Safety and tolerability of Rinvecalinase Alfa (DM199) for acute ischemic stroke (ReMEDy1)

BACKGROUND: Rinvecalinase alfa (DM199), a recombinant form of human tissue kallikrein-1 (KLK1), aims to promote local vasodilation to ischemic brain and enhance collateral blood flow. The ReMEDy1 trial tested the safety and tolerability of rinvecalinase alfa in ischemic stroke. METHODS: ReMEDy1 was a phase II, randomized, double-blind, placebo-controlled, study conducted at 13 Australian sites. Ninety-two patients with NIH Stroke Scale (NIHSS) 6-25 were enrolled within 24 h of ischemic stroke onset. Patients were randomized 1:1 to receive rinvecalinase alfa (1 µg/kg intravenous infusion followed by 3 µg/kg subcutaneously every 3 days for 22 days) or placebo. The primary outcome was safety, assessed by adverse events (AEs) and serious adverse events (SAEs). Secondary outcomes included changes in NIHSS, modified Rankin Scale (mRS), and Barthel Index (BI) at Days 22 and 90. Post hoc analyses excluded patients who underwent endovascular therapy (EVT). RESULTS: The median age was 72, NIHSS 10, and onset-to-randomization was 19.5 h. SAEs were reported in 20/47 (43.5%) rinvecalinase alfa patients and 14/45 (31.1%) placebo patients. Most patients experienced at least one AE; the most common in the rinvecalinase alfa group were constipation (60.9%), oral candidiasis (23.9%), and nausea (17.4%). Stroke-in-evolution by Day 90 occurred in 0 (0%) rinvecalinase alfa patients versus 6 (13.3%) placebo patients; 4/6 (66.7%) placebo patients with stroke-in-evolution died. No significant differences were observed in secondary efficacy outcomes at Day 90. Post hoc analyses in patients not treated with EVT suggested a tendency toward improved excellent global outcomes with rinvecalinase alfa. CONCLUSIONS: Rinvecalinase alfa appeared to be safe and generally well-tolerated in ischemic stroke patients, with potential efficacy in reducing stroke progression. Further studies are needed to confirm efficacy and long-term benefits in patients without EVT. REGISTRATIONS: https://www. CLINICALTRIALS: gov/study/NCT03290560.