|Trade names||Eylea, Zaltrap|
|Drug class||Inhibitor of VEGF and PlGF|
|Main uses||Wet macular degeneration, colorectal cancer|
|Side effects||Eye: Subconjunctival bleeding, eye pain, cataracts|
Cancer: Low white blood cells, diarrhea, increased liver enzymes, low platelets
|Intravenous, intravitreal injection|
|Chemical and physical data|
|Molar mass||96898.57 g·mol−1|
Aflibercept, sold under the brand names Eylea and Zaltrap, is a medication used to treat wet macular degeneration and colorectal cancer which has spread to other parts of the body. For colon cancer it is given together with fluorouracil, leucovorin, and irinotecan. It is used by injection into the eye or by intravenous infusion.
Common side effects when used in the eye include subconjunctival bleeding, eye pain, and cataracts. Common side effects when used for cancer include low white blood cells, diarrhea, increased liver enzymes, and low platelets. Other side effects when used for cancer include bleeding, gastrointestinal perforation, and poor wound healing. It is an inhibitor of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF).
Aflibercept was approved for medical use in Europe and the United States in 2012. For the eye it is initially given once a month with a dose of medication costing about 1,950 USD in the United States as of 2021. In the United Kingdom this amount costs the NHS about 41£. When used for cancer, 4 ml of 25 mg/ml solution costs about 1,680 USD as of 2021 in the USA and 296£ in the UK.
It is used for the treatment of wet macular degeneration and is administered as an injection into the eye. It is also used for people with macular edema due to diabetic retinopathy or following retinal vein occlusion.
When used for cancer the effects are typical of anti-cancer drugs, such as reduced blood cell count (leukopenia, neutropenia, thrombocytopenia), gastrointestinal disorders like diarrhoea and abdominal pain, and fatigue. Another common effect is hypertension (increased blood pressure).
Mechanism of action
Tumours need blood vessels sprouting into them when they become larger than a few millimetres, in order to get access to oxygen and nutritive substances to facilitate further growth.
Aflibercept binds to circulating VEGFs and acts like a "VEGF trap". It thereby inhibits the activity of the vascular endothelial growth factor subtypes VEGF-A and VEGF-B, as well as to placental growth factor (PGF), inhibiting the growth of new blood vessels in the choriocapillaris or the tumour, respectively. The aim of the cancer treatment, so to speak, is to starve the tumour.
Regeneron commenced clinical testing of aflibercept in cancer in 2001. In 2003, Regeneron signed a major deal with Aventis to develop aflibercept in the field of cancer. In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases, and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications.
In March 2011, Regeneron reported that aflibercept failed its primary endpoint of overall survival in the Vital phase III trial for second-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), although it improved the secondary endpoint of progression-free survival.
In April 2011, Regeneron reported that aflibercept improved its primary endpoint of overall survival in the Velour phase III clinical trial for second-line treatment for metastatic colorectal cancer (mCRC).
A 2016 Cochrane Review examined outcomes comparing aflibercept versus ranibizumab injections in neovascular AMD. Both treatment options yielded similar improvements in visual acuity and morphological outcomes, though the aflibercept treatment regimen has the potential to reduce treatment burden other risks from injections.
A 2017 review update studying the effects of anti-VEGF drugs on diabetic macular edema found that while all three studied treatments have advantages over laser therapy, there was moderate evidence that aflibercept is favored in all measured efficacy outcomes over ranibizumab and bevacizumab, after one year.
Society and culture
On 3 August 2012, the FDA approved aflibercept for use in combination with 5-fluorouracil, folinic acid and irinotecan to treat adults with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin‑containing regimen. To avoid confusion with the version that is injected into the eye, the FDA assigned a new name, ziv-aflibercept, to the active ingredient.
In February 2013, the European Medicines Agency (EMA) approved aflibercept (Zaltrap) for the treatment of adults with metastatic colorectal cancer for whom treatment based on oxaliplatin has not worked or the cancer got worse. Aflibercept (Zaltrap) is used with FOLFIRI, which is a treatment combining the medicines irinotecan, 5-fluorouracil, and folinic acid.
On 12 March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund. In 2017, injections of aflibercept (HCPCS code J0178) were responsible for the most billing to Medicare Part B, at $2.36 billion.
Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin.
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