Aflibercept

Last updated

Aflibercept
Clinical data
Trade names Eylea, Zaltrap
Other namesziv-aflibercept
Biosimilars Yesafili [1] [2]
AHFS/Drugs.com Aflibercept Monograph
Ziv-aflibercept Monograph
MedlinePlus a612004
License data
Pregnancy
category
  • AU:D [3]
  • Not recommended
Routes of
administration 		Intravenous, intravitreal injection
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only [4] [5] [6]
  • EU:Rx-only [7]
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C4318H6788N1164O1304S32
Molar mass 96898.57 g·mol−1
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Aflibercept, sold under the brand names Eylea among others, 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 the European Union. [7] [8]

Contents

It is an inhibitor of vascular endothelial growth factor (VEGF). [9] [10]

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. [4]

Aflibercept (Zaltrap), in combination with fluorouracil, leucovorin, irinotecan (FOLFIRI), is indicated for the treatment of people with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen. [5] [8]

It is used for the treatment of wet macular degeneration and is administered as an intravitreal injection, that is, into the eye. [4] For cancer treatment, it is given intravenously in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI). [5]

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. [11] In May 2019, the US FDA expanded the indication for aflibercept to include all stages of diabetic retinopathy. [12]

In February 2023, the US FDA approved aflibercept (Eylea) as a treatment for retinopathy of prematurity. [13]

Contraindications

Aflibercept (Eylea) is contraindicated in people with infections or active inflammations of or near the eye, [4] while Aflibercept (Zaltrap) has no contraindications. [5]

Adverse effects

Common adverse effects of the eye formulation include conjunctival hemorrhage, eye pain, cataract, vitreous detachment, floaters, and ocular hypertension. [4]

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). [5]

Interactions

No interactions are described for either formulation. [4] [5]

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". [14] 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. [15] 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. [16]

History

Regeneron commenced clinical testing of aflibercept in cancer in 2001. [17] In 2003, Regeneron signed a major deal with Aventis to develop aflibercept in the field of cancer. [18] In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases, [17] and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications. [19]

Society and culture

In November 2011, the United States Food and Drug Administration (FDA) approved aflibercept for the treatment of wet macular degeneration. [20]

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

In November 2012, the European Medicines Agency (EMA) approved aflibercept (Eylea) for the treatment of wet macular degeneration. [7] [22]

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. [8] [23] Aflibercept (Zaltrap) is used with FOLFIRI, which is a treatment combining the medicines irinotecan, 5-fluorouracil, and folinic acid. [8]

Economics

In March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund. [24] In 2017, injections of aflibercept (HCPCS code J0178) were responsible for the most billing to Medicare Part B, at $2.36 billion. [25]

Research

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. [15] [26]

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). [15]

Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer as of April 2011. [15]

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. [27]

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. [28]

Related Research Articles

<span class="mw-page-title-main">Diabetic retinopathy</span> Medical condition

Diabetic retinopathy, is a medical condition in which damage occurs to the retina due to diabetes mellitus. It is a leading cause of blindness in developed countries.

The National Eye Institute (NEI) is part of the U.S. National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services. The mission of NEI is "to eliminate vision loss and improve quality of life through vision research." NEI consists of two major branches for research: an extramural branch that funds studies outside NIH and an intramural branch that funds research on the NIH campus in Bethesda, Maryland. Most of the NEI budget funds extramural research.

<span class="mw-page-title-main">Macular edema</span> Medical condition

Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell (edema). The swelling may distort a person's central vision, because the macula holds tightly packed cones that provide sharp, clear, central vision to enable a person to see detail, form, and color that is directly in the centre of the field of view.

Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, ovarian cancer, glioblastoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).

<span class="mw-page-title-main">Intravitreal administration</span>

Intravitreal is a route of administration of a drug, or other substance, in which the substance is delivered into the vitreous humor of the eye. "Intravitreal" literally means "inside an eye". Intravitreal injections were first introduced in 1911 when Ohm gave an injection of air into the vitreous humor to repair a detached retina. In the mid-1940s, intravitreal injections became a standard way to administer drugs to treat endophthalmitis and cytomegalovirus retinitis.

<span class="mw-page-title-main">Regeneron Pharmaceuticals</span> American biotechnology company

Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Westchester County, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities, giving rise to its name, the company then branched out into the study of both cytokine and tyrosine kinase receptors, which gave rise to their first product, which is a VEGF-trap.

