Aflibercept Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:477243410
Tradename:Eylea, Zaltrap
Drugs.Com:Aflibercept
Ziv-aflibercept
Dailymedid:Aflibercept
Pregnancy Au:D
Pregnancy Au Comment:[1]
Pregnancy Category:Not recommended
Routes Of Administration:Intravenous, intravitreal injection
Atc Prefix:L01
Atc Suffix:XX44
Biosimilars:aflibercept-abzv,[2] aflibercept-jbvf,[3] aflibercept-yszy,[4] Enzeevu, Opuviz, Yesafili[5]
Legal Au:S4
Legal Ca:Rx-only
Legal Ca Comment:[6]
Legal Uk:POM
Legal Us:Rx-only
Legal Us Comment:[7]
Legal Eu:Rx-only
Legal Status:Rx-only
Cas Number:862111-32-8
Drugbank:DB08885
Chemspiderid:none
Unii:15C2VL427D
Kegg:D09574
Chembl:1742982
Synonyms:ziv-aflibercept
C:4318
H:6788
N:1164
O:1304
S:32

Aflibercept, sold under the brand names Eylea and Zaltrap, is a medication used to treat wet macular degeneration and metastatic colorectal cancer.[8] [9] It was developed by Regeneron Pharmaceuticals.

It is an inhibitor of vascular endothelial growth factor (VEGF).[10] [11]

Medical uses

Aflibercept (Eylea) is indicated for the treatment of people with neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and retinopathy of prematurity.

Aflibercept (Zaltrap), in combination with fluorouracil, leucovorin, and irinotecan (known as FOLFIRI), is indicated for the treatment of people with metastatic colorectal cancer that is resistant to, or has progressed following, an oxaliplatin-containing regimen.

It is used for the treatment of wet macular degeneration and is administered as an intravitreal injection, that is, into the eye.[12] For cancer treatment, it is given intravenously in combination with fluorouracil, leucovorin, and irinotecan.[13]

In August 2014, aflibercept (Eylea) was approved for the treatment of people with visual impairment due to diabetic macular edema, according to the updated summary of product characteristics.[14] In May 2019, the US FDA expanded the indication for aflibercept to include all stages of diabetic retinopathy.[15]

In February 2023, the US FDA approved aflibercept (Eylea) as a treatment for retinopathy of prematurity.[16]

Contraindications

Aflibercept (Eylea) is contraindicated in people with infections or active inflammations of or near the eye, while Aflibercept (Zaltrap) has no contraindications.

Adverse effects

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

Aflibercept (Zaltrap) has adverse effects typical of anti-cancer drugs, such as reduced blood cell count (leukopenia, neutropenia, thrombocytopenia), gastrointestinal disorders like diarrhea and abdominal pain, and fatigue. Another common effect is hypertension (increased blood pressure).

Interactions

No interactions are described for either formulation.

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.

Aflibercept (Zaltrap) binds to circulating VEGFs and acts like a "VEGF trap".[17] 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.

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.

History

Regeneron commenced clinical testing of aflibercept in cancer in 2001.[18] In 2003, Regeneron signed a major deal with Aventis to develop aflibercept in the field of cancer.[19] In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases,[18] and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications.[20]

Society and culture

Legal status

In November 2011, the US Food and Drug Administration (FDA) approved aflibercept for the treatment of wet macular degeneration.[21] [22]

In August 2012, the US 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.[23] [24] [25] [26] To avoid confusion with the version that is injected into the eye, the FDA assigned a new name, ziv-aflibercept, to the active ingredient.[27]

In November 2012, the European Medicines Agency (EMA) approved aflibercept (Eylea) for the treatment of wet macular degeneration.[28]

In February 2013, the European Medicines Agency (EMA) approved aflibercept (Zaltrap) for the treatment of adults with metastatic colorectal cancer for whom treatment based on oxaliplatin has not worked or the cancer got worse.[29] Aflibercept (Zaltrap) is used with irinotecan, 5-fluorouracil, and folinic acid.

