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Wednesday, August 20, 2025

Anti-angiogenic ophthalmic agents


Introduction

Pathological angiogenesis within the eye is a major cause of vision loss in several ocular diseases, most notably neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), retinal vein occlusion (RVO), and myopic choroidal neovascularization (mCNV). Uncontrolled angiogenesis is driven primarily by overexpression of vascular endothelial growth factor (VEGF), which promotes abnormal blood vessel growth, leakage, and edema within the retina and choroid.

Anti-angiogenic ophthalmic agents—primarily VEGF inhibitors—have become the gold standard of care for these sight-threatening conditions. Delivered directly into the vitreous cavity via intravitreal injection, these biologic drugs suppress abnormal blood vessel growth and restore retinal anatomy, significantly improving or stabilizing visual acuity.

Mechanism of Action

VEGF Pathway in the Eye

  • VEGF-A is a central mediator of angiogenesis and vascular permeability.

  • In retinal disease, hypoxia-induced VEGF overproduction leads to:

    • Choroidal neovascularization (CNV) in AMD

    • Capillary leakage and macular edema in DME and RVO

    • Pathologic vessel proliferation in proliferative diabetic retinopathy (PDR)

Anti-VEGF Agents

Anti-angiogenic ophthalmic agents act by neutralizing VEGF molecules or blocking VEGF receptors, preventing VEGF-driven angiogenesis and vascular leakage.

The main mechanisms include:

  1. Ligand binding blockade: Antibodies or fusion proteins sequester VEGF-A (and sometimes other isoforms like VEGF-B, PlGF).

  2. Receptor blockade: Small molecules or engineered proteins prevent VEGF from binding its receptors (VEGFR-1, VEGFR-2).

  3. VEGF-trap strategy: Decoy receptors fused to Fc fragments bind VEGF with high affinity.

Representative Drugs

1. Ranibizumab (Lucentis®)

  • Generic name: Ranibizumab

  • Type: Recombinant humanized monoclonal antibody fragment (Fab) against VEGF-A

  • Indications:

    • Neovascular (wet) AMD

    • Diabetic macular edema (DME)

    • Diabetic retinopathy (DR)

    • Macular edema following RVO

    • Myopic CNV

  • Dosing:

    • 0.5 mg intravitreal injection once monthly (q4 weeks) initially

    • Alternative regimens: “treat-and-extend” or “pro re nata (PRN)” after loading phase

2. Bevacizumab (Avastin® – off-label ophthalmic use)

  • Generic name: Bevacizumab

  • Type: Full-length humanized monoclonal antibody against VEGF-A

  • Indications:

    • Approved for systemic cancers (colorectal, lung, renal cell, etc.)

    • Widely used off-label in ophthalmology for AMD, DME, RVO, mCNV due to lower cost compared with ranibizumab and aflibercept

  • Dosing:

    • 1.25 mg intravitreal injection every 4 weeks

3. Aflibercept (Eylea®)

  • Generic name: Aflibercept

  • Type: Recombinant fusion protein (VEGF-trap) combining VEGFR-1 and VEGFR-2 extracellular domains fused to IgG Fc

  • Indications:

    • Wet AMD

    • DME

    • DR

    • Macular edema following RVO

  • Dosing:

    • 2 mg intravitreal injection every 4 weeks for the first 3 months

    • Then every 8 weeks (can extend up to 12–16 weeks with “treat-and-extend” regimens)

4. Brolucizumab (Beovu®)

  • Generic name: Brolucizumab-dbll

  • Type: Single-chain antibody fragment targeting VEGF-A

  • Indications:

    • Wet AMD

    • DME (FDA expanded approval)

  • Dosing:

    • 6 mg intravitreal injection every 4 weeks for 3 doses, then every 8–12 weeks

  • Notable issue: Associated with higher risk of intraocular inflammation and retinal vasculitis compared with other agents

5. Faricimab (Vabysmo®)

  • Generic name: Faricimab-svoa

  • Type: Bispecific antibody targeting VEGF-A and Angiopoietin-2 (Ang-2)

  • Indications:

    • Wet AMD

    • DME

    • RVO (2023 FDA approval)

  • Dosing:

    • 6 mg intravitreal injection every 4 weeks for 4 doses, then every 8–16 weeks

  • Advantage: Dual inhibition of VEGF and Ang-2 improves durability, reducing injection frequency

6. Pegaptanib (Macugen® – discontinued in many markets)

  • Generic name: Pegaptanib sodium

  • Type: RNA aptamer specifically binding VEGF165 isoform

  • Indications:

    • First anti-VEGF approved for AMD (2004), but now largely replaced by more effective broad-spectrum VEGF inhibitors

  • Dosing:

    • 0.3 mg intravitreal injection every 6 weeks

Clinical Uses

  • Neovascular AMD: All anti-VEGF agents provide vision stabilization and often improvement; aflibercept, ranibizumab, and faricimab dominate clinical use.

