Author: Anat Loewenstein (Israel)
Co-authors: Veeral Sheth, Karl Csaky, Rose Edmonds, Michael Chang, Jeffrey R. Willis, Zdenka Haskova
Purpose
Faricimab, a bispecific antibody currently in year 2 of phase 3 trials, targets both angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), which are key drivers of vascular instability. Faricimab demonstrated improvement in best-corrected visual acuity and sustained efficacy up to every 16 weeks (W) versus anti-VEGF monotherapy in phase 2 and 3 clinical trials in patients with diabetic macular edema (DME). The purpose of these analyses is to explore the impact of dual inhibition of Ang-2 and VEGF-A by faricimab on vascular stability.
Setting/Venue
BOULEVARD (NCT02699450) was a phase 2, prospective, multicentre clinical trial that took place at 59 sites in the United States. YOSEMITE (NCT03622580) and RHINE (NCT03622593) are 2 identical phase 3, randomised, double-masked, active comparator–controlled, multicentre clinical trials in DME ongoing at 353 study locations worldwide. Preclinical studies were performed in a mouse model of spontaneous choroidal neovascularisation (CNV).
Methods
In BOULEVARD, treatment-naïve patients were randomised 1:1:1 to intravitreal ranibizumab 0.3 mg, faricimab 1.5 mg or faricimab 6.0 mg, administered every 4W for 20W, followed by a 16W off-treatment observation period to assess durability. In a post hoc analysis of BOULEVARD, sustained retinal stability, defined as the occurrence and maintenance (< 10% worsening) of CST ≤ 325 µm to W24 was assessed in the intent-to-treat population. In a separate analysis of a subset of patients from BOULEVARD, inflammatory biomarker (ICAM-1) levels in aqueous humor were assessed from baseline to W28. Vascular stability was also assessed in the phase 3 trials. In a new set of preclinical experiments, JR5558 mice were treated intraperitoneally with antibodies against Ang-2, VEGF-A or both (bispecific anti–Ang-2/anti–VEGF-A antibody [VA2]). Untreated and immunoglobulin G (IgG)-treated mice were used as controls. Vascular stability was evaluated by examining neovascular leakage, subretinal infiltration of inflammatory cells (Iba1+, CD11b+, CD45+) and fibrosis using fluorescein angiography (FA) and fibronectin staining on the retinal pigment epithelium/choroid at baseline and 1W (PT1), 3W (PT2) and 5W (PT3) post treatment.
Results
In a post hoc analysis of BOULEVARD, > 50% of patients achieved sustained retinal stability through W24 beginning at W8, W16 (faricimab 6.0, 1.5 mg) and W20 (ranibizumab). In a separate analysis, mean (SD) % ICAM-1 levels versus baseline increased by 50 (75) (ranibizumab) and decreased by 56 (20) (faricimab 1.5 mg) and 42 (54) (faricimab 6.0 mg) at W28. Phase 3 vascular stability data will be presented. In preclinical experiments, significant reduction of FA-evaluated 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; only Ang-2– and VA2–treated mice showed significant reduction in CNV leakage versus controls (P<0.05 to P<0.0001) at PT2/PT3. Treatment with VA2 antibody, not anti–VEGF-A or anti–Ang-2 alone, 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).
Conlusions
We present post hoc analyses of the phase 2 BOULEVARD trial, in which patients receiving faricimab achieved sustained retinal stability earlier than those receiving ranibizumab, and showed reductions in inflammatory biomarkers versus ranibizumab. In phase 3, faricimab showed greater anatomic improvement versus aflibercept and potential for improved durability up to every 16W due to vascular stability by Ang-2 inhibition. Furthermore, research suggests that Ang-2 blockade drives vascular stability. These data support the involvement of Ang-2 signalling in vascular stability in patients with DME.
Financial Disclosure
Dr Anat Loewenstein: Consultant: Allergan, Bayer, BeyeOnics, ForSight Labs, NotalVision, Novartis and Roche. Dr Veeral Sheth: Speaker: Genentech, Inc.; Consultant: Alimera, EyePoint, Genentech, Inc., Novartis; Contracted research: Allergan, Alimera Sciences, DRCR, Genentech, Inc., Ionis, Novartis, Regeneron, Santen, SamChungDang, IvericBio, Gyroscope, Chengdu Kanghong, SalutarisMD, NGM Biopharmaceuticals. Dr Karl Csaky: Consultant: Acucela, Allergan, Applied Genetic Technologies Corporation, Astellas, Gyroscope, Heidelberg, Novartis, Ocular Therapeutix, Regeneron, Ribomics, Roche/Genentech, Inc. Ms Rose Edmonds, Dr Michael Chang, Dr Jeffrey R. Willis and Dr Zdenka Haskova are employees of Genentech, Inc. Dr Peter Westenskow (7th co-author) is an employee of F. Hoffmann-La Roche Ltd.
Comments
Please add below extra co-author: Co-author 7 first name: Peter Co-author 7 last name: Westenskow Co-author 7 affiliation: Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
