Aflibercept

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Aflibercept
Clinical data
Trade names Eylea, Zaltrap
Licence data US FDA:link
Pregnancy cat. C (US)
Legal status -only (US)
Routes Injection
Identifiers
CAS number 862111-32-8 N
ATC code L01XX44 S01LA05
UNII 15C2VL427D YesY
KEGG D09574 YesY
Chemical data
Formula C4318H6788N1164O1304S32 
Mol. mass 96.90 kDa
 N (what is this?)  (verify)

Aflibercept (INN, USAN) 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.

It is an inhibitor of vascular endothelial growth factor (VEGF).[1][2]

Aflibercept is being co-developed for cancer by Sanofi and Regeneron for cancer 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.[3]

Composition[edit]

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.[4]

Indications and administration[edit]

Eylea, the formulation for the treatment of wet macular degeneration, is administered as an intravitreal injection, that is, into the eye.[5] Zaltrap, for cancer treatment, is given intravenously in combination with the other cancer drugs 5-fluorouracil and irinotecan and the adjuvant folinic acid.[6]

Contraindications[edit]

Eylea is contraindicated in patients with infections or active inflammations of or near the eye,[5] while Zaltrap has no contraindications.[6]

Adverse effects[edit]

Common adverse effects of the eye formulation include conjunctival hemorrhage, eye pain, cataract, vitreous detachment, floaters, and ocular hypertension.[5]

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).[6]

Interactions[edit]

No interactions are described for either formulation.[5][6]

Mechanism of action[edit]

In wet macula degeneration, abnormal blood vessel grow in the choriocapillaris, a layer of capillaries in the eye, leading to blood and protein leakage below the macula.

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".[7] 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.[8] The aim of the cancer treatment, so to speak, is to starve the tumour.

History[edit]

Regeneron commenced clinical testing of aflibercept in cancer in 2001.[9] In 2003, Regeneon signed a major deal with Aventis to develop aflibercept in the field of cancer.[10] In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases,[9] and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications.[11]

Clinical trials[edit]

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.[8][12]

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).[8]

Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer as of April 2011.[8]

Approvals[edit]

In November 2011 the United States Food and Drug Administration (FDA) approved aflibercept (Eylea) for the treatment of wet macular degeneration.[13]

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.[4] To avoid confusion with Eylea, the FDA assigned a new name, ziv-aflibercept, to the active ingredient.[14]

In November 2012 the European Medicines Agency (EMA) approved aflibercept for the treatment of wet macular degeneration.[15]

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.[16]

References[edit]

  1. ^ Fraser HM, Wilson H, Silvestri A, Morris KD, Wiegand SJ (May 2008). "The Role of Vascular Endothelial Growth Factor and Estradiol in the Regulation of Endometrial Angiogenesis and Cell Proliferation in the Marmoset". Endocrinology 149 (9): 4413–20. doi:10.1210/en.2008-0325. PMID 18499749. 
  2. ^ Duncan WC, van den Driesche S, Fraser HM (July 2008). "Inhibition of Vascular Endothelial Growth Factor in the Primate Ovary Up-Regulates Hypoxia-Inducible Factor-1{alpha} in the Follicle and Corpus Luteum". Endocrinology 149 (7): 3313–20. doi:10.1210/en.2007-1649. PMID 18388198. 
  3. ^ The Vault. Regeneron Pharmaceuticals, Inc. Page accessed April 14, 2014
  4. ^ a b "Ziv-Aflibercept". FDA Drug Approvals Database. Food and Drug Administration. August 3, 2012. Retrieved 2013-10-16. 
  5. ^ a b c d FDA Professional Drug Information for Eylea
  6. ^ a b c d FDA Professional Drug Information for Zaltrap
  7. ^ "Aflibercept Approved for Colorectal Cancer in Europe". 7 Feb 2013. 
  8. ^ a b c d "Regeneron and Sanofi-Aventis Report Positive Phase III mCRC Trial Data". 27 Apr 2011. 
  9. ^ a b Regeneron Timeline
  10. ^ Candace Hoffmann for First Word Pharma. September 8th, 2003 Aventis inks deal with Regeneron for collaboration on cancer therapy
  11. ^ Genetic Engineering and Biotechnology News. Oct 19, 2006 Bayer HealthCare Signs On to Help Develop Regeneron’s VEGF Trap-Eye
  12. ^ "Regeneron and Sanofi-Aventis Cancer Drug Misses Phase III Primary Endpoint but Meets Secondary Targets". 11 Mar 2011. 
  13. ^ Gever, John (November 19, 2011). "FDA Approves Eylea for Macular Degeneration". MedpageToday.com. Retrieved 2013-10-16. 
  14. ^ BioWorld: GPhA: Common Name is Key to Biosimilar Competition
  15. ^ "Aflibercept Injection Approved for the Treatment of Wet Age-Related Macular Degeneration in Europe". Amd-fruehdiagnose.de. Retrieved 2013-10-16. 
  16. ^ http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002532/WC500139486.pdf