Aflibercept: VEGF trap in AMD, DME and mCRC
Aflibercept is a recombinant fusion protein of human extracellular domains of VEGF receptors VEGFR1 and VEGFR2 with the Fc fragment of human IgG1. It functions as a VEGF trap, binding and neutralising VEGF A, VEGF B and placental growth factor (PlGF) with high affinity. By inhibiting angiogenesis and vascular permeability, aflibercept is used in two very different fields: ophthalmology (Eylea) and oncology (Zaltrap).
In ophthalmology aflibercept has been approved since 2012 for wet age related macular degeneration (nAMD) and since 2015 for diabetic macular oedema (DME) and other retinal disorders. In oncology aflibercept is used in metastatic colorectal cancer (mCRC) in combination with FOLFIRI.
Mechanism of action
VEGF (vascular endothelial growth factor) is a key driver of angiogenesis, the formation of new blood vessels. In pathological processes such as nAMD or tumour growth, VEGF is overexpressed and stimulates leaky neovessels and increased permeability of existing vessels.
As a soluble fusion receptor, aflibercept binds VEGF A, VEGF B and PlGF with higher affinity than the natural VEGF receptors. This prevents binding to cell bound receptors and interrupts the signalling cascade. Clinically:
- Reduction of subretinal fluid and macular oedema
- Stabilisation or improvement of visual acuity
- In oncology, antiangiogenic effect with slowing of tumour growth
Unlike bevacizumab and ranibizumab, aflibercept additionally binds VEGF B and PlGF, theoretically enabling broader angiogenesis inhibition.
Indications
- Wet age related macular degeneration (nAMD)
- Diabetic macular oedema (DME)
- Macular oedema after retinal vein occlusion (BRVO, CRVO)
- Myopic choroidal neovascularisation
- Retinopathy of prematurity (with Eylea HD)
- Metastatic colorectal cancer (Zaltrap): in combination with FOLFIRI after failure of an oxaliplatin based therapy
Dosing and administration
Eylea (intravitreal): initial 2 mg (0.05 ml) intravitreally monthly for 3 injections, then every 2 months. With stable disease, a flexible treat and extend regimen with 8 to 16 week intervals is possible. Eylea HD (8 mg) has allowed longer intervals since 2023.
Zaltrap (intravenous): 4 mg per kg body weight intravenously over 1 hour every 2 weeks, in combination with FOLFIRI chemotherapy.
Intravitreal use: performed in a sterile setting in an ophthalmology practice or clinic. Skin disinfection, topical anaesthesia, lid speculum, sterile injection through the pars plana with a fine needle.
Post injection checks: intraocular pressure, visual acuity, funduscopy. Patients are informed about endophthalmitis symptoms (vision loss, pain, redness).
Adverse effects
Intravitreal common: conjunctival haemorrhage at the injection site, eye pain, raised intraocular pressure, vitreous detachment, visual disturbance, conjunctivitis, floaters.
Intravitreal rare: endophthalmitis (sight threatening), retinal detachment, traumatic cataract, severe rise in intraocular pressure.
Systemic (Zaltrap): hypertension, proteinuria, wound healing problems, bleeding, gastrointestinal perforation, fistula formation, posterior reversible encephalopathy syndrome (PRES), arterial thromboembolic events, fatigue, diarrhoea.
Important points:
- Endophthalmitis is rare but sight threatening; patients must know early signs
- Monitor blood pressure regularly under systemic therapy
- Pause therapy before surgery because of wound healing and bleeding risk
- Pregnancy contraception during and after therapy
Interactions
- Other antiangiogenic agents (bevacizumab, ranibizumab): intravitreal switching is possible, simultaneous use not established
- High dose chemotherapy: additive toxicity in oncology use
- Anticoagulants: increased bleeding risk
- Live vaccines: contraindicated with systemic use
Special considerations
Pregnancy: contraindicated due to teratogenic potential. Reliable contraception during and at least 6 months after therapy.
Breastfeeding: contraindicated.
Surgery: pause systemic therapy at least 4 weeks before elective surgery because of wound healing and bleeding risk.
Hypertension: regular blood pressure monitoring; adapt antihypertensive therapy as needed.
Patient information for intravitreal use: with worsening vision, eye pain, redness or photophobia after injection, see an ophthalmologist immediately to rule out endophthalmitis.
Treatment success: in ophthalmology monthly checks with OCT (optical coherence tomography) and visual acuity, individual adjustment of injection intervals. In oncology imaging every 6 to 12 weeks.
Patient communication: realistic information about the need for repeated injections over long periods in chronic retinal disease. Therapy cannot cure the disease but can slow or prevent vision loss.
Related substances
- Bimatoprost, prostaglandin analogue in glaucoma
- Tafluprost, another prostaglandin analogue in glaucoma
- Regorafenib, oral multikinase inhibitor
- Fruquintinib, highly selective VEGFR TKI
- Sotorasib, KRAS G12C inhibitor
Frequently asked questions
How often do I need to attend the eye clinic?
In nAMD or DME monthly injections initially, then individually adjusted every 8 to 16 weeks depending on disease activity. With Eylea HD (8 mg) longer intervals are possible. Regular use is decisive for treatment success.
What is endophthalmitis?
A rare but serious intraocular infection after injection, with vision loss, eye pain, redness and photophobia. It occurs in about 1 in 1,000 to 5,000 injections and requires immediate antibiotic therapy and possibly vitrectomy. Patients should know the early signs and seek hospital care immediately.
Does aflibercept cure macular degeneration?
No. Aflibercept slows progression and can stabilise or improve vision but cannot cure the disease. Continuing therapy is usually required to maintain the result. With discontinuation deterioration is likely.
How does aflibercept differ from ranibizumab?
Besides VEGF A, aflibercept also binds VEGF B and PlGF, has higher affinity and generally allows longer injection intervals. Ranibizumab is an antibody fragment that only binds VEGF A. Both are clinically effective; choice depends on patient factors, course and tolerability.
Sources
- EMA Eylea (aflibercept) EPAR
- EMA Zaltrap (aflibercept) EPAR
- BfArM German Federal Institute for Drugs and Medical Devices
- Gelbe Liste aflibercept monograph
Legal notice and disclaimer
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