Chemistry:Aflibercept

From HandWiki

Aflibercept, sold under the brand names Eylea and Zaltrap among others, is a medication used to treat wet macular degeneration and metastatic colorectal cancer.[1][2] It was developed by Regeneron Pharmaceuticals.

It is an inhibitor of vascular endothelial growth factor (VEGF).[3][4] Aflibercept is a recombinant fusion protein consisting of the extracellular domains of human VEGF receptor 1 and 2 fused to the Fc portion of human IgG1.[5] By acting as a soluble decoy for the natural VEGF receptors, aflibercept inhibits their activation, thereby reducing angiogenesis.[5]

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.[6]

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.[7][2]

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, it is given intravenously in combination with fluorouracil, leucovorin, and irinotecan.[7]

In July 2014, aflibercept (Eylea) was approved for the treatment of people with visual impairment due to diabetic macular edema[8] In May 2019, the US FDA expanded the indication for aflibercept to include all stages of diabetic retinopathy.[9]

In February 2023, the US FDA approved aflibercept (Eylea) as a treatment for retinopathy of prematurity.[10]

Contraindications

Aflibercept (Eylea) is contraindicated in people with infections or active inflammations of or near the eye,[6] while aflibercept (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]

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).[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.

Aflibercept (Zaltrap) binds to circulating VEGFs and acts like a "VEGF trap".[11] 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.[12]

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.[13]

History

Regeneron commenced clinical testing of aflibercept in cancer in 2001.[14] In 2003, Regeneron signed a major deal with Aventis to develop aflibercept in the field of cancer.[15] In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases,[14] and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications.[16]

Society and culture

In November 2011, the US Food and Drug Administration (FDA) approved aflibercept for the treatment of wet macular degeneration.[17][18]

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.[19][13][20][21] To avoid confusion with the version that is injected into the eye, the FDA assigned a new name, ziv-aflibercept, to the active ingredient.[22]

In November 2012, the European Medicines Agency (EMA) authorized aflibercept (Eylea) for the treatment of wet macular degeneration.[1][23]

In February 2013, the European Medicines Agency (EMA) authorized 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.[2][24] Aflibercept (Zaltrap) is used with irinotecan, 5-fluorouracil, and folinic acid.[2]

In August 2023, the FDA approved aflibercept (Eylea) for the treatment of wet age-related macular degeneration, diabetic macular edema, and diabetic retinopathy.[25]

Biosimilars

Yesafili was authorized for medical use in the European Union in September 2023.[26]

In May 2024, aflibercept-jbvf (Yesafili)[27] and aflibercept-yszy (Opuviz)[28] were approved for medical use in the United States.[29][30]

Aflibercept-mrbb (Ahzantive) was approved for medical use in the US in June 2024.[31][32][30] It is a biosimilar to Eylea.[31]

In August 2024, aflibercept-abzv (Enzeevu) was approved for medical use in the US.[33][34][30] It is a biosimilar to Eylea.[33]

In August 2024, aflibercept-ayyh (Pavblu) was approved for medical use in the US.[35][36][30] It is a biosimilar to Eylea.[35]

In September 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Opuviz, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[37] The applicant for this medicinal product is Samsung Bioepis NL B.V.[37] Opuviz is a biosimilar medicinal product that is highly similar to the reference product Eylea, which was authorized in the EU in November 2012.[37]

In September 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Afqlir, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[38] The applicant for this medicinal product is Sandoz GmbH.[38] Afqlir is a biosimilar medicinal product that is highly similar to the reference product Eylea.[38] Afqlir was authorized for medical use in the EU in November 2024.[39][40]

In November 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ahzantive, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[41] The applicant for this medicinal product is Klinge Biopharma GmbH.[41] Ahzantive is a biosimilar medicinal product that is highly similar to the reference product Eylea.[41][42] Ahzantive was authorized for medical use in the EU in January 2025.[41][43]

In November 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Baiama, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[44] The applicant for this medicinal product is Formycon AG.[44] Baiama is a biosimilar medicinal product that is highly similar to the reference product Eylea.[44][42] Baiama was authorized for medical use in the EU in January 2025.[44][45]

In December 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Eydenzelt, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[5] The applicant for this medicinal product is Celltrion Healthcare Hungary Kft.[5] Eydenzelt is a biosimilar medicinal product that is highly similar to the reference product Eylea.[5]

