Objective: To summarize the efficacy of the oral MT200605 formulation in a Huntington’s disease (HD) mouse model and current clinical progress of MT200605.

Background: MT200605 is a small-molecule TrkB receptor agonist with neuroprotective and antioxidant properties. BDNF–TrkB signaling is essential for neuronal survival, synaptic maintenance, and mitochondrial stability, making TrkB activation a promising strategy for central nervous system diseases, including HD and acute ischemic stroke,both oral and intravenous formations of the MT200605 are under development.

Method: N171-82Q HD transgenic mice were orally administered MT200605 (5mg/kg) from 7 weeks to 37 weeks of age. Evaluations included body weight, behavior, motor function (balance beam, rotarod), survival rate, neuropathology (DARPP-32, mHTT aggregates), and brain MRI. The first-in-human (FIH) study was a randomized, double-blind, placebo-controlled conducted in healthy subjects. It evaluated single-dose escalation (SAD, 0.15–1.2 mg/kg) and multiple-dose escalation (MAD, 0.3, 0.6, 1.2 mg/kg BID for 7 days) to assess the safety, tolerability, and PK profiles of the intravenous formulation.

Results: Nonclinical finding: In vitro, MT200605 activated TrkB phosphorylation and downstream AKT signaling in cortical neurons, enhanced mitochondrial ATP production in HD cells. MT200605 significantly improved motor coordination and exerted neuroprotective effects in HD mice, delaying death onset over 37 weeks. It antagonized whole-brain, cerebral cortex, and striatal atrophy, via maintaining striatal DARPP-32 levels, reducing cerebral cortex mHtt aggregation, activating the BDNF-TrkB pathway, and attenuating brain atrophy. FIH study result: Following single and multiple IV administrations,  MT200605 exhibited dose-proportional increases in exposure (Cmax and AUC). The elimination half-life was short (0.38–3.89 h), with no obvious accumulation after multiple doses. Clearance and volume of distribution were consistent across dose groups. Urinary excretion of MT200605 was minimal (<0.1%).

Conclusion: MT200605 demonstrated neuroprotective efficacy in a preclinical HD model by activating TrkB signaling, preserving neuronal integrity, and reducing mHTT aggregation. FIH study results indicated that MT200605 exhibited favorable safety and predictable PK properties in healthy volunteers. These findings support the further clinical development of MT200605 as a promising therapy for HD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mt200605-for-huntingtons-disease-nonclinical-finding-and-phase-i-clinical-result/