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Aflibercept

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Aflibercept

Aflibercept
Clinical data
Trade names Eylea, Zaltrap
Licence data US FDA:
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Injection
Identifiers
CAS Registry Number  N
ATC code L01 S01
UNII  YesY
KEGG  YesY
Chemical data
Formula C4318H6788N1164O1304S32
Molecular mass 96.90 kDa
 N   

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 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.[3]

Contents

  • Composition 1
  • Indications and administration 2
  • Contraindications 3
  • Adverse effects 4
  • Interactions 5
  • Mechanism of action 6
  • History 7
    • Clinical trials 7.1
    • Approvals 7.2
  • References 8

Composition

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

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] 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.[7]

Contraindications

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

Adverse effects

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

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

Mechanism of action

In wet macular 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".[8] 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.[9] The aim of the cancer treatment, so to speak, is to starve the tumour.

History

Regeneron commenced clinical testing of aflibercept in cancer in 2001.[10] In 2003, Regeneon signed a major deal with Aventis to develop aflibercept in the field of cancer.[11] In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases,[10] and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications.[12]

Clinical trials

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.[9][13]

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).[9]

Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer as of April 2011.[9]

Approvals

In November 2011 the United States Food and Drug Administration (FDA) approved aflibercept (Eylea) for the treatment of wet macular degeneration.[14]

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.[15]

In November 2012 the European Medicines Agency (EMA) approved aflibercept for the treatment of wet macular degeneration.[16]

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.[17]

References

  1. ^
  2. ^
  3. ^ The Vault. Regeneron Pharmaceuticals, Inc. Page accessed April 14, 2014
  4. ^ a b
  5. ^ a b c d for Eylea
  6. ^ a b c d for Zaltrap
  7. ^
  8. ^
  9. ^ a b c d
  10. ^ a b Regeneron Timeline
  11. ^ Candace Hoffmann for First Word Pharma. September 8th, 2003 Aventis inks deal with Regeneron for collaboration on cancer therapy
  12. ^ Genetic Engineering and Biotechnology News. Oct 19, 2006 Bayer HealthCare Signs On to Help Develop Regeneron’s VEGF Trap-Eye
  13. ^
  14. ^
  15. ^ BioWorld: GPhA: Common Name is Key to Biosimilar Competition
  16. ^
  17. ^ http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002532/WC500139486.pdf
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