderate disabling stroke patients (n=118, 40% of the total study) treated with LT3001 (combined dose) showed mRS 0–1 and 0–2 improvements of 8% and 13% versus placebo. In the LAA-enriched moderate subgroup (n=149, 50% of the total study), gains were 6% (mRS 0–1) and 9% (mRS 0–2). In moderate disabling LAA-enriched patients (n=75, 25% of the total study), LT3001 improved both mRS 0–1 and 0–2 by 18%. In LT3001-205 (n=88; 0.05 mg/kg=43, placebo=45), the smaller sample size limited analysis. Patients with disabling features (n=23, 31% of the total study) achieved mRS 0–1 more often with LT3001 (27%) than placebo (11%) [RR 2.00, 95% CI 0.16–24.33]. Among mismatch-positive patients (n=34, ~39% of the total study), LT3001 showed a 7% relative increase in mRS 0–1 and 10% in mRS 0–2 versus placebo. Conclusions: Across two independent Phase 2 trials, LT3001 demonstrated signals of improved functional outcomes in AIS patients with disabling symptoms and moderate stroke severity. Benefits were observed both in clinically selected (LAA-enriched) and imaging-selected (mismatch-positive) subgroups, despite limitations of small sample size and patient heterogeneity. These findings support the potential of LT3001 as a broadly applicable treatment option for patients ineligible for reperfusion therapies.