Biosimilars

Yesafili was approved for medical use in the European Union in September 2023.[30]

In May 2024, aflibercept-jbvf (Yesafili) and aflibercept-yszy (Opuviz) were approved for medical use in the United States.[31]

In August 2024, aflibercept-abzv (Enzeevu) was approved for medical use in the United States. It is indicated to improve and maintain visual acuity in patients with neovascular age-related macular degeneration (nAMD).[32]

Economics

In March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund.[33] In 2017, injections of aflibercept (HCPCS code J0178) were responsible for the most billing to Medicare Part B, at .[34]

Research

In March 2011, 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, although it improved the secondary endpoint of progression-free survival.[35]

In April 2011, aflibercept improved its primary endpoint of overall survival in the Velour phase III clinical trial for second-line treatment for metastatic colorectal cancer.[36]

Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer .[36]

A 2016 Cochrane Review examined outcomes comparing aflibercept versus ranibizumab injections in over 2400 people with neovascular AMD, from two randomized controlled trials. Both treatment options yielded similar improvements in visual acuity and morphological outcomes, though the authors note that the aflibercept treatment regimen has the potential to reduce treatment burden and risks from frequent injections.[37]

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, longer term advantages were unclear.[38]

External links

Notes and References

  1. Web site: Ziv-aflibercept (Zaltrap) Use During Pregnancy . Drugs.com . 25 December 2019 . 12 March 2020 . 29 November 2020 . https://web.archive.org/web/20201129055243/https://www.drugs.com/pregnancy/ziv-aflibercept.html . live .
  2. Web site: Sandoz receives FDA approval for Enzeevu™ (aflibercept-abzv), further strengthening US biosimilar position. 12 August 2024. Morningstar, Inc..
  3. Full Prescribing Information - Yesafili. May 2024. accessdata.fda.gov. 19 August 2024.
  4. Web site: Opuviz (aflibercept-yszy) injection, for intravitreal use . 21 May 2024 . 21 May 2024 . https://web.archive.org/web/20240521025155/https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761350s000lbl.pdf . live .
  5. Web site: Yesafili Product information . Union Register of medicinal products . 19 September 2023 . 2 October 2023 . 2 October 2023 . https://web.archive.org/web/20231002061941/https://ec.europa.eu/health/documents/community-register/html/h1751.htm . live .
  6. Web site: Regulatory Decision Summary for Eylea HD . Drug and Health Products Portal . 2 February 2024 . 2 April 2024 . 2 April 2024 . https://web.archive.org/web/20240402033640/https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1708532368148 . live .
  7. Web site: Eylea HD- aflibercept injection, solution . DailyMed . 18 August 2023 . 28 August 2023 . 29 August 2023 . https://web.archive.org/web/20230829040233/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=86d8848b-111b-4da9-8957-7cccef1b8f66 . live .
  8. Web site: Eylea EPAR . European Medicines Agency (EMA) . 9 July 2019 . 12 March 2020 . 9 November 2020 . https://web.archive.org/web/20201109043834/https://www.ema.europa.eu/en/medicines/human/EPAR/eylea . live .
  9. Web site: Zaltrap EPAR . European Medicines Agency (EMA) . 12 November 2019 . 12 March 2020 . 11 November 2020 . https://web.archive.org/web/20201111223030/https://www.ema.europa.eu/en/medicines/human/EPAR/zaltrap . live .
  10. Fraser HM, Wilson H, Silvestri A, Morris KD, Wiegand SJ . 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 . September 2008 . 18499749 . 10.1210/en.2008-0325 . free . 3 July 2008 . 8 December 2019 . https://web.archive.org/web/20191208165552/http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=18499749 . live .
