VEGF-C and VEGF-D signaling pathways: Potential targets for treating wet AMD


A novel formulation may prevent blood vessel growth and vascular leakage in the retina

Arrows hit a target on a yellow background. Image credit: ©MclittleStock –

Investigators said wet AMD's pathophysiology "is broader than dysregulation or overproduction of VEGF-A." Image credit: ©MclittleStock –

There is more than one way to target vascular endothelial growth factor (VEGF) in wet age-related macular degeneration (AMD) because of the recognition of the number of signaling pathways in the retina.

To now, most of the research has focused on targeting VEGF-A. In a press release, Opthea Limited Inc. announced its formulation of sozinibercept (OPT-302), a novel, first-in-class formulation to target the VEGF-C and -D pathways. The current published review1 shows sozinibercept’s potential to prevent blood vessel growth and vascular leakage in the retina as a treatment for wet AMD. The recognition is that the “pathophysiology is broader than dysregulation or overproduction of VEGF-A,” the investigators pointed out.

In addition, the review discusses both the role of VEGF-C and VEGF-D signaling in both health and disease and strategies to target the VEGF-C and -D signaling pathways to focus on better visual outcomes for this patient population.

The expectation is that the company will report topline data for the COAST trial (NCT04757636) in early Q2 and for the ShORe trial (NCT04757610) in mid CY 2025.

Phase 2b trial

In the prospective, randomised, controlled Phase 2b trial,2 366 treatment-naïve patients with wet AMD received sozinibercept in combination with standard-of-care ranibizumab (Lucentis, Genentech Inc.). Sozinibercept combination therapy met the pre-specified primary efficacy endpoint of a statistically superior gains in visual acuity at 24 weeks compared to ranibizumab alone. The secondary outcomes were positive with the combination therapy, including more patients gaining vision of 10 or more letters, improved anatomy, with reduced swelling and vascular leakage and a favorable safety profile, the company reported.

According to Frederic Guerard, PharmD, Chief Executive Officer of Opthea, “This review underpins sozinibercept’s potential as a novel, first-in-class VEGF-C/D ‘trap’ to prevent blood vessel growth and vascular leakage in the retina and deliver superior visual outcomes in wet AMD patients when combined with standard-of-care anti-VEGF-A therapies. Our fully enrolled sozinibercept Phase 3 clinical program in wet AMD is designed to assess the safety and superior efficacy of sozinibercept in combination with standard-of-care anti-VEGF-A therapies compared to standard-of-care alone.”

Sozinibercept has received Fast Track Designation from the US FDA for the treatment of wet AMD, according to the press release.


  1. Leitch IM, Gerometta M, Eichenbaum D, et al. Vascular endothelial growth factor C and D signaling pathways as potential targets for the treatment of neovascular age-related macular degeneration: a narrative review. Ophthalmol Ther. 2024;13:1857–1875;
  2. Jackson TL, Slakter J, Buyse M, et al. for theOpthea Study Group Investigators. A randomized controlled trial of OPT-302, a VEGF-C/D inhibitor for neovascular age-related macular degeneration. Ophthalmology. 2023; DOI:
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