Systemic Ang2 Upregulation Represents Potential Treatment Target for nAMD

Researchers consider the potential for Ang2 as a target for antiangiogenic agents in treatment of the disease.

A significant increase in systemic angiopoietin-2 (Ang2) levels following intravitreal aflibercept injection may increase susceptibility to vascular endothelial growth factor (VEGF) and limit therapeutic effect duration in neovascular age-related macular degeneration (nAMD), according to research published in Acta Ophthalmologica. As such, Ang2 may be a potential new target for antiangiogenic agents in treatment for this disease.  

Through a prospective, randomized, case-series study, researchers sought to both analyze and compare systemic levels of Ang2 and VEGF-A in patients with nAMD treated via intravitreal injections of either aflibercept or ranibizumab. 

Included patients were treatment naïve for at least 8 months and had AMD diagnosed and classified by a retinal specialist. Following inclusion, 38 patients with nAMD were randomly assigned to receive either aflibercept or ranibizumab therapy. A loading dose of 3 intravitreal injections of either drug (2.0 mg/50 µl aflibercept or 0.5 mg/50 µl ranibizumab) for 3 consecutive months was administered; blood samples were collected 7- and 28-days following injection 1, and follow-up and clinical evaluations were performed 4 weeks after injection 3. A control group of 22 age- and sex matched participants without a history of ocular or systemic pathologies were also recruited. 

At baseline, both groups had similar characteristics in terms of age and sex distribution, and there were no significant differences between pretreatment systemic VEGF-A levels or Ang2 (P =.086 and P =.280) among the 3 groups. 

Median systemic Ang2 concentration was 1375 pg/mL (interquartile range [IQR], 1135-2007 pg/mL) in the control group. A statistically nonsignificant increase to 1662 pg/ml of systemic Ang2 was observed in the ranibizumab group, which remained stable at 7 and 28 days (1806 pg/ml; P =.472 and 1787 pg/ml; P =.653, respectively). 

In the aflibercept group, significant Ang2 feedback upregulation was observed (median, 2123 pg/ml; IQR, 1441-3769 pg/ml); this increase was noted in 73% of patients in this group. At day 28, systemic Ang2 concentration remained increased (median 1944 pg/ml; IQR 1431-2546 pg/ml), but no statistical significance was observed when compared with pretreatment concentration. Systemic Ang2 concentration did not significantly differ across treatment groups at either 7 or 29 days (P =.463 and P =.557, respectively). 

In a post-hoc subgroup analysis of both responders and nonresponders receiving aflibercept therapy demonstrated no differences in baseline characteristics. However, Ang2 levels between responders and nonresponders differed significantly at 28 days. No difference in systemic Ang2 levels between ranibizumab responders and nonresponders was noted. 

Median VEGF-A concentration in the ranibizumab group did not change significantly from baseline at 7 and 28 days (61 pg/ml vs 55 pg/ml vs 59 pg/ml, respectively). The aflibercept group demonstrated a significant decrease in systemic VEGF-A levels, from median 40 pg/ml to a concentration below the minimal detection level of 9 pg/ml at day 7 and 16 pg/ml at day 28 (P <.0001; 99% CI, 0-0 and P <.001, respectively). 

Study limitations include the collection of Ang2 and VEGF-A levels via blood samples, rather than aqueous humor or nonvascular tissue and the potential for the current study to underestimate intraocular response of Ang2 to anti-VEGF therapy.

The researchers described “an urgent need to better understand VEGF-independent pathways leading to recurrent disease activity in nAMD. Promising new substances are currently emerging driven by the demand to further decrease the treatment burden and injection rate through prolonged durability.” 


Angermann R, Rauchegger T, Nowosielski Y, et al. Systemic counterregulatory response of angiopoietin-2 after aflibercept therapy for nAMD: A potential escape mechanism. Acta Ophthalmol. Published online December 16, 2020. doi: 10.1111/aos.14691