Abstract Body: Background:
Otaplimastat (SP-8203) is a first-in-class, small-molecule neuroprotectant that improves blood brain barrier disruption and significantly ameliorates cerebral infarction induced by ischemia or delayed reperfusion in animal models. We evaluated otaplimastat efficacy in patients with moderate to severe acute stroke patients (AIS) receiving rtPA as standard of care, using pooled data from two multicenter, double-blind, randomized, placebo-controlled phase 2 studies: SAFE-TPA 2a (NCT02787278) and 2b (NCT04479449).
Methods:
In total, 48 and 178 patients with AIS were randomized 1:1 to receive 40 mg otaplimastat or placebo in addition to rtPA, with six doses at 12-hour intervals. Endovasculary therapy (EVT) was performed if arterial occlusion was confirmed by imagings, after rtPA administration, with pre- or post-operative modified Treatment in Cerebral Infarction (mTICI) scores evaluated. Patients with baseline NIHSS ≥7 or ≥16 were assessed for mRS and NIHSS up to 90 days. Logistic regression models adjusted items such as site, age, sex, stroke onset, and baseline NIHSS. Infarct growth within 5 days from baseline was evaluated using MRI.
Results:
The pooled analysis included 201 patients with primary outcome, of whom 114 had a baseline NIHSS≥7. Among 62 who received rtPA without EVT, the maximum treatment difference in NIHSS change from baseline between otaplimastat and placebo groups was observed on Day 5 and persisted through Day 28 and Day 90, with mean differences of -4.0 (95% CI: -6.0, -1.0; p=0.020), -4.0 (95% CI: -7.0, -1.0; p=0.002), and -3.0 (-6.0, -1.0; p=0.005), respectively. Good outcomes (mRS 0–1) were observed in 53% and 54% of the otaplimastat group vs. 35% and 48% in the placebo group at Day 28 and Day 90, respectively, with odds ratios of 5.19 (p=0.069) and 1.86 (p=0.326). Otaplimastat reduced infarct growth within 5 days by 89% [4.7% in otaplimastat group vs. 44.5% in placebo]. Among 41 patients with baseline NIHSS ≥16, good outcomes (mRS 0–2) were achieved in otaplimastat group irrespective of EVT: 43% and 55% vs. 33% and 44% in placebo group at Day 28 and Day 90, respectively, among those who underwent EVT following rtPA (20 participants).
Conclusions:
Otaplimastat demonstrated safety and efficacy in improving neurological and functional outcomes in moderate to severe AIS patients receiving reperfusion therapy, suggesting its potential as a promising therapeutic strategy to be advanced to a phase 3 study (NCT06660719).