Beyond VEGF

DME, nAMD, and RVO are multifactorial diseases driven by various signalling pathways, with factors other than VEGF involved in pathogenesis.

Opportunities to address patients with unmet needs in the real world

Unmet needs exist for patients with nAMD, DME, and RVO-related macular edema worldwide.

Although anti-VEGF therapies have redefined the care of patients with retinal diseases…

nAMD, DME, and RVO remain a leading cause of vision loss with increasing global prevalence.


~20 million people globally have nAMD*,1


~18 million people worldwide have DME†,2


>28 million adults globally have RVO3


*Based on ~200 million people having AMD globally, of which ~10% have nAMD. People with clinically significant macular edema

…New treatments are still required to reduce treatment burden

Treatment burden

Patient/caregiver burdens create a barrier to treatment resulting in undertreatment.4–15


Undertreatment contributes to suboptimal long-term vision outcomes in patients with nAMD4–8, DME9–13, and RVO.13–15

The nature of retinal diseases

Anti-VEGF injections do not completely address the multifactorial nature of retinal diseases16–19, which may include an inflammatory component.


Beyond VEGF: Signalling pathways in vascular instability

DME, nAMD, and RVO are multifactorial diseases16,18–20 driven by vascular instability, characterised by vascular leakage, inflammation, and neovascularisation.21

Multiple signalling pathways, including the Ang–Tie pathway, work together to contribute to this vascular instability, and are stimulated by conditions of cellular stress.21,22

Hear from the experts:
Pathways mediating
nAMD, DME, and DR

Stephan Michels, MD

Augenklinik Zürich West and University of Zürich, Zürich, Switzerland

Register your interest

Register to receive notifications from Roche Ophthalmology, including website updates and news about angiopoietins.


Clinical relevance of Ang-2

What happens to Ang-2 levels in retinal diseases?

Ang-2 levels in human vitreous samples
1 4 16 64 1024 256 4096 16,384 (pg/mL) Log scale Control nAMD R VO DR PDR **** 1625 **** 302 **** 1 140 * 139 68.4

Median values

*p<0.05; ****p<0.0001.

A nonparametric Kruskal–Wallis analysis followed by Dunn’s method for multiple comparisons was used to show significant differences of the groups to control.

Adapted from Regula JT, et al. EMBO Mol Med. 2016;8(11):1265–88.


Ang-2 levels are increased in the vitreous of patients with retinal or choroidal vascular diseases, including AMD, DR, and RVO, supporting a role for Ang-2–Tie2 signalling in these pathologic conditions.23,24


AMD, age-related macular degeneration; Ang, angiopoietin; DME, diabetic macular edema; DR, diabetic retinopathy; nAMD, neovascular age-related macular degeneration; PDR, proliferative diabetic retinopathy; RVO, retinal vein occlusion; Tie, tyrosine kinase with immunoglobulin-like domains; VEGF, vascular endothelial growth factor.

Learn more about the key players of the Ang–Tie pathway, and uncover a timeline of key discoveries...

Continue to


  1. Hayashi-Mercado R, et al. Int J Retin Vitr. 2022;8:29
  2. Teo ZL, et al. Ophthalmology. 2021;128:1580–91
  3. Song P, et al. J Glob Health. 2019;9:010427
  4. Holz FG, et al. Br J Ophthalmol. 2015;99:220–6
  5. Tufail A, et al. Ophthalmology. 2014;121:1092–101
  6. Maguire MG, et al. Ophthalmology. 2016;123:1751–61
  7. Rofagha S, et al. Ophthalmology. 2013;120:2292–9
  8. Ciulla TA, et al. Ophthalmol Retina. 2020;4:19–30
  9. Willis JR, et al. JAMA Ophthalmol. 2017;135:926–32
  10. Gonder JR, et al. J Ophthalmol. 2014;2014:939315
  11. Kiss S, et al. Clin Ophthalmol. 2016:10 2443–53
  12. Ciulla TA, et al. Br J Ophthalmol. 2021;105:216–21
  13. Sivrapraasad S, et al. Clin Ophthalmol. 2016;10:939–46
  14. Ciulla TA, et al. Br J Ophthalmol. 2021;105:1696–704
  15. Laouri M, et al. Eye (Lond). 2011;25:981–8
  16. Chakravarthy U, et al. Retina. 2018;38:343–51
  17. Ratnapriya R, et al. Clin Genet. 2013;84:160–6
  18. Kolar P. J Ophthalmol. 2014;2014:724780
  19. Kleinman ME, et al. Ophthalmologica. 2010;224:16–24
  20. Swaroop A, et al. Annu Rev Genomics Hum Genet. 2009;10:19–43
  21. Joussen AM, et al. Eye. 2021;35:1305–16
  22. Saharinen P, et al. Nat Rev Drug Discov. 2017;16:635–61
  23. Regula JT, et al. EMBO Mol Med. 2016;8:1265–88
  24. Regula JT, et al. EMBO Mol Med. 2019;11:e10666