Angiopoietin-2 (Ang-2) signaling and vascular stability with faricimab in diabetic macular edema (DME)

Abstract

Purpose : Ang-2 and vascular endothelial growth factor (VEGF)-A are key drivers of vascular instability in DME. We explored the effect of dual Ang-2/VEGF-A pathway inhibition on vascular stability using preclinical and phase 2/3 clinical data.

Methods : JR5558 mice (spontaneous model of choroidal neovascularization [CNV]) received anti−Ang-2, anti−VEGF-A, dual anti–Ang-2/anti–VEGF-A (VA2), or none/immunoglobulin G (IgG) as controls. Vascular stability was evaluated by analyzing neovascular leakage and subretinal inflammatory cell infiltration (Iba1+, CD11b+, CD45+) at baseline and at 1 week (1W), 3W, and 5W posttreatment. In the phase 2 BOULEVARD trial (NCT02699450), the effect of faricimab, a bispecific Ang-2/VEGF-A neutralizing antibody, on sustained retinal stability (SRS; defined as the achievement and maintenance [< 10% worsening] of central subfield thickness [CST] ≤ 325 µm to week 24) was assessed. Vascular stability with faricimab was also evaluated in the phase 3 YOSEMITE/RHINE trials (NCT03622580/NCT03622593) over 2 years.

Results : In JR5558 mice, CNV lesion leakage was reduced at 1W with anti−Ang-2, anti−VEGF-A, and VA2 versus controls (P < 0.05 to P < 0.001); at 3W and 5W, this was maintained with anti−Ang-2 and VA2 only (P < 0.05 to P < 0.0001). Compared with IgG, VA2 treatment reduced Iba1+, CD11b+, and CD45+ cell infiltration at 1W (P < 0.05); at 5W, only anti−Ang-2 and VA2 reduced Iba1+ cell infiltration (P < 0.0001). In BOULEVARD, SRS was achieved by > 50% of patients receiving faricimab 6.0 mg and 1.5 mg at weeks 8 and 16, respectively, compared with week 20 for patients receiving ranibizumab. During year 1 of YOSEMITE/RHINE, change in CST from baseline consistently favored faricimab over aflibercept, and absence of DME and intraretinal fluid were achieved by a higher proportion of patients treated with faricimab versus aflibercept. Year 2 vascular stability data from YOSEMITE/RHINE will be presented at the meeting.

Conclusions : Preclinical data suggest that Ang-2 inhibition may contribute to reduced inflammation and increased vascular stability. Furthermore, dual Ang-2/VEGF-A blockade with faricimab promoted SRS in BOULEVARD and improved DME disease control in YOSEMITE/RHINE. These data support the role of Ang-2 in vascular stability and the potential for dual Ang-2/VEGF-A inhibition with faricimab to improve outcomes in patients with DME over anti-VEGF alone.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.