Aflibercept

Last updated

Aflibercept
Clinical data
Trade names Eylea, Zaltrap
Other namesziv-aflibercept
Biosimilars aflibercept-abzv, [1] [2] aflibercept-ayyh, [3] [2] aflibercept-jbvf, [4] [2] aflibercept-mrbb, [5] [2] aflibercept-yszy, [6] [2] Ahzantive, [5] [2] Enzeevu, [1] [2] Opuviz, [6] [2] Pavblu, [3] [2] Yesafili [4] [7] [8] [2]
AHFS/Drugs.com
MedlinePlus a612004
License data
Pregnancy
category
  • AU:D [9]
  • Not recommended
Routes of
administration 		Intravenous, intravitreal injection
ATC code
Legal status
Legal status
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 and Zaltrap, is a medication used to treat wet macular degeneration and metastatic colorectal cancer. [14] [15] It was developed by Regeneron Pharmaceuticals.

Contents

It is an inhibitor of vascular endothelial growth factor (VEGF). [16] [17]

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. [11]

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. [12] [15]

It is used for the treatment of wet macular degeneration and is administered as an intravitreal injection, that is, into the eye. [11] For cancer treatment, it is given intravenously in combination with fluorouracil, leucovorin, and irinotecan. [12]

In July 2014, aflibercept (Eylea) was approved for the treatment of people with visual impairment due to diabetic macular edema [18] In May 2019, the US FDA expanded the indication for aflibercept to include all stages of diabetic retinopathy. [19]

In February 2023, the US FDA approved aflibercept (Eylea) as a treatment for retinopathy of prematurity. [20]

Contraindications

Aflibercept (Eylea) is contraindicated in people with infections or active inflammations of or near the eye, [11] while aflibercept (Zaltrap) has no contraindications. [12]

Adverse effects

Common adverse effects of the eye formulation include conjunctival hemorrhage, eye pain, cataract, vitreous detachment, floaters, and ocular hypertension. [11]

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). [12]

Interactions

No interactions are described for either formulation. [11] [12]

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". [21] 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. [22] The aim of the cancer treatment, so to speak, is to starve the tumor.

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. [23]

History

Regeneron commenced clinical testing of aflibercept in cancer in 2001. [24] In 2003, Regeneron signed a major deal with Aventis to develop aflibercept in the field of cancer. [25] In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases, [24] and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications. [26]

Society and culture

In November 2011, the US Food and Drug Administration (FDA) approved aflibercept for the treatment of wet macular degeneration. [27] [28]

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. [29] [23] [30] [31] To avoid confusion with the version that is injected into the eye, the FDA assigned a new name, ziv-aflibercept, to the active ingredient. [32]

In November 2012, the European Medicines Agency (EMA) approved aflibercept (Eylea) for the treatment of wet macular degeneration. [14] [33]

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. [15] [34] Aflibercept (Zaltrap) is used with irinotecan, 5-fluorouracil, and folinic acid. [15]

In August 2023, the FDA approved aflibercept (Eylea) for the treatment of wet age-related macular degeneration, diabetic macular edema, and diabetic retinopathy. [35]

Biosimilars

Yesafili was approved for medical use in the European Union in September 2023. [7]

In May 2024, aflibercept-jbvf (Yesafili) [4] and aflibercept-yszy (Opuviz) [6] were approved for medical use in the United States. [36] [2]

Aflibercept-mrbb (Ahzantive) was approved for medical use in the United States in June 2024. [5] [37] [2] It is a biosimilar to Eylea. [5]

In August 2024, aflibercept-abzv (Enzeevu) was approved for medical use in the United States. [1] [38] [2] It is a biosimilar to Eylea. [1]

In August 2024, aflibercept-ayyh (Pavblu) was approved for medical use in the United States. [3] [39] [2] It is a biosimilar to Eylea. [3]

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 (branch RVO or central RVO), visual impairment due to diabetic macular edema (DME) and visual impairment due to myopic choroidal neovascularization (myopic CNV). [40] The applicant for this medicinal product is Samsung Bioepis NL B.V. [40] Opuviz is a biosimilar medicinal product. [40]

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 (branch RVO or central RVO), visual impairment due to diabetic macular edema (DME) and visual impairment due to myopic choroidal neovascularization (myopic CNV). [41] The applicant for this medicinal product is Sandoz GmbH. [41] Afqlir is a biosimilar medicinal product. [41]

Economics

In March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund. [42] In 2017, injections of aflibercept (HCPCS code J0178) were responsible for the most billing to Medicare Part B, at US$2.36 billion. [43]

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. [22] [44]

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. [22]

Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer as of April 2011. [22]

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. [45]

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. [46]

Related Research Articles

<span class="mw-page-title-main">Diabetic retinopathy</span> Diabetes-induced damage to the retina of the eye

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

<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.

<span class="mw-page-title-main">Macular degeneration</span> Vision loss due to damage to the macula of the eye

Macular degeneration, also known as age-related macular degeneration, is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur.

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, hepatocellular carcinoma, 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">Triamcinolone acetonide</span> Medicinal chemical compound, steroid

Triamcinolone acetonide, sold under the brand name Kenalog among others, is a synthetic corticosteroid medication used topically to treat various skin conditions, to relieve the discomfort of mouth sores, and by injection into joints to treat various joint conditions. It is also injected into lesions to treat inflammation in some parts of the body, particularly the skin. In nasal spray form, it is used to treat allergic rhinitis. It is used for the treatment of macular edema associated with uveitis. It is a more potent derivative of triamcinolone, and is about eight times as potent as prednisone.

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

Intravitreal administration 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 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">Choroidal neovascularization</span> Creation of new blood vessels in the choroid layer of the eye

Choroidal neovascularization (CNV) is the creation of new blood vessels in the choroid layer of the eye. Choroidal neovascularization is a common cause of neovascular degenerative maculopathy commonly exacerbated by extreme myopia, malignant myopic degeneration, or age-related developments.

<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.

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">Adagrasib</span> Medication

Adagrasib, sold under the brand name Krazati, is an anticancer medication used to treat non-small cell lung cancer. Adagrasib is an inhibitor of G12C mutated KRAS GTPase. It is taken by mouth. It is being developed by Mirati Therapeutics.

Pegcetacoplan, sold under the brand name Empaveli, among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria and geographic atrophy of the retina. Pegcetacoplan is a complement inhibitor.

References

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  41. 1 2 3 "Afqlir EPAR". European Medicines Agency (EMA). 19 September 2024. Archived from the original on 21 September 2024. Retrieved 21 September 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
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