In January 2025, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Pavblu, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[46] The applicant for this medicinal product is Amgen Technology (Ireland) UC.[46] Pavblu is a biosimilar medicinal product that is highly similar to the reference product Eylea.[46] Pavblu was authorized for medical use in the EU in April 2025.[46][47]

In January 2025, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Skojoy, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, and visual impairment due to myopic choroidal neovascularization.[48] The applicant for this medicinal product is Amgen Technology (Ireland) UC.[48] Skojoy is a biosimilar medicinal product that is highly similar to the reference product Eylea.[48]

In June 2025, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Afiveg, intended for the treatment of adults with neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[49] The applicant for this medicinal product is STADA Arzneimittel AG.[49] Afiveg is a biosimilar medicinal product that is highly similar to the reference product Eylea.[49] Afiveg was authorized for medical use in the EU in August 2025.[49][50]

In June 2025, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Eiyzey, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[51] The applicant for this medicinal product is Zakłady Farmaceutyczne Polpharma S.A.[51] Eiyzey is a biosimilar medicinal product that is highly similar to the reference product Eylea.[51] Eiyzey was authorized for medical use in the EU in August 2025.[51][52]

In June 2025, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Mynzepli, intended for the treatment of adults with neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[53] The applicant for this medicinal product is Advanz Pharma Limited.[53] Mynzepli is a biosimilar medicinal product that is highly similar to the reference product Eylea.[53] Mynzepli was authorized for medical use in the EU in August 2025.[53][54]

In June 2025, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vgenfli, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular V secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[55] The applicant for this medicinal product is Zakłady Farmaceutyczne Polpharma S.A.[55] Vgenfli is a biosimilar medicinal product that is highly similar to the reference product Eylea.[55] Vgenfli was authorized for medical use in the EU in August 2025.[55][56]

In June 2025, Yesafili, a biosimilar of Eylea, was approved for medical use in Canada.[57]

In July 2025, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Eyluxvi, intended for the treatment of adults with neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion, visual impairment due to diabetic macular edema and visual impairment due to myopic choroidal neovascularization.[58] The applicant for this medicinal product is Biolitec Pharma Limited Zweigniederlassung Jena.[58] Eyluxvi is a biosimilar medicinal product.[58] It is highly similar to the reference product Eylea.[58] Eyluxvi was authorized for medical use in the EU in September 2025.[58][59]

In July 2025, Pavblu, a biosimilar of Eylea, was approved for medical use in Canada.[60]

Economics

In March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund.[61] In 2017, injections of aflibercept (HCPCS code J0178) were responsible for the most billing to Medicare Part B, at US$2.36 billion.[62]

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.[12][63]

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.[12]

Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer as of April 2011.[12]

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.[64]

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.[65]

