Aflibercept is a biopharmaceutical drug invented by Regeneron Pharmaceuticals, approved in the United States and Europe for the treatment of wet macular degeneration under the trade name Eylea, and for metastatic colorectal cancer as Zaltrap. As the active ingredient of Zaltrap, the substance is called ziv-aflibercept in the US.
|Trade names||Eylea, Zaltrap|
|Chemical and physical data|
|Molar mass||96.90 kg/mol g·mol−1|
|(what is this?)|
Aflibercept is being co-developed for cancer treatment by Sanofi and Regeneron under a deal signed in 2003, and is being co-developed for eye diseases by Bayer HealthCare and Regeneron under a deal signed in 2006.
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.
Indications and administrationEdit
Eylea, the formulation for the treatment of wet macular degeneration, is administered as an intravitreal injection, that is, into the eye. Zaltrap, for cancer treatment, is given intravenously in combination with the other cancer drugs 5-fluorouracil and irinotecan and the adjuvant folinic acid. In August 27, 2014, Eylea was also indicated for the treatment of patients with visual impairment due to diabetic macular oedema, according to the updated summary of product characteristics. In May 2019 FDA expanded the indication for Eylea (aflibercept) to include all stages of diabetic retinopathy. Conclusion: Eylea (aflibercept) Injection 2 mg (0.05 mL) is indicated for the treatment of patients with Neovascular (Wet) Age-related Macular Degeneration (AMD), Macular Edema following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME), and Diabetic Retinopathy (DR).
Zaltrap has adverse effects 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 actionEdit
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, Regeneon 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 over 2400 patients with neovascular AMD, from two randomized controlled trials. Both treatment options yielded similar improvements in visual acuity and morphological outcomes in patients, though the authors note that 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 significantly favored in all measured efficacy outcomes over ranibizumab and bevacizumab, after one year.
On August 3, 2012 the FDA approved aflibercept (Zaltrap) 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 Eylea, the FDA assigned a new name, ziv-aflibercept, to the active ingredient.
On February 1, 2013 the European Commission granted a marketing authorisation valid throughout the European Union for treatment of adults with metastatic colorectal cancer for whom treatment based on oxaliplatin has not worked or the cancer got worse, in combination with the other drugs mentioned above.
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.
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