Arvinas has presented promising first-in-human data for ARV-102, its investigational PROteolysis TArgeting Chimera (PROTAC) therapy designed to degrade leucine-rich repeat kinase 2 (LRRK2), a protein implicated in Parkinson's disease and progressive supranuclear palsy.
Results from the randomized, double-blind, placebo-controlled Phase 1 trial in healthy volunteers demonstrated substantial LRRK2 reduction in both cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs), indicating the compound successfully crosses the blood-brain barrier with a favorable safety profile.
The data was presented at the 2025 International Conference on Alzheimer's and Parkinson's Diseases in Vienna, Austria, providing a potential breakthrough in the treatment approach for neurodegenerative disorders.
Key Clinical Findings
The Phase 1 study evaluated ARV-102 in both single ascending dose (SAD) cohorts with doses ranging from 10 mg to 200 mg, and multiple ascending dose (MAD) cohorts with doses ranging from 10 mg to 80 mg.
At single oral doses of at least 60 mg and once-daily repeated doses of at least 20 mg, ARV-102 achieved greater than 50% LRRK2 reduction in CSF and greater than 90% reduction in PBMCs. This demonstrates substantial central and peripheral target engagement, a critical factor for neurodegenerative disease therapies.
The compound also showed downstream LRRK2 pathway engagement, evidenced by inhibition of Rab10 phosphorylation in PBMCs and reduction of bis(monoacylglycerol)phosphate (BMP) in urine following single doses of 30 mg or higher.
Noah Berkowitz, Chief Medical Officer at Arvinas, emphasized the significance of these findings: "The ability of ARV-102 to cross the blood-brain barrier and degrade the LRRK2 protein offers a potentially transformative therapeutic approach in the treatment of devastating neurodegenerative diseases."
Safety and Pharmacokinetic Profile
ARV-102 was generally well-tolerated across all dose cohorts. Among the 47 volunteers in the SAD cohort, the most common treatment-related adverse events were headache (17.1% in treated vs. 0% in placebo) and fatigue (8.6% in treated vs. 25% in placebo). No serious adverse events were reported in either the SAD or MAD cohorts.
The compound exhibited favorable pharmacokinetic properties with a median maximum concentration reached 6 hours after oral administration and a median terminal plasma half-life of 73 hours. Both plasma concentration and CSF levels increased in a dose-dependent manner, supporting predictable drug exposure.
LRRK2 as a Therapeutic Target
LRRK2 has emerged as a significant target in neurodegenerative disease research. While primarily known for its role in Parkinson's disease, emerging evidence suggests it also plays a role in tauopathies, including progressive supranuclear palsy.
ARV-102 represents a novel approach as a PROTAC designed specifically to cross the blood-brain barrier and target LRRK2 for degradation, rather than merely inhibiting its function. This degradation approach may offer advantages over traditional inhibitors by more completely eliminating the protein's activity.
Clinical Development Path
Based on these encouraging results, Arvinas has already advanced ARV-102 into patient studies. In the fourth quarter of 2024, the company initiated dosing in the SAD cohort of a Phase 1 clinical trial in patients with Parkinson's disease.
The company expects to complete enrollment and present initial data from this ongoing SAD cohort in 2025, along with initiating the MAD cohort in Parkinson's disease patients.
Renewed Hope for PROTAC Platform
The positive ARV-102 data comes at a critical time for Arvinas, following recent setbacks with another PROTAC therapy being developed with Pfizer for HER2-negative breast cancer, which showed mixed results in extending progression-free survival.
This latest Parkinson's data provides renewed confidence in Arvinas' PROTAC platform technology, particularly for central nervous system applications where traditional therapeutic approaches have faced significant challenges in crossing the blood-brain barrier.
The ability of ARV-102 to achieve meaningful target engagement in the brain while maintaining a favorable safety profile positions it as a potentially important addition to the neurodegenerative disease treatment landscape, where effective disease-modifying therapies remain an urgent unmet need.
