FLORetina 2025: Fibrosis, a limiting factor in visual acuity outcomes in neovascular AMD

Preventing the development of fibrosis is a major unmet need in patients with neovascular age-related macular degeneration (AMD) and a major cause of irreversible visual loss in neovascular AMD. While great strides have been made recently in AMD treatments, the development of fibrosis can occur in high percentages of eyes undergoing treatment with anti-vascular endothelial growth factor (VEGF) therapies, according to Anat Loewenstein, MD, MHA, who discussed this topic at the FLOretina 2025 Congress in Florence, Italy, from December 4-7.

She is professor and director of the Division of Ophthalmology and vice president of Ambulatory Services at the Tel Aviv Medical Center, all in Tel Aviv, Israel.

She commented, “Even though anti-VEGF therapy has revolutionized the standard of care of neovascular AMD, up to one-third of treated eyes develop fibrotic scars within 1 year of the onset of treatment and nearly half of patients by 2 years of treatment, regardless of the type of anti-VEGF treatment or the dosing regimen.”

She added that with the appearance of fibrosis, the visual acuity is significantly affected, especially in Type 2 and mixed macular neovascularization, in which the prevalence of fibrosis can exceed 85% to 95%.

A few different factors are instrumental in the development of fibrosis, with the major drivers being transforming growth factor (TGF)-β2, VEGF-mediated vascular modifications, a cascade of growth factors and cytokines that promote fibroproliferation, and extracellular matrix deposition, she explained.

What treatments are under development to prevent fibrosis?

Currently, several emerging treatments are moving through the pipeline that are designed to block the pathways to fibrosis development.

Nintedanib (CBT-001, Santen and Cloudbreak Pharma) is an investigational tyrosine kinase inhibitor that blocks epithelial-to-mesenchymal transition changes in retinal pigment epithelial cells and has minimized the development of fibrosis and neovascularization among preclinical models, Dr. Loewenstein reported.

Investigations have also found strong anti-fibrotic effects exhibited by dual pathway inhibition with angiotensin-2/VEGF-A blockers. In murine models, these combination formulations were shown to prevent collagen remodelling and reduce fibronectin; these are treatment effects that VEGF-A alone cannot achieve.

A treatment that is the furthest along in the pipeline is ISTH0036 (Isarna Therapeutics), which Dr. Loewenstein described as an antisense therapy targeting TGF-β2. The results of the phase 2 BETTER clinical trial evaluated the ability of this investigational drug to suppress TGF-β2, a key cytokine in fibrosis. Treatment-naïve patients and those treated with anti-VEGF drugs received intravitreal injections of ISTH0036 every eight weeks.

The final positive results from the clinical trial conducted in Austria and India showed that treated patients had stable or improved best-corrected visual acuity and meaningful anatomic improvements in the retina. The central retinal thickness decreased in all patient groups.¹

Loewenstein said, “This has shown potential suppression of fibrosis in preclinical studies and produced promising phase 2 clinical data in neovascular AMD. Outcomes consist of reduced central retinal thickness, prevention or reduction of hyper-reflective material, and in some cases improvement in visual acuity.”

In conclusion, fibrosis remains a major unmet need in patients with neovascular AMD. Novel agents targeting TGF-β2, vascular remodeling, and EMT pathways look promising for preventing or reversing fibrotic progression along with or beyond the standard anti-VEGF therapy.

Reference

1. Isarna Therapeutics Presents Positive Phase 2 BETTER Trial Final Results at ARVO 2025. Isarna Therapeutics. May 7, 2025. Accessed May 7, 2025. https://www.streetinsider.com/Globe+Newswire/Isarna+Therapeutics+Presents+Positive+Phase+2+BETTER+Trial+Final+Results+at+ARVO+2025/24752465.html