  11. Duncan WC, van den Driesche S, Fraser HM . 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 . July 2008 . 18388198 . 10.1210/en.2007-1649 . free .
  12. Web site: Eylea- aflibercept injection, solution . DailyMed . 12 August 2019 . 13 August 2020 . 25 March 2021 . https://web.archive.org/web/20210325013817/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f96cfd69-da34-41ee-90a9-610a4655cd1c . live .
  13. Web site: Zaltrap- ziv-aflibercept solution, concentrate . DailyMed . 10 June 2020 . 13 August 2020 . 4 August 2020 . https://web.archive.org/web/20200804175756/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6725df6-50ee-4b0a-b900-d02ba634395d . live .
  14. News: New indication for Eylea. 20 September 2014. The Pharmaceutical Journal. 7826. Royal Pharmaceutical Society. 27 August 2014. live. https://web.archive.org/web/20150620031447/http://www.pharmaceutical-journal.com/news-and-analysis/notice-board/new-indication-for-eylea/20066279.article. 20 June 2015.
  15. FDA Approves Eylea (aflibercept) Injection for Diabetic Retinopathy . Regeneron Pharmaceuticals Inc. . 13 May 2019 . https://web.archive.org/web/20190514055732/https://investor.regeneron.com/news-releases/news-release-details/fda-approves-eylear-aflibercept-injection-diabetic-retinopathy . 14 May 2019 . live . 28 June 2023.
  16. Eylea (aflibercept) Injection Approved as the First Pharmacologic Treatment for Preterm Infants with Retinopathy of Prematurity (ROP) by the FDA . Regeneron Pharmaceuticals Inc. . 8 February 2023 . 28 June 2023 . 28 June 2023 . https://web.archive.org/web/20230628230201/https://investor.regeneron.com/news-releases/news-release-details/eylear-aflibercept-injection-approved-first-pharmacologic . live .
  17. News: Aflibercept Approved for Colorectal Cancer in Europe . 7 February 2013 . live . https://web.archive.org/web/20130210084012/http://www.medscape.com/viewarticle/778918 . 10 February 2013 .
  18. Web site: Our History - A 25 year commitment to repeated innovation. www.regeneron.com. 1988 . 7 May 2018. live. https://web.archive.org/web/20170517181158/https://www.regeneron.com/history. 17 May 2017.
  19. Candace Hoffmann for First Word Pharma. 8 September 2003 Aventis inks deal with Regeneron for collaboration on cancer therapy
  20. Genetic Engineering and Biotechnology News. 19 October 2006 Bayer HealthCare Signs On to Help Develop Regeneron's VEGF Trap-Eye
  21. Web site: Drug Approval Package: Eylea (Aflibercept) NDA #125387 . U.S. Food and Drug Administration (FDA) . 18 November 2011 . 21 May 2024 . 17 October 2023 . https://web.archive.org/web/20231017030822/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125387s0000toc.cfm . live .
  22. Web site: Gever J . FDA Approves Eylea for Macular Degeneration . MedpageToday.com . 19 November 2011 . 16 October 2013 . live . https://web.archive.org/web/20130528151430/http://www.medpagetoday.com/Ophthalmology/GeneralOphthalmology/29811 . 28 May 2013 .
  23. Web site: Drug Approval Package: Zaltrap (ziv-aflibercept) NDA #125418 . U.S. Food and Drug Administration (FDA) . 6 September 2012 . 21 May 2024 . 26 September 2022 . https://web.archive.org/web/20220926220226/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125418_zaltrap_toc.cfm . live .
  24. Web site: Ziv-Aflibercept . FDA Drug Approvals Database . U.S. Food and Drug Administration (FDA) . 3 August 2012 . 16 October 2013 . dead . https://web.archive.org/web/20131016041012/https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm314438.htm . 16 October 2013 .
  25. Web site: 2012 Notifications . U.S. Food and Drug Administration (FDA) . 17 December 2012 . 21 May 2024 . 26 December 2019 . https://web.archive.org/web/20191226010037/https://www.fda.gov/drugs/resources-information-approved-drugs/2012-notifications . live .
