Arvinas to Present on PROTAC® Programs Targeting BCL6 and LRRK2

Arvinas Inc., a clinical-stage biotechnology company, has announced significant advancements in its investigational drugs targeting specific proteins. The company presented preclinical data at two major events in June 2024: the European Hematology Association (EHA) Annual Congress in Madrid, Spain, and the Biennial International LRRK2 Meeting in Crete, Greece.

At the EHA Congress, Arvinas unveiled promising preclinical data regarding its BCL6 PROTAC degrader, ARV-393. This investigational drug demonstrated notable anti-tumor efficacy in various preclinical models of B-cell lymphoma. Specifically, ARV-393 effectively degraded the BCL6 protein, inhibiting cell growth in diffuse large B-cell lymphoma (DLBCL) and Burkitt cell lines. Tumor growth inhibition, including regression, was observed in multiple cell line-derived xenograft (CDX) models of DLBCL and in patient-derived xenograft (PDX) models of non-Hodgkin lymphoma (NHL). These results covered various subtypes, such as germinal center B-cell-like (GCB), activated B-cell (ABC), GCB/ABC, BCL not otherwise specified (BCL/NOS) subtypes of DLBCL, and Burkitt lymphoma.

John Houston, Ph.D., Chairperson, President, and CEO of Arvinas, emphasized the significance of these findings by stating that ARV-393 could potentially be developed into a novel treatment for patients with specific types of non-Hodgkin lymphoma, especially those who have not responded to other treatments.

In addition to the findings presented at the EHA, Arvinas also highlighted the potential of its PROTAC LRRK2 degraders at the Biennial International LRRK2 Meeting. These degraders aim to treat neurodegenerative diseases by targeting LRRK2, a protein associated with these conditions. Preclinical studies in mice demonstrated full target engagement of LRRK2 kinase inhibition and near-complete degradation of LRRK2 with PROTAC LRRK2 degraders. Notably, these degraders caused significantly less Type II pneumocyte enlargement compared to an experimental LRRK2 kinase inhibitor. Additionally, the accumulation of surfactant protein C in the lungs, a phenotype seen with the experimental inhibitor, was absent in treatments with the PROTAC LRRK2 degrader.

Angela Cacace, Ph.D., Chief Scientific Officer at Arvinas, noted that the preclinical findings indicate a broad therapeutic index and a manageable safety profile for PROTAC degraders compared to experimental LRRK2 kinase inhibitors. Earlier studies also demonstrated that Arvinas’ PROTAC LRRK2 degraders could cross the blood-brain barrier and degrade LRRK2 in deep brain regions.

Arvinas' investigational drugs are currently being evaluated in clinical trials. The BCL6 degrader ARV-393 is in a phase 1 trial for patients with non-Hodgkin lymphoma, while the LRRK2 degrader ARV-102 is being tested in healthy volunteers.

ARV-393 is designed to degrade the BCL6 protein, a key driver of B-cell lymphomas by repressing cell cycle checkpoints, terminal differentiation, apoptosis, and the DNA damage response. This investigational PROTAC has the potential to address the traditionally undruggable nature of BCL6 and is currently in clinical trials for non-Hodgkin lymphoma.

On the other hand, ARV-102 targets Leucine-rich repeat kinase 2 (LRRK2), a protein implicated in the pathogenesis of neurodegenerative diseases like Parkinson’s Disease and progressive supranuclear palsy. Arvinas is developing oral PROTAC degraders of LRRK2 that can penetrate the blood-brain barrier.

Arvinas is a pioneering biotechnology company focused on developing protein degradation therapies. Their innovative PROTAC platform harnesses the body’s natural protein disposal system to selectively degrade disease-causing proteins. In addition to ARV-393 and ARV-102, Arvinas is advancing other investigational drugs targeting various diseases through clinical development programs. The company is based in New Haven, Connecticut.