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.