  • Diabetic Macular Edema and Diabetic Retinopathy: Ranibizumab, aflibercept, bevacizumab (off-label), brolucizumab, and faricimab are standard.

  • Retinal Vein Occlusion (central or branch): Ranibizumab, aflibercept, faricimab, and off-label bevacizumab reduce macular edema and improve vision.

  • Myopic Choroidal Neovascularization: Ranibizumab, aflibercept, and bevacizumab (off-label) are used effectively.

  • Retinopathy of Prematurity (ROP): Bevacizumab has been investigated off-label, especially for severe cases.

Contraindications

  • Ocular or periocular infection

  • Active intraocular inflammation

  • Hypersensitivity to active drug or formulation components

  • Pregnancy: Anti-VEGF therapy should be used with caution (possible risk of systemic VEGF suppression affecting fetal development)

Adverse Effects

Ocular Adverse Effects

  • Endophthalmitis (serious but rare)

  • Intraocular inflammation and uveitis

  • Retinal detachment or tear

  • Vitreous hemorrhage

  • Transient rise in intraocular pressure (IOP)

  • Retinal vasculitis and vascular occlusion (notably with brolucizumab)

Systemic Adverse Effects (rare due to low systemic absorption)

  • Arterial thromboembolic events (stroke, myocardial infarction)

  • Hypertension

  • Proteinuria (theoretical risk from systemic VEGF blockade, more relevant with systemic bevacizumab)

Precautions

  • Strict aseptic technique during intravitreal injection

  • Monitor for signs of endophthalmitis (eye pain, redness, photophobia, vision loss)

  • Caution in patients with a history of stroke, myocardial infarction, or thromboembolic disease

  • Regular monitoring of IOP post-injection

  • Pregnant or breastfeeding women: Use only if potential benefit outweighs risk

Drug Interactions

  • Systemic anti-VEGF therapy (bevacizumab, aflibercept for cancer): May increase risk of systemic VEGF suppression if combined with intravitreal agents.

  • Anticoagulants/antiplatelets: May increase risk of ocular hemorrhage, though not a strict contraindication.

  • Other intravitreal therapies (steroids): Can be used sequentially or in combination for refractory cases but increase risks of infection, cataract, or elevated IOP.

Dosing Regimens and Strategies

  1. Fixed dosing: Monthly or bimonthly injections (ranibizumab, aflibercept).

  2. PRN (as needed): Injections based on disease activity assessed via OCT and visual acuity.

  3. Treat-and-extend: Injection intervals gradually extended (up to 12–16 weeks) while maintaining disease control. This approach reduces treatment burden without compromising efficacy.

Future Directions

  • Long-acting delivery systems:

    • Ranibizumab Port Delivery System (PDS) allows refillable implants for 6-month dosing.

  • Gene therapy approaches:

    • Investigational vectors delivering anti-VEGF genes for continuous intraocular expression.

  • Novel targets beyond VEGF:

    • Angiopoietin/Tie2 pathway modulators (faricimab already approved)

    • PDGF inhibitors and integrin inhibitors under study

Summary of Key Anti-Angiogenic Ophthalmic Agents

  • Ranibizumab: 0.5 mg IVT monthly, widely used

  • Bevacizumab: 1.25 mg IVT monthly, off-label but cost-effective

  • Aflibercept: 2 mg IVT every 4 weeks × 3, then q8 weeks (extendable)

  • Brolucizumab: 6 mg IVT q4 weeks × 3, then q8–12 weeks

  • Faricimab: 6 mg IVT q4 weeks × 4, then q8–16 weeks

  • Pegaptanib: 0.3 mg IVT q6 weeks (largely obsolete)




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