Arvinas Presents First-in-Human Data for Investigational Oral PROTAC ARV-102 Demonstrating Blood-Brain Barrier Penetration, and Central and Peripheral LRRK2 Degradation

Core Insights - Arvinas, Inc. presented data from the first-in-human clinical trial of ARV-102, demonstrating its potential in reducing LRRK2 protein associated with neurodegenerative diseases like Parkinson's disease and progressive supranuclear palsy [1][3][7] Group 1: Clinical Trial Findings - ARV-102 was well tolerated and showed substantial LRRK2 reduction in both central and peripheral systems, indicating effective protein degradation [1][5] - The Phase 1 trial included a single ascending dose (SAD) cohort with doses from 10 mg to 200 mg and a multiple ascending dose (MAD) cohort with doses from 10 mg to 80 mg [2][3] - At doses of 60 mg or higher, ARV-102 achieved over 50% LRRK2 reduction in cerebrospinal fluid (CSF) and over 90% reduction in peripheral blood mononuclear cells (PBMCs) [5][9] Group 2: Safety and Tolerability - No serious adverse events were reported, and the drug was generally safe and well tolerated among healthy volunteers [4][5] - Common treatment-related adverse events included headache (17.1%) and fatigue (8.6%), with procedural pain from lumbar puncture reported in 28.6% of treated individuals [9] Group 3: Pharmacokinetics and Pharmacodynamics - ARV-102 demonstrated dose-dependent increases in exposure in both plasma and CSF, with a median terminal plasma half-life of 73 hours [9] - The drug's pharmacodynamic effects included significant reductions in phospho-Rab10T73 and bis(monoacylglycerol)phosphate (BMP) in urine, indicating engagement with downstream LRRK2 pathways [5][9] Group 4: Future Directions - Arvinas plans to continue the clinical program for ARV-102, with ongoing trials in patients with Parkinson's disease and expectations to present initial data in 2025 [7][10]