Abstract
Purpose :
To present new preclinical data supporting the vessel-stabilization potential of Ang-2 inhibition in a mouse model of spontaneous choroidal neovascularization (sCNV), in the context of observed phase 2 clinical data indicating sustained efficacy of faricimab, a bispecific antibody that binds and neutralizes both Ang-2 and VEGF-A.
Methods :
Durability of effect of faricimab 6 mg was studied in two phase 2 studies. In BOULEVARD, disease stability in DME was evaluated in an off-treatment observation period. In STAIRWAY, faricimab Q16W and Q12W dosing regimens were explored for neovascular AMD. To support clinical findings, JR5558 mice (aged 7 weeks at baseline), developing spontaneous neovascular lesions in both eyes, were treated intraperitoneally with mouse cross-reactive tool antibodies against Ang-2, VEGF-A, or bispecific anti-VEGF-A/Ang-2 antibody (VA2); n = 5–10 per group. Neovascular leakage was evaluated using fluorescein angiography (FA) at 1 and 3 weeks post treatment. Controls were untreated/IgG-exposed eyes.
Results :
In BOULEVARD, median time to disease reactivation in faricimab- and ranibizumab-treated patients was 15.1 and 8.6 weeks, respectively. In STAIRWAY, 65% (36/55) of faricimab-treated patients showed disease stability at week 24, 3 months after the last loading dose, and were eligible for Q16W dosing. Initial best-corrected visual acuity (BCVA) gains were fully maintained and comparable at week 52 (11.4, 10.1, and 9.6 letters for faricimab Q16W, Q12W, and ranibizumab Q4W, respectively). In preclinical experiments, significant reduction of CNV leakage 1 week post treatment (p<0.001) was observed in mice treated with Ang-2, VEGF-A or VA2 compared with untreated/IgG controls. At week 3 post treatment, only Ang-2 and VA2 inhibition maintained statistical significance in FA-evaluated leakage over both control groups (p<0.01). Lesions treated with anti-VEGF alone showed reactivation on FA and the leakage area was no longer significantly different from the control groups.
Conclusions :
In the mouse model, CNV leakage was suppressed for longer with Ang-2 inhibition. These findings help explain the durability observed in the BOULEVARD and STAIRWAY phase 2 data, supporting the hypothesis that the sustained efficacy seen in patients treated with faricimab is driven by its Ang-2 inhibition properties.
This is a 2020 ARVO Annual Meeting abstract.