Authors: Varun Chaudhary, Anat Loewenstein, Veeral Sheth, Karl Csaky, Rose Edmonds, Michael Chang, Jeffrey R. Willis, Zdenka Haskova, Peter D. Westenskow. 
Author Disclosure Block: V. Chaudhary: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Novartis, Bayer. Any direct financial payments including receipt of honoraria; Description of relationship(s); Speaker fees. Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Novartis, Bayer, Roche, Alcon Inc.. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Advisory board. Funded grants or clinical trials; Name of for-profit or not-for-profit organization(s); Novartis, Bayer. Funded grants or clinical trials; Description of relationship(s); Grants and clinical trials. A. Loewenstein: Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Allergan, Bayer, BeyeOnics, ForSight Labs, NotalVision, Novartis and Roche. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Consultant. V. Sheth: Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Genentech, Inc., Alimera, EyePoint, Genentech, Inc., Novartis. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Speaker, Consultant. Funded grants or clinical trials; Name of for-profit or not-for-profit organization(s); Allergan, Alimera Sciences, DRCR, Genentech, Inc., Ionis, Novartis, Regeneron, Santen, SamChungDang, IvericBio, Gyroscope, Chengdu Kanghong, SalutarisMD, NGM Biopharmaceuticals. Funded grants or clinical trials; Description of relationship(s); Contracted research. K. Csaky: Membership on advisory boards or speakers’ bureaus; Name of for-profit or not-for-profit organization(s); Acucela, Allergan, Applied Genetic Technologies Corporation, Astellas, Gyroscope, Heidelberg, Novartis, Ocular Therapeutix, Regeneron, Ribomics, Roche/Genentech, Inc.. Membership on advisory boards or speakers’ bureaus; Description of relationship(s); Consultant. R. Edmonds: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Genentech, Inc.. Any direct financial payments including receipt of honoraria; Description of relationship(s); Employee. M. Chang: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Genentech, Inc.. Any direct financial payments including receipt of honoraria; Description of relationship(s); Employee. J.R. Willis: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Genentech, Inc.. Any direct financial payments including receipt of honoraria; Description of relationship(s); Employee. Z. Haskova: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); Genentech, Inc.. Any direct financial payments including receipt of honoraria; Description of relationship(s); Employee. P.D. Westenskow: Any direct financial payments including receipt of honoraria; Name of for-profit or not-for-profit organization(s); F. Hoffmann-La Roche Ltd.. Any direct financial payments including receipt of honoraria; Description of relationship(s); Employee.

Purpose: Faricimab, a bispecific antibody, targets both angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), which are key drivers of vascular instability. The purpose of these analyses is to explore the impact of dual inhibition of Ang-2 and VEGF-A by faricimab on vascular stability. 

Study Design: BOULEVARD (NCT02699450) was a phase 2, prospective, multicentre clinical trial. YOSEMITE (NCT03622580) and RHINE (NCT03622593) are two identical phase 3, randomised, double-masked, active comparator-controlled, multicentre clinical trials in DME, currently ongoing. Preclinical studies were performed in a mouse model of spontaneous choroidal neovascularisation (CNV). 

Methods: In BOULEVARD, patients were randomized to intravitreal ranibizumab 0.3 mg, faricimab 1.5 mg or faricimab 6.0 mg, administered every 4W for 20W, followed by a 16W observation period to assess durability. In a post hoc analysis, sustained retinal stability to W24 was assessed. Vascular stability was also assessed in the phase 3 trials. In preclinical experiments, JR5558 mice were treated with antibodies against Ang-2, VEGF-A or both (bispecific antibody [VA2]). Untreated and immunoglobulin G (IgG)-treated mice were used as controls. Vascular stability was evaluated at baseline and 1W (PT1), 3W (PT2) and 5W (PT3) post treatment. 

Results: In a post hoc analysis of BOULEVARD, > 50% of patients achieved retinal stability through W24. Phase 3 vascular stability data will be presented. In preclinical experiments, significant reduction of CNV leakage (P<0.05 to P<0.001) was observed in JR5558 mice treated with Ang-2, VEGF-A or VA2 versus controls at PT1. Treatment with VA2 antibody significantly reduced Iba1+ cell infiltration versus IgG control at PT1/PT2 (P<0.05) and CD45+ CD11b+ cell infiltration versus untreated control at PT1 (P<0.05). At PT3, only anti-Ang-2- and VA2-treated mice showed significant reduction in number of Iba1+ macrophages (P<0.0001) versus IgG control. There was significant reduction in fibronectin+ area with VA2 (P<0.01) and anti-Ang-2 (P<0.001) versus IgG at PT1, not with anti-VEGF-A alone. This was maintained only with VA2 at PT2 (P<0.01) and PT3 (P<0.05). 

Conclusions: These data support the involvement of Ang-2 signalling in vascular stability in patients with DME.