Aflibercept

Aflibercept, sold under the brandname Eylea and Zaltrap, is a medication used to treat wet macular degeneration and metastatic colorectal cancer. It was developed by Regeneron Pharmaceuticals and is approved in the United States and Europe.[2][3]

Aflibercept
Clinical data
Trade namesEylea, Zaltrap
Other namesziv-aflibercept
AHFS/Drugs.comMonograph
MedlinePlusa612004
License data
Pregnancy
category
  • AU: D [1]
  • US: C (Risk not ruled out) [1]
  • Not recommended
Routes of
administration		Injection
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC4318H6788N1164O1304S32
Molar mass96898.57 g·mol−1
 NY (what is this?)  (verify)

It is an inhibitor of vascular endothelial growth factor (VEGF).[4][5]

Medical use

It is used for the treatment of wet macular degeneration and is administered as an intravitreal injection, that is, into the eye.[6] For cancer treatment, is given intravenously in combination with the other cancer drugs 5-fluorouracil and irinotecan and the adjuvant folinic acid.[7] In 27 August 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.[8] In May 2019 FDA expanded the indication for aflibercept to include all stages of diabetic retinopathy.[9]

Contraindications

Eylea is contraindicated in patients with infections or active inflammations of or near the eye,[6] while Zaltrap has no contraindications.[7]

Adverse effects

Common adverse effects of the eye formulation include conjunctival hemorrhage, eye pain, cataract, vitreous detachment, floaters, and ocular hypertension.[6]

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).[7]

Interactions

No interactions are described for either formulation.[6][7]

Mechanism of action

In wet macular degeneration, abnormal blood vessels 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".[10] 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.[11] The aim of the cancer treatment, so to speak, is to starve the tumour.

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.[12]

History

Regeneron commenced clinical testing of aflibercept in cancer in 2001.[13] In 2003, Regeneron signed a major deal with Aventis to develop aflibercept in the field of cancer.[14] In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases,[13] and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications.[15]

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.[11][16]

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).[11]

Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer as of April 2011.[11]

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.[17]

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.[18]

Approvals

In November 2011, the United States Food and Drug Administration (FDA) approved aflibercept for the treatment of wet macular degeneration.[19]

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.[12] To avoid confusion with the version that is injected into the eye, the FDA assigned a new name, ziv-aflibercept, to the active ingredient.[20]

In November 2012, the European Medicines Agency (EMA) approved aflibercept for the treatment of wet macular degeneration.[2][21]

On 1 February 2013, the European Medicines Agency (EMA) 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.[3][22]

Reimbursement

On 12 March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund.[23] In 2017, injections of aflibercept (HCPCS code J0178) were responsible for the most billing to Medicare Part B, at $2.36 billion.[24]

References
  1. "Ziv-aflibercept (Zaltrap) Use During Pregnancy". Drugs.com. 25 December 2019. Retrieved 12 March 2020.
  2. "Eylea EPAR". European Medicines Agency (EMA). 9 July 2019. Retrieved 12 March 2020.
  3. "Zaltrap EPAR". European Medicines Agency (EMA). 12 November 2019. Retrieved 12 March 2020.
  4. Fraser HM, Wilson H, Silvestri A, Morris KD, Wiegand SJ (September 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.
  5. 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-1alpha in the follicle and corpus luteum". Endocrinology. 149 (7): 3313–20. doi:10.1210/en.2007-1649. PMID 18388198.
  6. FDA Professional Drug Information for Eylea
  7. FDA Professional Drug Information for Zaltrap
  8. "New indication for Eylea". The Pharmaceutical Journal (7826). Royal Pharmaceutical Society. 27 August 2014. Archived from the original on 20 June 2015. Retrieved 20 September 2014.
  9. FDA Approves Eylea (aflibercept) Injection for Diabetic Retinopathy, PM Regeneron 13 May 2019 - retrieved 14 May 2019
  10. "Aflibercept Approved for Colorectal Cancer in Europe". 7 February 2013. Archived from the original on 10 February 2013.
  11. "Regeneron and Sanofi-Aventis Report Positive Phase III mCRC Trial Data". 27 April 2011. Archived from the original on 2 February 2012.
  12. "Ziv-Aflibercept". FDA Drug Approvals Database. Food and Drug Administration. 3 August 2012. Archived from the original on 16 October 2013. Retrieved 16 October 2013.
  13. "Our History - A 25 year commitment to repeated innovation". www.regeneron.com. Archived from the original on 17 May 2017. Retrieved 7 May 2018.
  14. Candace Hoffmann for First Word Pharma. 8 September 2003 Aventis inks deal with Regeneron for collaboration on cancer therapy Archived 2014-04-14 at the Wayback Machine
  15. Genetic Engineering and Biotechnology News. 19 Oct 2006 Bayer HealthCare Signs On to Help Develop Regeneron's VEGF Trap-Eye Archived 2014-04-14 at the Wayback Machine
  16. "Regeneron and Sanofi-Aventis Cancer Drug Misses Phase III Primary Endpoint but Meets Secondary Targets". 11 March 2011. Archived from the original on 6 April 2012.
  17. Sarwar S, Clearfield E, Soliman MK, Sadiq MA, Baldwin AJ, Hanout M, Agarwal A, Sepah YJ, Do DV, Nguyen QD (February 2016). "Aflibercept for neovascular age-related macular degeneration". The Cochrane Database of Systematic Reviews. 2: CD011346. doi:10.1002/14651858.CD011346.pub2. PMC 5030844. PMID 26857947.
  18. Virgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E (October 2018). "Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis". The Cochrane Database of Systematic Reviews. 10: CD007419. doi:10.1002/14651858.CD007419.pub6. PMC 6517135. PMID 30325017.
  19. Gever, John (19 November 2011). "FDA Approves Eylea for Macular Degeneration". MedpageToday.com. Archived from the original on 28 May 2013. Retrieved 16 October 2013.
  20. BioWorld: GPhA: Common Name is Key to Biosimilar Competition Archived 2013-12-13 at the Wayback Machine
  21. "Aflibercept Injection Approved for the Treatment of Wet Age-Related Macular Degeneration in Europe". Amd-fruehdiagnose.de. Archived from the original on 25 November 2013. Retrieved 16 October 2013.
  22. "Archived copy" (PDF). Archived (PDF) from the original on 16 October 2013. Retrieved 1 July 2013.CS1 maint: archived copy as title (link)
  23. "Cancer: Drugs:Written question - HL3340". UK Parliament. 19 November 2015. Archived from the original on 2 April 2018.
  24. "Physician/Supplier National Data" (PDF). www.cms.gov. Retrieved 11 June 2019.
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