Aflibercept, sold under the brand names Eylea and Zaltrap, is a medication used to treat

wet macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), 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, som ...

and metastatic

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...

. It was developed by

Regeneron Pharmaceuticals 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 i ...

and is approved in the United States and the European Union. It is an inhibitor of

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

(VEGF).

Medical uses

It is used for the treatment of wet macular degeneration and is administered as an

intravitreal 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 w ...

injection, that is, into the eye. For cancer treatment, is given

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

ly in combination with the other cancer drugs

5-fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancrea ...

and

irinotecan Irinotecan, sold under the brand name Camptosar among others, is a medication used to treat colon cancer, and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cispl ...

and the

adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analgesic ...

folinic acid Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to tr ...

. On 27 August 2014, Eylea was also indicated for the treatment of people with visual impairment due to diabetic macular oedema, according to the updated summary of product characteristics. In May 2019 FDA expanded the indication for aflibercept to include all stages of

diabetic retinopathy Diabetic retinopathy (also known as diabetic eye disease), 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. Diabetic retinopathy affects up to 80 perc ...

Contraindications

Eylea is contraindicated in patients with infections or active

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

s of or near the eye, while Zaltrap has no contraindications.

Adverse effects

Common adverse effects of the eye formulation include conjunctival

hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...

, eye pain, cataract,

vitreous detachment A posterior vitreous detachment (PVD) is a condition of the eye in which the vitreous membrane separates from the retina. It refers to the separation of the posterior hyaloid membrane from the retina anywhere posterior to the vitreous base (a 3� ...

floater Floaters or eye floaters are sometimes visible deposits (e.g., the shadows of tiny structures of protein or other cell debris projected onto the retina) within the eye's vitreous humour ("the vitreous"), which is normally transparent, or betwee ...

s, and

ocular hypertension Ocular hypertension is the presence of elevated fluid pressure inside the eye (intraocular pressure), usually with no optic nerve damage or visual field loss. For most individuals, the normal range of intraocular pressure is between 10 mmHg and 2 ...

. Zaltrap has adverse effects typical of anti-cancer drugs, such as reduced blood cell count (

leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...

), gastrointestinal disorders like diarrhoea and abdominal pain, and fatigue. Another common effect is

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

(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 The capillary lamina of choroid or choriocapillaris is a layer of capillaries that is immediately adjacent to Bruch's membrane in the choroid. The choriocapillaris was first described in man by Hovius in 1702, although it was not so named until 1 ...

, a layer of

capillaries A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...

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". It thereby inhibits the activity of the vascular endothelial growth factor subtypes

VEGF-A Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the ''VEGFA'' gene. Function This gene is a member of the platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF) family and encod ...

and

VEGF-B Vascular endothelial growth factor B also known as VEGF-B is a protein that, in humans, is encoded by the ''VEGF-B'' gene. VEGF-B is a growth factor that belongs to the vascular endothelial growth factor family, of which VEGF-A is the best-known ...

, as well as to

placental growth factor Placental growth factor (PlGF) is a protein that in humans is encoded by the ''PGF'' gene. Placental growth factor (PGF) is a member of the VEGF (vascular endothelial growth factor) sub-family - a key molecule in angiogenesis and vasculogenesis, ...

(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 Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this ''fusion gene'' r ...

consisting of

(VEGF)-binding portions from the extracellular domains of human VEGF

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

s 1 and 2, that are fused to the Fc portion of the human IgG1

immunoglobulin An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

History

Regeneron commenced clinical testing of aflibercept in cancer in 2001. In 2003, Regeneron signed a major deal with

Aventis Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...

to develop aflibercept in the field of cancer. In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases, and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications.

Clinical trials

In March 2011, Regeneron reported that aflibercept failed its primary

endpoint An endpoint, end-point or end point may refer to: * Endpoint (band), a hardcore punk band from Louisville, Kentucky * Endpoint (chemistry), the conclusion of a chemical reaction, particularly for titration * Outcome measure, a measure used as an e ...

of overall survival in the Vital

phase III trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

for second-line treatment of locally advanced or metastatic

non-small cell lung cancer Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to sm ...

(NSCLC), although it improved the secondary endpoint of progression-free survival. 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 A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...

for metastatic

(mCRC). Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer . A 2016

Cochrane Review Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...

examined outcomes comparing aflibercept versus ranibizumab injections in over 2400 patients with neovascular AMD, from two randomized controlled trials. Both treatment options yielded similar improvements in visual acuity and morphological outcomes in patients, though the authors note that the aflibercept treatment regimen has the potential to reduce treatment burden other risks from injections. A 2017 review update studying the effects of anti-VEGF drugs on

diabetic macular edema Diabetic retinopathy (also known as diabetic eye disease), 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. Diabetic retinopathy affects up to 80 perc ...

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 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 m ...

and

bevacizumab Bevacizumab, sold under the brand name Avastin among others, is a 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, l ...

, after one year.

Society and culture

Legal status

In November 2011, the United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) approved aflibercept for the treatment of wet macular degeneration. On 3 August 2012, the FDA approved aflibercept for use in combination with

and

to treat adults with metastatic colorectal cancer that is resistant to or has progressed following an

oxaliplatin Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication (platinum-based antineoplastic class) used to treat colorectal cancer. It is given by injection into a vein. Common side effects include numbness, feeling ti ...

‑containing regimen. To avoid confusion with the version that is injected into the eye, the FDA assigned a new name, ''ziv''-aflibercept, to the active ingredient. In November 2012, the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) approved aflibercept (Eylea) for the treatment of wet macular degeneration. In February 2013, the

(EMA) approved aflibercept (Zaltrap) for the treatment of adults with metastatic colorectal cancer for whom treatment based on

has not worked or the cancer got worse. Aflibercept (Zaltrap) is used with FOLFIRI, which is a treatment combining the medicines irinotecan, 5-fluorouracil, and folinic acid.

Economics

On 12 March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund. In 2017, injections of aflibercept (

HCPCS The Healthcare Common Procedure Coding System (HCPCS, often pronounced by its acronym as "hick picks") is a set of health care procedure codes based on the American Medical Association's Current Procedural Terminology (CPT). History The acronym ''H ...

code J0178) were responsible for the most billing to Medicare Part B, at $2.36 billion.

References

External links

* * {{Portal bar , Medicine Angiogenesis inhibitors Bayer brands Breakthrough therapy Engineered proteins Ophthalmology drugs Sanofi