ARV-102 showed dose-dependent increases in CSF concentration and central LRRK2 degradation. From your perspective, how critical is this evidence of brain penetration for validating the PROTAC approach in CNS disorders, especially given the historical challenges of CNS drug delivery?

ARV-102 demonstrated >90% peripheral and >50% central LRRK2 degradation at certain doses. What does this dual-compartment activity suggest about its potential efficacy in modulating disease progression in PD and PSP?

Inhibition of Rab10 phosphorylation and reduction in urinary BMP levels were observed. How do these pharmacodynamic markers help in assessing downstream engagement of the LRRK2 pathway, and what do they tell us about the biological impact of ARV-102?

Given the once-daily oral dosing and a terminal half-life of 73 hours, how does ARV-102’s pharmacokinetic profile align with patient needs and expectations in chronic neurodegenerative conditions like PD?

The study reported post-lumbar puncture syndrome in some treated individuals. While not necessarily drug-related, do such procedural side effects complicate data interpretation in early CNS trials, and how might they be addressed in future PD patient cohorts?

What are the implications of the observed dose thresholds (≥60 mg single, ≥20 mg repeated) for achieving meaningful central LRRK2 degradation, and how might these guide the upcoming MAD cohort in PD patients?

The trial emphasizes potential relevance to PSP due to LRRK2's role in tauopathies. In your opinion, what kind of mechanistic or biomarker data would further strengthen the rationale for expanding into PSP or related tauopathies?

Considering ARV-102’s potential disease-modifying activity, how do you see it being positioned in the treatment paradigm—possibly in combination with α-synuclein-targeted agents, dopamine modulators, or as monotherapy in genetically defined LRRK2 subgroups?