Beyond anti-VEGF: The next wave in retinal therapy

The rise of anti-VEGF therapies marked the beginning of a new era in ophthalmology, and fundamentally changed how ophthalmologists manage neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), and other retinal vascular disorders.¹ However, despite the great benefits seen from anti-VEGF therapies over the past 2 decades, for those who respond suboptimally to anti-VEGF agents or those with degenerative conditions such as dry AMD or macular telangiectasia (MacTel), treatment options remained scarce.

Now, fueled by rapid advances in complement modulation, Tie2 pathway targeting, and neurotrophic factor–based therapy, the field stands at the threshold of a truly transformative era in eye care. These new approaches reflect a deeper understanding of the underlying pathophysiology behind retinal conditions and are reshaping the perspective on the long-term preservation of retinal structure and function.

The complement cascade: From histopathology to clinical practice

In AMD, dysregulated activation of the complement cascade contributes to chronic inflammation, cellular injury, and progressive atrophy.² Histopathologic analyses consistently demonstrated deposition of complement components, particularly C3 and C5, within regions of AMD damage,^3,4 and the discovery of genetic associations cemented complement dysregulation as a central driver of the disease.⁵

Although the complement cascade has long been understood to be implicated in the pathogenesis of dry AMD, until recently it has not been possible to translate this understanding into an effective treatment. The approval of two complement inhibitors for geographic atrophy (GA)—pegcetacoplan (Syfovre; Apellis Pharmaceuticals; C3 inhibitor, dosed every other month) and avacincaptad pegol (Izervay; Astellas/IVERIC Bio; C5 inhibitor, dosed monthly)—represents the culmination of decades of research and marks a turning point for the treatment of GA.

Although the two agents differ in molecular target and dosing frequency, their overall risk-benefit profiles are remarkably similar, and both agents were found to slow GA progression by approximately 20% in pivotal trials.⁶ Emerging data suggest that longer-term treatment may yield incremental benefit, likely due to the chronic and progressive nature of GA.⁷ Although these therapies do not halt or reverse atrophy, slowing lesion expansion represents meaningful progress in a disease that previously lacked any approved intervention.

These complement inhibitors were generally well tolerated in the clinical trials leading to their approval, with most of the adverse events related to the intravitreal injection procedure.⁸ It should also be noted that there is a principal class risk of a moderate increase in choroidal neovascularization with complement inhibitors.⁹

The approvals of these first two complement inhibitors have ignited a rapid acceleration in the complement pipeline, and multiple late-stage programs are currently underway, including a phase 3 C1q inhibitor.^10,11 Other approaches currently being explored include alternative complement targets, systemic delivery, and combination strategies.^12,13 Dry AMD is an inherently multifactorial condition, so the future will likely involve combination approaches that can address inflammation, degeneration, and microvascular dysfunction in parallel.

Enhancing vascular stability by targeting the Tie2 pathway

Methods to enhance vascular stability are another area where theoretical understandings of disease pathophysiology are transitioning into therapeutic reality. Specifically, investigators have focused on the Tie2 receptor pathway, which regulates endothelial quiescence and barrier integrity through its interaction with angiopoietins.¹⁴ In healthy individuals, angiopoietin-1 (Ang-1) activates Tie2 to promote vascular stability; conversely, angiopoietin-2 (Ang-2) antagonizes Tie2 signaling, promoting leakage and inflammation. In disease states such as neovascular AMD and DME, this balance is shifted pathologically towards Ang-2.

Faricimab (Vabysmo; Genentech/Roche), a bispecific antibody targeting both VEGF-A and Ang-2, represents the realization of the investigations into this pathway’s therapeutic potential. In the matched phase of pivotal DME trials, faricimab achieved superior anatomic drying compared with aflibercept (Eylea; Regeneron), even with comparable visual outcomes.¹⁵ These findings reinforce earlier studies showing enhanced anatomic outcomes when Ang-2 and VEGF are inhibited together.¹⁶ Building on the success of faricimab, multiple VEGF/Ang-2 bispecific agents are now under investigation.¹⁷

Another compelling approach to this pathway has been the emergence of direct Tie2 agonists, which stimulate the receptor directly rather than inhibiting its antagonists.^18,19 By activating Tie2 directly, small exposures could potentially produce comparable or even superior vascular stabilization. If efforts towards clinical translation of this approach fulfill their preclinical promise, Tie2 agonism could represent the next major leap in retinal vascular therapy.

