Objective: The aim of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BT-267 in healthy adults.

Background: Leucine rich repeat kinase 2 (LRRK2) mutations are a well-known genetic cause of Parkinson’s disease (PD).¹ Brains of individuals with idiopathic PD have increased LRRK2 kinase activity, which contributes to endolysosomal dysfunction and accumulation of ⍺-synuclein.² Activation of LRRK2 kinase activity contributes to the pathogenesis of PD, suggesting inhibition of LRRK2 kinase activity may be useful for the treatment of PD.²  BT-267 is a potential best-in-class, highly selective oral small molecule inhibitor of LRRK2 with high brain permeability.

Method: A Randomized, double-blind, placebo-controlled Phase 1 study evaluating the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of BT-267 for up to 10 days in healthy adults (HA) is being conducted. Pharmacodynamic measures include total and phosphorylated LRRK2, and total and phosphorylated Rab10 levels in multiple matrices including plasma and cerebrospinal fluid (CSF).

Results: As of March 12, 2026, BT-267 was well tolerated in 71 HA (55 active and 12 placebo) after single and multiple doses. There were no SAEs, withdrawals or discontinuations.  Most treatment emergent adverse events (TEAEs) were mild; headache, nausea, venipuncture related AEs and presyncope were reported by >2 participants. There were no changes in vitals, ECGs, or labs. The PK profile of BT-267 supports once-daily dosing. BT-267 CSF/plasma concentration ratio was greater than or equal to 2.3 . Single and multiple doses of BT-267 demonstrated reductions from baseline in phosphorylated LRRK2/total LRRK2 ratio, and phosphorylated Rab10/total Rab10 ratio in peripheral blood mononuclear cells and CSF.

Conclusion: BT-267 has preferential distribution in the central nervous system, with potential to maximize central exposures while minimizing peripheral exposures. These results suggest that BT-267 may provide a differentiated safety profile and support continued development of BT-267 in individuals with PD.

References: 1. Di Fonzo A, et al. Lancet. 2005 Jan 29-Feb 4; 365:412-5
2. Di Maio R, et al. Science Translational Medicine. 2018 Jul 25;10 (451)

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phase-1-study-of-bt-267-a-potent-selective-brain-penetrant-and-oral-small-molecule-inhibitor-of-lrrk2/