References

  1. ↑ 1.0 1.1 "Eylea EPAR". 9 July 2019. https://www.ema.europa.eu/en/medicines/human/EPAR/eylea. 
  2. ↑ 2.0 2.1 2.2 2.3 "Zaltrap EPAR". 12 November 2019. https://www.ema.europa.eu/en/medicines/human/EPAR/zaltrap. 
  3. ↑ "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. doi:10.1210/en.2008-0325. PMID 18499749. http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=18499749. Retrieved 3 July 2008. 
  4. ↑ "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. doi:10.1210/en.2007-1649. PMID 18388198. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Eydenzelt EPAR". 12 December 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/eydenzelt.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Eylea- aflibercept injection, solution". 12 August 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f96cfd69-da34-41ee-90a9-610a4655cd1c. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Zaltrap- ziv-aflibercept solution, concentrate". 10 June 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6725df6-50ee-4b0a-b900-d02ba634395d. 
  8. ↑ "Eylea (aflibercept) FDA Approval History". 18 November 2011. https://www.drugs.com/history/eylea.html. 
  9. ↑ "FDA Approves Eylea (aflibercept) Injection for Diabetic Retinopathy". Regeneron Pharmaceuticals Inc. (Press release). 13 May 2019. Archived from the original on 14 May 2019. Retrieved 28 June 2023.
  10. ↑ "Eylea (aflibercept) Injection Approved as the First Pharmacologic Treatment for Preterm Infants with Retinopathy of Prematurity (ROP) by the FDA". Regeneron Pharmaceuticals Inc. (Press release). 8 February 2023. Archived from the original on 28 June 2023. Retrieved 28 June 2023.
  11. ↑ "Aflibercept Approved for Colorectal Cancer in Europe". 7 February 2013. http://www.medscape.com/viewarticle/778918. 
  12. ↑ 12.0 12.1 12.2 12.3 "Regeneron and Sanofi-Aventis Report Positive Phase III mCRC Trial Data". 27 April 2011. https://www.genengnews.com/news/regeneron-and-sanofi-aventis-report-positive-phase-iii-mcrc-trial-data/. 
  13. ↑ 13.0 13.1 "Ziv-Aflibercept". U.S. Food and Drug Administration (FDA). 3 August 2012. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm314438.htm. 
  14. ↑ 14.0 14.1 "Our History - A 25 year commitment to repeated innovation". 1988. https://www.regeneron.com/history. 
  15. ↑ Hoffmann, Candace (8 September 2003). "Aventis inks deal with Regeneron for collaboration on cancer therapy". http://www.firstwordpharma.com/node/215613. 
  16. ↑ "Bayer HealthCare Signs On to Help Develop Regeneron's VEGF Trap-Eye". 19 October 2006. https://www.genengnews.com/news/bayer-healthcare-signs-on-to-help-develop-regenerons-vegf-trap-eye/. 
  17. ↑ "Drug Approval Package: Eylea (aflibercept) NDA #125387". 18 November 2011. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125387s0000TOC.cfm. 
  18. ↑ "FDA Approves Eylea for Macular Degeneration". MedpageToday.com. 19 November 2011. http://www.medpagetoday.com/Ophthalmology/GeneralOphthalmology/29811. 
  19. ↑ "Drug Approval Package: Zaltrap (ziv-aflibercept) NDA #125418". 6 September 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125418_zaltrap_toc.cfm. 
  20. ↑ "2012 Notifications". 17 December 2012. https://www.fda.gov/drugs/resources-information-approved-drugs/2012-notifications. 
  21. ↑ "U.S. FDA Approves Zaltrap (ziv-aflibercept) After Priority Review for Previously Treated Metastatic Colorectal Cancer" (Press release). Sanofi and Regeneron. 3 August 2012. Archived from the original on 21 May 2024. Retrieved 21 May 2024 – via PR Newswire.
  22. ↑ Serebrov, Mari. "GPhA: Common Name is Key to Biosimilar Competition". http://www.bioworld.com/content/gpha-common-name-key-biosimilar-competition-1. 
  23. ↑ "Aflibercept Injection Approved for the Treatment of Wet Age-Related Macular Degeneration in Europe". Amd-fruehdiagnose.de. http://www.amd-fruehdiagnose.de/eylea/eylea-aflibercept-injection-approved-treatment-of-wet-age-related-macular-degeneration-europe.htm. 
  24. ↑ "Zaltrap: EPAR - Summary for the public". https://www.ema.europa.eu/documents/overview/zaltrap-epar-summary-public_en.pdf. 
  25. ↑ "Eylea HD (aflibercept) Injection 8 mg Approved by FDA for Treatment of Wet Age-related Macular Degeneration (wAMD), Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)" (Press release). Regeneron Pharmaceuticals. 18 August 2023. Archived from the original on 26 August 2023. Retrieved 26 August 2024 – via GlobeNewswire.
  26. ↑ "Yesafili EPAR". 15 September 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/yesafili. 
  27. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Yesafili FDA label
  28. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Opuviz FDA label
  29. ↑ "FDA approves first interchangeable biosimilars to Eylea to treat macular degeneration and other eye conditions". U.S. Food and Drug Administration (FDA) (Press release). 20 May 2024. Archived from the original on 21 May 2024. Retrieved 21 May 2024.
  30. ↑ 30.0 30.1 30.2 30.3 "Biosimilar Drug Information". 26 August 2024. https://www.fda.gov/drugs/biosimilars/biosimilar-product-information. 
  31. ↑ 31.0 31.1 "Ahzantive". https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761378s000lbl.pdf. 
  32. ↑ "Ahzantive Biologic License Application Approval". https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/761378Orig1s000ltr.pdf. 