Protecting the photoreceptor with neurotrophic factors

Neurotrophic factors are essential proteins secreted by retinal neurons that support photoreceptor survival, modulate stress responses, and maintain retinal homeostasis.²⁰ Although neurotrophic factors have received less attention than the complement or Tie2 pathways, their long-term therapeutic potential may be equally significant, and these pathways are emerging as compelling targets for treating neurodegenerative disease.

One area where there is potential for the use of neurotrophic factors has been in pursuing a treatment for MacTel. MacTel is a neurodegenerative disease in which the Müller cells—glial cells that support retinal neurons—become dysfunctional, leading to eventual photoreceptor atrophy and loss of vision.²¹ Ciliary neurotrophic factor (CNTF) is a neurotrophic factor that has been found to reduce the loss of photoreceptors,²² and as such has been investigated for its safety and efficacy in MacTel.²³

Another neurotrophic factor that may have clinical significance is brain-derived neurotrophic factor (BDNF). BDNF is a key neurotrophin involved in neuronal survival, plasticity, and repair, and alterations in BDNF levels have been implicated in retinal neurodegeneration.²⁴ Although no therapy has yet emerged from BDNF, it is under investigation as an emerging target of interest for the treatment of conditions such as diabetic retinopathy and glaucoma.^24,25

Looking ahead

A shift is under way from a VEGF-centric framework for addressing retinal disease to a paradigm in which individualized, multi-pathway interventions are the norm. This proliferation of options brings both excitement and complexity. The field will not have ten therapeutics that each solve everything; it will have ten that address different aspects of multifactorial diseases. The challenge becomes: what to reach for first? How to layer therapies? When to combine versus sequence? In confronting these questions, I believe the field can take a page from oncology colleagues and develop evidence-based guidelines that do not dictate care, but help to navigate the plethora of rapidly expanding options while allowing clinicians to retain their individual clinical judgment.

Ultimately, the future of retinal care will involve integrating diverse mechanisms into cohesive, patient-centered strategies. The technological progress we have already made is astounding, and now it falls to the field to harness these advances to give every patient their best possible chance at excellent vision.

Mark R. Barakat, MD

E: Mark.Barakat@gmail.com

Barakat is founder and director of research at Retina Macula Institute of Arizona in Scottsdale, Arizona, and medical director of Spectra Eye Institute in Sun City, Arizona. He is a clinical assistant professor of ophthalmology at the University of Arizona College of Medicine–Phoenix and a fellow of the American Academy of Ophthalmology and the American Society of Retina Specialists.

Financial disclosures: Barakat reports being a consultant for AbbVie, Adverum Biotech, Alcon, Alkeus, ANI Pharmaceuticals, Annexon, Apellis, Astellas, Bausch + Lomb, Beacon, Biocryst, Boehringer Ingelheim, Celltrion, Cencora, Clearside Biomedical, EyePoint Pharma, Genentech, Glaukos, Kodiak Sciences, Harrow, Janssen, Neurotech, Ocular Therapeutix, Oculis, Opthea, Outlook Therapeutics, Palatin Technologies, Regeneron, RegenxBio, RetinAI, RevOpsis Therapeutics, Roche, Sanofi, Stealth Biotherapeutics and Surrozen; being an investigator for 4DMT, Adverum Biotech, Annexon Biosciences, Beacon, Boehringer Ingelheim, Clearside Biomedical, EyeBio, EyePoint Pharma, Genentech, Glaukos, Kanghong/Vanotech, Kodiak Sciences, Ocular Therapeutix, Oculis, Opthea, Perceive Bio, Perfuse, Regeneron, RegenxBio, Roche, and Stealth Biotherapeutics; being a speaker for Alcon, ANI Pharmaceuticals, Apellis, Astellas, Genentech, and Regeneron; and having stock/stock options in NeuBase, Oxurion, and RevOpsis Therapeutics.

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