  26. U.S. FDA Approves Zaltrap (ziv-aflibercept) After Priority Review for Previously Treated Metastatic Colorectal Cancer . Sanofi and Regeneron . PR Newswire . 3 August 2012 . 21 May 2024 . 21 May 2024 . https://web.archive.org/web/20240521024356/https://www.prnewswire.com/news-releases/us-fda-approves-zaltrap-ziv-aflibercept-after-priority-review-for-previously-treated-metastatic-colorectal-cancer-164919796.html . live .
  27. BioWorld: GPhA: Common Name is Key to Biosimilar Competition
  28. Web site: Aflibercept Injection Approved for the Treatment of Wet Age-Related Macular Degeneration in Europe . Amd-fruehdiagnose.de . 16 October 2013 . live . https://web.archive.org/web/20131125185521/http://www.amd-fruehdiagnose.de/eylea/eylea-aflibercept-injection-approved-treatment-of-wet-age-related-macular-degeneration-europe.htm . 25 November 2013 .
  29. Web site: Zaltrap : EPAR - Summary for the public . 1 July 2013 . live . https://web.archive.org/web/20131016041239/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002532/WC500139486.pdf . 16 October 2013 .
  30. Web site: Yesafili EPAR . European Medicines Agency . 15 September 2023 . 21 May 2024 . 17 February 2024 . https://web.archive.org/web/20240217185524/https://www.ema.europa.eu/en/medicines/human/EPAR/yesafili . live .
  31. Web site: FDA approves first interchangeable biosimilars to Eylea to treat macular degeneration and other eye conditions . U.S. Food and Drug Administration (FDA) . 20 May 2024 . 21 May 2024 . 21 May 2024 . https://web.archive.org/web/20240521025145/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-interchangeable-biosimilars-eylea-treat-macular-degeneration-and-other-eye . live .
  32. Web site: 2024-08-12 . Sandoz receives FDA approval for Enzeevu (aflibercept-abzv), further strengthening US biosimilar position . 2024-08-12 . Yahoo Finance .
  33. Web site: Cancer: Drugs:Written question - HL3340. UK Parliament. 19 November 2015. live. https://web.archive.org/web/20180402225615/https://www.parliament.uk/written-questions-answers-statements/written-question/lords/2015-11-05/HL3340. 2 April 2018.
  34. Web site: Physician/Supplier National Data . . 11 June 2019 . 17 August 2018 . https://web.archive.org/web/20180817194521/https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/MedicareFeeforSvcPartsAB/Downloads/LEVEL2CHARG17.pdf . live .
  35. News: Regeneron and Sanofi-Aventis Cancer Drug Misses Phase III Primary Endpoint but Meets Secondary Targets . 11 March 2011 . live . https://web.archive.org/web/20120406205554/http://www.genengnews.com/gen-news-highlights/regeneron-and-sanofi-aventis-cancer-drug-misses-phase-iii-primary-endpoint-but-meets-secondary-targets/81244807/ . 6 April 2012 .
  36. News: Regeneron and Sanofi-Aventis Report Positive Phase III mCRC Trial Data . 27 April 2011 . live . https://web.archive.org/web/20120202212928/http://www.genengnews.com/gen-news-highlights/regeneron-and-sanofi-aventis-report-positive-phase-iii-mcrc-trial-data/81245067 . 2 February 2012 .
  37. Sarwar S, Clearfield E, Soliman MK, Sadiq MA, Baldwin AJ, Hanout M, Agarwal A, Sepah YJ, Do DV, Nguyen QD . Aflibercept for neovascular age-related macular degeneration . The Cochrane Database of Systematic Reviews . 2016 . CD011346 . February 2016 . 2 . 26857947 . 5030844 . 10.1002/14651858.CD011346.pub2 .
  38. Virgili G, Curran K, Lucenteforte E, Peto T, Parravano M . Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis . The Cochrane Database of Systematic Reviews . 2023 . 6 . CD007419 . June 2023 . 38275741 . 10294542 . 10.1002/14651858.CD007419.pub7 . Cochrane Eyes and Vision Group .

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