Ranibizumab, sold under the brand name Lucentis among others, is a monoclonal antibody fragment (Fab) created from the same parent mouse antibody as bevacizumab. It is an anti-angiogenic that is approved to treat the "wet" type of age-related macular degeneration, diabetic retinopathy, and macular edema due to branch retinal vein occlusion or central retinal vein occlusion.

<span class="mw-page-title-main">Pegaptanib</span> Drug to treat macular degeneration

Pegaptanib sodium injection is an anti-angiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration (AMD). It was discovered by NeXstar Pharmaceuticals and licensed in 2000 to EyeTech Pharmaceuticals, now OSI Pharmaceuticals, for late stage development and marketing in the United States. Gilead Sciences continues to receive royalties from the drugs licensing. Outside the US pegaptanib is marketed by Pfizer. Approval was granted by the U.S. Food and Drug Administration (FDA) in December 2004.

<span class="mw-page-title-main">Semaxanib</span> Chemical compound

Semaxanib is a tyrosine-kinase inhibitor drug designed by SUGEN as a cancer therapeutic. It is an experimental stage drug, not licensed for use on human patients outside clinical trials. Semaxanib is a potent and selective synthetic inhibitor of the Flk-1/KDR vascular endothelial growth factor (VEGF) receptor tyrosine kinase. It targets the VEGF pathway, and both in vivo and in vitro studies have demonstrated antiangiogenic potential.

Ramucirumab is a fully human monoclonal antibody (IgG1) developed for the treatment of solid tumors. This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

<span class="mw-page-title-main">Macular telangiectasia</span> Disease of the retina affecting central vision

Macular telangiectasia is a condition of the retina, the light-sensing tissue at the back of the eye that causes gradual deterioration of central vision, interfering with tasks such as reading and driving.

<span class="mw-page-title-main">Laser coagulation</span> Procedure widely used in eye surgery

Laser coagulation or laser photocoagulation surgery is used to treat a number of eye diseases and has become widely used in recent decades. During the procedure, a laser is used to finely cauterize ocular blood vessels to attempt to bring about various therapeutic benefits.

Nesvacumab is an experimental monoclonal antibody originally designed for the treatment of cancer. It targets the protein angiopoietin 2. As of May 2017, it is in Phase II clinical trials for the treatment of diabetic macular edema.

Joan Whitten Miller is a Canadian-American ophthalmologist and scientist who has made notable contributions to the treatment and understanding of eye disorders. She is credited for developing photodynamic therapy (PDT) with verteporfin (Visudyne), the first pharmacologic therapy for retinal disease. She also co-discovered the role of vascular endothelial growth factor (VEGF) in eye disease and demonstrated the therapeutic potential of VEGF inhibitors, forming the scientific basis of anti-VEGF therapy for age-related macular degeneration (AMD), diabetic retinopathy, and related conditions.

Anti–vascular endothelial growth factor therapy, also known as anti-VEGF therapy or medication, is the use of medications that block vascular endothelial growth factor. This is done in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab, antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: sunitinib, sorafenib, axitinib, and pazopanib.

Brolucizumab sold under trade name Beovu among others, is a humanized single-chain antibody fragment for the treatment of neovascular (wet) age-related macular degeneration (AMD).

<span class="mw-page-title-main">Faricimab</span> Medication for macular degeneration

Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody to target both vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2). By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection by an ophthalmologist.

<span class="mw-page-title-main">Intravitreal injection</span> Method of administration of drugs into the eye by injection with a fine needle

Intravitreal injection is the method of administration of drugs into the eye by injection with a fine needle. The medication will be directly applied into the vitreous humor. It is used to treat various eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and infections inside the eye such as endophthalmitis. As compared to topical administration, this method is beneficial for a more localized delivery of medications to the targeted site, as the needle can directly pass through the anatomical eye barrier and dynamic barrier. It could also minimize adverse drug effects on other body tissues via the systemic circulation, which could be a possible risk for intravenous injection of medications. Although there are risks of infections or other complications, with suitable precautions throughout the injection process, chances for these complications could be lowered.

Conbercept, sold under the commercial name Lumitin, is a novel vascular endothelial growth factor (VEGF) inhibitor used to treat neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). The anti-VEGF was approved for the treatment of neovascular AMD by the China State FDA (CFDA) in December 2013. As of December 2020, conbercept is undergoing phase III clinical trials through the U.S. Food and Drug Administration’s PANDA-1 and PANDA-2 development programs.

