Author: Markus Linder (Switzerland)
Co-authors: Richard Foxton, Sabine Uhles, Franco Revelant, Mirjana Lazendic, Jérémie Canonica, Marina Garcia Garrido
Faricimab, a bispecific antibody currently in year 2 of phase 3 trials (TENAYA: NCT03823287; LUCERNE: NCT03823300), 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 durability up to every 16 weeks versus anti-VEGF monotherapy in phase 2 and 3 clinical trials in patients with neovascular age-related macular degeneration. We present new preclinical data from 2 mouse models of choroidal neovascularisation (CNV) showing that dual Ang-2/VEGF-A blockade, through its vessel-stabilising potential, significantly reduces fibrosis linked to vision loss versus anti-VEGF monotherapy.
Two independent mouse models of CNV were used: laser-induced CNV and spontaneous CNV (JR5558 mice).
Effect of Ang-2/VEGF-A blockade on subretinal fibrosis was analysed in a laser-induced CNV mouse model by treating 10- to 12-week-old wild-type mice intraperitoneally with mouse cross-reactive tool antibodies against Ang-2, VEGF-A or both (with the bispecific anti–Ang-2/VEGF-A antibody) on days 0, 7 and 21 post laser injury. Untreated or immunoglobulin G (IgG)-treated mice were used as controls. Subretinal fibrosis was characterised by fibronectin immunostaining and binding of fluorophore-labelled collagen hybridising peptides (CHPs), which detect collagen remodelling in active fibrotic lesions. Seven-week-old JR5558 mice developing bilateral spontaneous neovascular fibrotic lesions were treated intraperitoneally with mouse cross-reactive tool antibodies against Ang-2, VEGF-A or both (with the bispecific antibody), and IgG (control). Fibronectin immunostaining was performed on retinal pigment epithelium (RPE)/choroid flat mounts to assess fibrosis at 1 (PT1), 3 (PT2) and 5 (PT3) weeks post treatment. CHP binding was assessed 3 weeks post treatment (PT2).
In the laser-induced CNV mouse model, dual inhibition significantly reduced both fibronectin-positive (47%; P < 0.05) and CHP-positive (39%; P < 0.01) areas at 3 weeks; blocking Ang-2 or VEGF-A alone had no significant effect. There was significant reduction in fibronectin-positive area in the RPE/choroid of JR5558 mice with the bispecific antibody (38%; P < 0.01) and anti–Ang-2 (41%; P < 0.001) versus IgG at PT1; effect of anti–VEGF-A alone was not significant. Only dual Ang-2/VEGF-A inhibition maintained significant reduction at PT2 (47%; P < 0.01) and PT3 (54%; P < 0.05). Dual inhibition significantly prevented collagen remodelling, as shown by reduced CHP in RPE/choroid lesions at PT2 (66%; P < 0.01). Anti–Ang-2 or anti–VEGF-A alone showed no significant effect.
We present preclinical data from 2 independent CNV mouse models suggesting sustained prevention of fibrosis with dual Ang-2/VEGF-A pathway inhibition. Our findings support the hypotheses that Ang-2 and VEGF-A contribute to vascular instability and drive subretinal fibrosis. Future studies are underway to determine how dual Ang-2/VEGF-A inhibition limits subretinal fibrosis.
All authors are employees of F. Hoffmann-La Roche Ltd.
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