Preclinical and first-in-human phase I trial of MT200605: A novel TrkB agonist for acute ischaemic stroke.

AIMS: MT200605 is a novel small-molecule TrkB agonist designed to mimic BDNF for neuroprotection. This first-in-human phase I trial evaluated its safety, tolerability and pharmacokinetics (PK) in healthy volunteers, alongside preclinical data. METHODS: Preclinical efficacy was assessed in tMCAO rats; PK in healthy rats. The phase I trial was a single-centre, randomized, double-blind, placebo-controlled study comprising single ascending dose (SAD; 0.15-1.2 mg/kg) and multiple ascending dose (MAD; 0.3-1.2 mg/kg/day q12h for 7 days) phases in healthy volunteers. RESULTS: In rats, MT200605 at ≥1.35 mg/kg improved day 8 survival (peak survival: 79.2%), reduced infarct volume by 59.7% and improved neurological scores, with quantifiable brain exposure supporting central nervous system penetration. In humans (n = 60), MT200605 was well tolerated, with all drug-related AEs being mild and self-limiting. Free MT200605 demonstrated dose-proportional PK, whereas total MT200605 exposure increased in a slightly more-than-dose-proportional manner during MAD, with no accumulation (R < 2). Steady-state total AUC at 0.6 mg/kg BID (858 h·ng/mL) matched the rat efficacious exposure (906 h·ng/mL, 5.3% difference). Urinary excretion of total MT200605 was minimal (<4%). CONCLUSIONS: MT200605 shows promising preclinical neuroprotection and an acceptable safety profile with predictable PK in humans. A twice-daily intravenous regimen of 0.6 mg/kg (1.2 mg/kg/day) is recommended for phase II trials in acute ischaemic stroke patients.