<span class="mw-page-title-main">Fruquintinib</span> Medication

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References

  1. ↑ "Yesafili: Pending EC decision". European Medicines Agency. 21 July 2023. Archived from the original on 2 October 2023. Retrieved 2 October 2023.
  2. ↑ "Yesafili Product information". Union Register of medicinal products. 19 September 2023. Archived from the original on 2 October 2023. Retrieved 2 October 2023.
  3. ↑ "Ziv-aflibercept (Zaltrap) Use During Pregnancy". Drugs.com. 25 December 2019. Archived from the original on 29 November 2020. Retrieved 12 March 2020.
  4. 1 2 3 4 5 6 "Eylea- aflibercept injection, solution". DailyMed. 12 August 2019. Archived from the original on 25 March 2021. Retrieved 13 August 2020.
  5. 1 2 3 4 5 6 "Zaltrap- ziv-aflibercept solution, concentrate". DailyMed. 10 June 2020. Archived from the original on 4 August 2020. Retrieved 13 August 2020.
  6. ↑ "Eylea HD- aflibercept injection, solution". DailyMed. 18 August 2023. Archived from the original on 29 August 2023. Retrieved 28 August 2023.
  7. 1 2 3 "Eylea EPAR". European Medicines Agency (EMA). 9 July 2019. Archived from the original on 9 November 2020. Retrieved 12 March 2020.
  8. 1 2 3 4 "Zaltrap EPAR". European Medicines Agency (EMA). 12 November 2019. Archived from the original on 11 November 2020. Retrieved 12 March 2020.
  9. ↑ 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. Archived from the original on 8 December 2019. Retrieved 3 July 2008.
  10. ↑ 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.
  11. ↑ "New indication for Eylea". The Pharmaceutical Journal. No. 7826. Royal Pharmaceutical Society. 27 August 2014. Archived from the original on 20 June 2015. Retrieved 20 September 2014.
  12. ↑ "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.
  13. ↑ "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.
  14. ↑ "Aflibercept Approved for Colorectal Cancer in Europe". 7 February 2013. Archived from the original on 10 February 2013.
  15. 1 2 3 4 "Regeneron and Sanofi-Aventis Report Positive Phase III mCRC Trial Data". 27 April 2011. Archived from the original on 2 February 2012.
  16. 1 2 "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.
  17. 1 2 "Our History - A 25 year commitment to repeated innovation". www.regeneron.com. 1988. Archived from the original on 17 May 2017. Retrieved 7 May 2018.
  18. ↑ Candace Hoffmann for First Word Pharma. 8 September 2003 Aventis inks deal with Regeneron for collaboration on cancer therapy Archived 14 April 2014 at the Wayback Machine
  19. ↑ Genetic Engineering and Biotechnology News. 19 October 2006 Bayer HealthCare Signs On to Help Develop Regeneron's VEGF Trap-Eye Archived 14 April 2014 at the Wayback Machine
  20. ↑ Gever J (19 November 2011). "FDA Approves Eylea for Macular Degeneration". MedpageToday.com. Archived from the original on 28 May 2013. Retrieved 16 October 2013.
  21. ↑ BioWorld: GPhA: Common Name is Key to Biosimilar Competition Archived 13 December 2013 at the Wayback Machine
  22. ↑ "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.
  23. ↑ "Zaltrap : EPAR - Summary for the public" (PDF). Archived (PDF) from the original on 16 October 2013. Retrieved 1 July 2013.
  24. ↑ "Cancer: Drugs:Written question - HL3340". UK Parliament. 19 November 2015. Archived from the original on 2 April 2018.
  25. ↑ "Physician/Supplier National Data" (PDF). Centers for Medicare & Medicaid Services . Archived (PDF) from the original on 17 August 2018. Retrieved 11 June 2019.
  26. ↑ "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.
  27. ↑ Sarwar S, Clearfield E, Soliman MK, Sadiq MA, Baldwin AJ, Hanout M, et al. (February 2016). "Aflibercept for neovascular age-related macular degeneration". The Cochrane Database of Systematic Reviews. 2016 (2): CD011346. doi:10.1002/14651858.CD011346.pub2. PMC   5030844 . PMID   26857947.
  28. ↑ Virgili G, Curran K, Lucenteforte E, Peto T, Parravano M (27 June 2023). Cochrane Eyes and Vision Group (ed.). "Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis". Cochrane Database of Systematic Reviews. 2023 (6): CD007419. doi:10.1002/14651858.CD007419.pub7. PMC  10294542. PMID   38275741.
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