Company: ARVN
Filing Date: 2025-02-11
Form Type: 10-K
Source: 0001655759-25-000016
Chunk: 294

Company: ARVINAS, INC.
Filing Date: 2025-02-11
Form: 10-K
Item: Item 7
Chunk 294
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 human genetics, single cell ribonucleic acid sequencing from post-mortem PD brain samples and protein data from PD patient derived induced pluripotent stem cell microglia suggest that increased activity and expression of LRRK2 are genetically involved in the pathogenesis of neurological diseases including PSP and PD.

In the second quarter of 2024, we presented preclinical data at the Biennial International LRRK2 Meeting, which further supported the potential of PROTAC-induced LRRK2 degradation as a potential treatment for neurodegenerative diseases. The preclinical data presented at the Biennial International LRRK2 Meeting highlighted, with our PROTAC LRRK2 degrader, near complete LRRK2 target engagement, as well as LRRK2 degradation, in mouse and non-human primate, or NHP, lung and brain. The preclinical data also showed differing effects of the PROTAC LRRK2 degraders in the lungs compared to kinase inhibitors, suggesting reduced pulmonary function risk, including:

•substantially less Type II pneumocyte enlargement compared to MLi-2, an experimental LRRK2 kinase inhibitor;

•surfactant protein accumulation in mouse lung was observed after treatment with the LRRK2 kinase inhibitor MLi-2, but not after treatment with the PROTAC LRRK2 degrader; and

•no evidence of collagen deposition in lung to date with PROTAC LRRK2 degraders in NHPs.

In October 2024, we presented preclinical data at the 2024 Michael J. Fox Foundation Parkinson’s Disease Conference further supporting the potential of PROTAC-induced LRRK2 degradation as a potential treatment for patients with neurodegenerative diseases. New findings presented included data demonstrating:

•orally delivered ARV-102 crosses the blood-brain barriers and degrades LRRK2 in the cerebrospinal fluid, or CSF, of NHPs;

•degradation of LRRK2 by ARV-102 induces changes in pathway (lysosomal and inflammation) biomarkers in the CSF of NHPs, which has not previously been demonstrated by kinase inhibitors of LRRK2; and

•in murine tauopathy models, oral PROTAC LRRK2 degrader treatment led to ~50% pathologic tau reduction.

The European Medicines Agency cleared our clinical trial application for ARV-102 in the fourth quarter of 2023. We currently are conducting two clinical trials with AR