Beyond VEGF

DME and nAMD are multifactorial diseases driven by various signalling pathways, with factors other than VEGF involved in pathogenesis.
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Opportunities to optimise outcomes in the real world

Real-world analyses of >78,000 patient eyes have shown that patients with DME or nAMD tend to receive fewer anti-VEGF injections in clinical practice compared with clinical trials, and may fall short of efficacy expectations, potentially leading to suboptimal vision.1,2

Hear from the experts:
VEGF inhibition and
beyond: Building on
existing foundations

Patricio G. Schlottmann, MD

Charles Wykoff, MD, PhD

Anat Loewenstein, MD

Real-world injection frequency correlates with vision improvement
nAMD
Chart / nAMD −2 −4 0 2 4 8 6 10 1 5 9 2 6 10 3 7 11 4 8 12 13 Number of anti-VEGF injections in 1st year Mean vision change (letters)

Reprinted from Ophthalmology Retina, 4(1), Ciulla TA, et al., Visual acuity outcomes and anti-vascular endothelial growth factor therapy intensity in neovascular age-related macular degeneration patients: a real-world analysis of 49485 eyes, 19–30, Copyright (2020), with permission from Elsevier.

DME
Chart / DME −2 −4 0 2 4 8 6 10 1 5 9 2 6 10 3 7 11 4 8 12 13 Number of anti-VEGF injections in 1st year Mean vision change (letters)

Reproduced from Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28658 eyes, Ciulla TA, et al. 0:1–6, Copyright (2020), with permission from BMJ Publishing Group Ltd

Beyond VEGF: Signalling pathways in vascular instability

DME and nAMD are multifactorial diseases3,4 driven by vascular instability, characterised by vascular leakage, inflammation, and neovascularisation.5

Multiple signalling pathways, including the Ang–Tie pathway, work together to contribute to this vascular instability, and are stimulated by conditions of cellular stress.5,6

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

Stephan Michels, MD

Augenklinik Zürich West and University of

Zürich, Switzerland

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AMD, age-related macular degeneration; Ang, angiopoietin; DME, diabetic macular edema; DR, diabetic retinopathy; IVT, intravitreal; 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...

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References

  1. Ciulla TA, et al. Ophthalmol Retina. 2020;4:19–30
  2. Ciulla TA, et al. Br J Ophthalmol. 2021;105:216–21
  3. Chakravarthy U, et al. Retina. 2018;38:343–51
  4. Swaroop A, et al. Annu Rev Genomics Hum Genet. 2009;10:19–43
  5. Joussen AM, et al. Eye. 2021;35:1305–16
  6. Saharinen P, et al. Nat Rev Drug Discov. 2017;16:635–61
  7. Regula JT, et al. EMBO Mol Med. 2016;8:1265–88
  8. Regula JT, et al. EMBO Mol Med. 2019;11:e10666
nAMD
Chart / nAMD −2 −4 0 2 4 8 6 10 1 5 9 2 6 10 3 7 11 4 8 12 13 Number of anti-VEGF injections in 1st year Mean vision change (letters)

Reprinted from Ophthalmology Retina, 4(1), Ciulla TA, et al., Visual acuity outcomes and anti-vascular endothelial growth factor therapy intensity in neovascular age-related macular degeneration patients: a real-world analysis of 49485 eyes, 19–30, Copyright (2020), with permission from Elsevier. Figure adapted from Ciulla TA, et al. Ophthalmol Retina. 2020;4:19–30

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In real-world analyses of treatment-naive patients with nAMD, patients received fewer anti-VEGF injections and experienced worse visual outcomes on average compared with patients receiving fixed, frequent therapy in clinical trials. Less than 25% of real-world patient eyes received sufficient injections (10 or more) to achieve maximal vision gains with IVT anti-VEGF therapy.1

DME
Chart / DME −2 −4 0 2 4 8 6 10 1 5 9 2 6 10 3 7 11 4 8 12 13 Number of anti-VEGF injections in 1st year Mean vision change (letters)

Reproduced from Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28658 eyes, Ciulla TA, et al. 0:1–6, Copyright (2020), with permission from BMJ Publishing Group Ltd

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In real-world analyses of treatment-naive patients with DME, patients received fewer anti-VEGF injections and experienced worse visual outcomes on average compared with patients receiving fixed, frequent therapy in clinical trials. Less than 20% of real-world patient eyes received sufficient injections (10 or more) to achieve maximal vision gains with IVT anti-VEGF therapy.2

Ang-2
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.

© 2019 F. Hoffmann‐La Roche AG Published under the terms of the CC BY 4.0 license

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

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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.7,8

Ang-1
Ang-1 levels in human vitreous samples
1 4 16 64 1024 256 4096 16,384 (pg/mL) Log scale Control nAMD R VO DR PDR 34.8 107.6 107.3 86.2 65.4

Median values

Adapted from Regula JT, et al. EMBO Mol Med. 2019;11:e10666.

© 2019 F. Hoffmann‐La Roche AG Published under the terms of the CC BY 4.0 license

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

icon-info.png

Ang-1 levels were similar in the vitreous samples from patients with retinal or choroidal vascular diseases and in samples from healthy individuals, suggesting stable expression in normal and pathologic conditions.7,8