  33. ↑ 33.0 33.1 "Enzeevu (aflibercept-abzv) injection, for intravitreal use". https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761382s000lbl.pdf. 
  34. ↑ "Enzeevu Biologic License Application Approval". https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/761382Orig1s000ltr.pdf. 
  35. ↑ 35.0 35.1 "Pavblu- aflibercept-ayyh injection, solution". 28 October 2024. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c61062f3-80ec-4a20-8c28-46e468592a06. 
  36. ↑ "Pavblu Biologic License Application Approval". https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/761298Orig1s000ltr.pdf. 
  37. ↑ 37.0 37.1 37.2 "Opuviz EPAR". 19 September 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/opuviz.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  38. ↑ 38.0 38.1 38.2 "Afqlir EPAR". 19 September 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/afqlir.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  39. ↑ "Afqlir PI". 14 November 2024. https://ec.europa.eu/health/documents/community-register/html/h1867.htm. 
  40. ↑ "Sandoz receives European Commission approval for Afqlir (aflibercept), further strengthening leading biosimilar portfolio". Yahoo News. https://finance.yahoo.com/news/sandoz-receives-european-commission-approval-060000286.html. 
  41. ↑ 41.0 41.1 41.2 41.3 "Ahzantive EPAR". 14 November 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/ahzantive.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  42. ↑ 42.0 42.1 "Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 11-14 November 2024". European Medicines Agency (EMA) (Press release). 15 November 2024. Retrieved 16 November 2024.
  43. ↑ "Ahzantive PI". 14 January 2025. https://ec.europa.eu/health/documents/community-register/html/h1888.htm. 
  44. ↑ 44.0 44.1 44.2 44.3 "Baiama EPAR". 14 November 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/baiama.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  45. ↑ "Baiama PI". 14 January 2025. https://ec.europa.eu/health/documents/community-register/html/h1887.htm. 
  46. ↑ 46.0 46.1 46.2 46.3 "Pavblu EPAR". 30 January 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/pavblu.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  47. ↑ "Pavblu Product information". 7 April 2025. https://ec.europa.eu/health/documents/community-register/html/h1909.htm. 
  48. ↑ 48.0 48.1 48.2 "Skojoy EPAR". 30 January 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/skojoy.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  49. ↑ 49.0 49.1 49.2 49.3 "Afiveg EPAR". 20 June 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/afiveg.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  50. ↑ "Afiveg PI". 22 August 2025. https://ec.europa.eu/health/documents/community-register/html/h1965.htm. 
  51. ↑ 51.0 51.1 51.2 51.3 "Eiyzey EPAR". 20 June 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/eiyzey.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  52. ↑ "Eiyzey PI". 19 August 2025. https://ec.europa.eu/health/documents/community-register/html/h1963.htm. 
  53. ↑ 53.0 53.1 53.2 53.3 "Mynzepli EPAR". 20 June 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/mynzepli.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  54. ↑ "Mynzepli PI". 20 August 2025. https://ec.europa.eu/health/documents/community-register/html/h1964.htm. 
  55. ↑ 55.0 55.1 55.2 55.3 "Vgenfli EPAR". 20 June 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/vgenfli.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  56. ↑ "Vgenfli PI". 19 August 2025. https://ec.europa.eu/health/documents/community-register/html/h1961.htm. 
  57. ↑ "Summary Basis of Decision for Yesafili". 22 August 2025. https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1755873445495. 
  58. ↑ 58.0 58.1 58.2 58.3 58.4 "Eyluxvi EPAR". 25 July 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/eyluxvi.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  59. ↑ "Eyluxvi PI". 16 September 2025. https://ec.europa.eu/health/documents/community-register/html/h1972.htm. 
  60. ↑ "Summary Basis of Decision for Pavblu". 12 September 2025. https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1757691075272. 
  61. ↑ "Cancer: Drugs:Written question - HL3340". UK Parliament. 19 November 2015. https://questions-statements.parliament.uk/written-questions/detail/2015-11-05/HL3340. 
  62. ↑ "Physician/Supplier National Data". https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/MedicareFeeforSvcPartsAB/Downloads/LEVEL2CHARG17.pdf. 
  63. ↑ "Regeneron and Sanofi-Aventis Cancer Drug Misses Phase III Primary Endpoint but Meets Secondary Targets". 11 March 2011. http://www.genengnews.com/gen-news-highlights/regeneron-and-sanofi-aventis-cancer-drug-misses-phase-iii-primary-endpoint-but-meets-secondary-targets/81244807/. 
  64. ↑ "Aflibercept for neovascular age-related macular degeneration". The Cochrane Database of Systematic Reviews 2016 (2). February 2016. doi:10.1002/14651858.CD011346.pub2. PMID 26857947. 
  65. ↑ "Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis". The Cochrane Database of Systematic Reviews 2023 (6). June 2023. doi:10.1002/14651858.CD007419.pub7. PMID 38275741. 

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