Aflibercept

Aflibercept
Names
Trade namesEylea, Zaltrap
Other namesZiv-aflibercept
Clinical data
Drug classInhibitor of VEGF and PlGF[1][2]
Main usesWet macular degeneration, colorectal cancer[1][2]
Side effectsEye: Subconjunctival bleeding, eye pain, cataracts[1]
Cancer: Low white blood cells, diarrhea, increased liver enzymes, low platelets[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D[3]
  • US: C (Risk not ruled out)[3]
  • Not recommended
Routes of
use		Intravenous, intravitreal injection
External links
AHFS/Drugs.comAflibercept Monograph
Ziv-aflibercept Monograph
MedlinePlusa612004
Legal
License data
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Chemical and physical data
FormulaC4318H6788N1164O1304S32
Molar mass96898.57 g·mol−1

Aflibercept, sold under the brand names Eylea and Zaltrap, is a medication used to treat wet macular degeneration and colorectal cancer which has spread to other parts of the body.[1][2] For colon cancer it is given together with fluorouracil, leucovorin, and irinotecan.[2] It is used by injection into the eye or by intravenous infusion.[1][2]

Common side effects when used in the eye include subconjunctival bleeding, eye pain, and cataracts.[1] Common side effects when used for cancer include low white blood cells, diarrhea, increased liver enzymes, and low platelets.[2] Other side effects when used for cancer include bleeding, gastrointestinal perforation, and poor wound healing.[2] It is an inhibitor of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF).[1][2]

Aflibercept was approved for medical use in Europe and the United States in 2012.[2][4][5] For the eye it is initially given once a month with a dose of medication costing about 1,950 USD in the United States as of 2021.[6] In the United Kingdom this amount costs the NHS about 41£.[7] When used for cancer, 4 ml of 25 mg/ml solution costs about 1,680 USD as of 2021 in the USA and 296£ in the UK.[8]

Medical uses

Eye

It is used for the treatment of wet macular degeneration and is administered as an injection into the eye.[9] It is also used for people with macular edema due to diabetic retinopathy or following retinal vein occlusion.[1]

Colon cancer

For cancer treatment, is given intravenously in combination with the other cancer drugs 5-fluorouracil and irinotecan and the adjuvant folinic acid.[10]

Contraindications

Eylea is contraindicated in patients with infections or active inflammations of or near the eye,[9] while Zaltrap has no contraindications.[10]

Side effects

Common Side effects of the eye formulation include conjunctival hemorrhage, eye pain, cataract, vitreous detachment, floaters, and ocular hypertension.[9]

When used for cancer the effects are 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).[10]

Interactions

No interactions are described for either formulation.[9][10]

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".[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] 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.[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.[12][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).[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 neovascular AMD. Both treatment options yielded similar improvements in visual acuity and morphological outcomes, though 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 favored in all measured efficacy outcomes over ranibizumab and bevacizumab, after one year.[18]

Society and culture

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.[20] 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.[4][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.[5][23] Aflibercept (Zaltrap) is used with FOLFIRI, which is a treatment combining the medicines irinotecan, 5-fluorouracil, and folinic acid.[5]

Economics

On 12 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]

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.[20]

References

  1. 1 2 3 4 5 6 7 8 "Aflibercept Monograph for Professionals". Drugs.com. Archived from the original on 4 November 2019. Retrieved 18 July 2021.
  2. 1 2 3 4 5 6 7 8 9 10 "Ziv-aflibercept Monograph for Professionals". Drugs.com. Archived from the original on 8 September 2015. Retrieved 18 July 2021.
  3. 1 2 "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 "Eylea EPAR". European Medicines Agency (EMA). 9 July 2019. Archived from the original on 9 November 2020. Retrieved 12 March 2020.
  5. 1 2 3 "Zaltrap EPAR". European Medicines Agency (EMA). 12 November 2019. Archived from the original on 11 November 2020. Retrieved 12 March 2020.
  6. ↑ "Eylea Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 29 December 2018. Retrieved 18 July 2021.
  7. ↑ BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1253. ISBN 978-0-85711-369-6.
  8. ↑ "Zaltrap Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 17 January 2021. Retrieved 18 July 2021.
  9. 1 2 3 4 "Eylea- aflibercept injection, solution". DailyMed. 12 August 2019. Archived from the original on 25 March 2021. Retrieved 13 August 2020.
  10. 1 2 3 4 "Zaltrap- ziv-aflibercept solution, concentrate". DailyMed. 10 June 2020. Archived from the original on 4 August 2020. Retrieved 13 August 2020.
  11. ↑ "Aflibercept Approved for Colorectal Cancer in Europe". 7 February 2013. Archived from the original on 10 February 2013.
  12. 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.
  13. 1 2 "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. 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.
  21. ↑ BioWorld: GPhA: Common Name is Key to Biosimilar Competition Archived 2013-12-13 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). www.cms.gov. Archived (PDF) from the original on 17 August 2018. Retrieved 11 June 2019.
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