Aflibercept

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 United States.

Aflibercept
Clinical data
Trade namesEylea, Zaltrap
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		Injection
    ATC code
    Legal status
    Legal status
    Identifiers
    CAS Number
    ChemSpider
    • none
    UNII
    KEGG
    Chemical and physical data
    FormulaC4318H6788N1164O1304S32
    Molar mass96.90 kg/mol g·mol−1
     NY (what is this?)  (verify)

    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]

    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 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.[7] In May 2019 FDA expanded the indication for Eylea (aflibercept) to include all stages of diabetic retinopathy.[8] 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).[9]

    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 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.

    History

    Regeneron commenced clinical testing of aflibercept in cancer in 2001.[12] In 2003, Regeneon signed a major deal with Aventis to develop aflibercept in the field of cancer.[13] In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases,[12] and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications.[14]

    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][15]

    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.[16]

    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.[17]

    Approvals

    In November 2011 the United States Food and Drug Administration (FDA) approved aflibercept (Eylea) for the treatment of wet macular degeneration.[18]

    On 3 August 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.[19]

    In November 2012 the European Medicines Agency (EMA) approved aflibercept for the treatment of wet macular degeneration.[20]

    On 1 February 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.[21]

    Reimbursement

    On 12 March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund.[22] In 2017, injections of aflibercept (HCPCS code J0178) were responsible for the most billing to Medicare Part B, at $2.36 billion.[23]

    References
    1. 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.
    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-1alpha 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. Archived 2014-04-14 at the Wayback Machine Page accessed 14 April 2014
    4. "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.
    5. FDA Professional Drug Information for Eylea
    6. FDA Professional Drug Information for Zaltrap
    7. "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.
    8. FDA Approves Eylea (aflibercept) Injection for Diabetic Retinopathy, PM Regeneron 13 May 2019 - retrieved 14 May 2019
    9. "Indications". regeneron.com. 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. "Our History - A 25 year commitment to repeated innovation". www.regeneron.com. Archived from the original on 17 May 2017. Retrieved 7 May 2018.
    13. 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
    14. 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
    15. "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.
    16. 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.
    17. 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.
    18. 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.
    19. BioWorld: GPhA: Common Name is Key to Biosimilar Competition Archived 2013-12-13 at the Wayback Machine
    20. "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.
    21. "Archived copy" (PDF). Archived (PDF) from the original on 16 October 2013. Retrieved 1 July 2013.CS1 maint: archived copy as title (link)
    22. "Cancer: Drugs:Written question - HL3340". UK Parliament. 19 November 2015. Archived from the original on 2 April 2018.
    23. "Physician/Supplier National Data" (PDF). www.cms.gov. Retrieved 11 June 2019.
    • "Aflibercept". Drug Information Portal. U.S. National Library of Medicine.
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