Aflibercept

Aflibercept
Mass / length primary structure	115 kDa
Identifier
External IDs	CAS number : 862111-32-8;
Drug information
ATC code	S01 LA05 , L01 xx44
DrugBank	DB08885
Drug class	Recombinant Fusion Protein

Aflibercept (trade name Eylea ) is a human, recombinant fusion protein which is used, among other things, to treat neovascular (wet) age- related macular degeneration (AMD) in adults. Under the trade name Zaltrap , aflibercept is also used for metastatic colorectal cancer (mCRC) in adults in combination with chemotherapy . Eylea is marketed by Regeneron Pharmaceuticals in the United States of America, while Bayer AG has distribution rights outside the United States. Zaltrap is marketed and distributed worldwide by Sanofi .

history

Eylea was approved in the US in 2011 , while it received approval in the European Union in 2012. Zaltrap has been approved on the European market since 2013.

Properties of the molecule and its manufacturing process

Aflibercept is a human, recombinantly produced glycosylated fusion protein. It consists of two identical polypeptide chains, which also contain the second domain of the Vascular Endothelial Growth Factor 1 receptor and the third domain of the Vascular Endothelial Growth Factor 2 receptor and have been linked to the Fc domain of the human IgG1 antibody . Aflibercept is produced in a cell line from Chinese hamster ovaries ( CHO cells ).

Mode of action

The Vascular Endothelial Growth Factor plays an essential role in the formation of new blood vessels ( angiogenesis ), which is decisive in both AMD and tumor growth in mCRC. In neovascular (wet) age-dependent macular degeneration, new blood vessels form in the choroid ( choroidal neovascularization (CNV) ), which can lead to retinal edema, retinal thickening or sub / intraretinal hemorrhage and thus impair visual acuity. Aflibercept acts as an inhibitor of the Vascular Endothelial Growth Factor A ( VEGF Trap , English VEGF catcher) and also binds the placenta growth factor (PGF). On the one hand, cancer cells in mCRC are prevented from building up an additional blood supply system and thus the supply of nutrients; on the other hand, the mean CNV lesion size is reduced in AMD .

administration

Eylea is injected directly into the vitreous humor of the eye ( intravitreally ) at a dose of 2 mg every four weeks. After three months, the interval increases to 8 weeks. Zaltrap is given as an infusion at a dose of 4 mg / kg body weight over a period of one hour. In the treatment of colorectal cancer, Zaltrap is given every two weeks in addition to FOLFIRI .

Side effects

Common side effects when giving Zaltrap include leukopenia and neutropenia , diarrhea, and increased liver enzyme levels. The most common side effects when Eylea was given were conjunctival bleeding, decreased visual acuity, eye pain and increased intraocular pressure. A recent Rote-Hand-Brief also refers to the development of osteonecrosis of the jawbone under Zaltrap , mostly in combination therapy with chemotherapy, intravenously administered bisphosphonates and / or invasive dental interventions.

Early benefit assessment

In Germany, since 2011, newly approved drugs with new active ingredients must be subjected to an " early benefit assessment " by the Federal Joint Committee (G-BA) in accordance with Section 35a SGB V if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . Only if there is an additional benefit can the pharmaceutical manufacturer negotiate a price with the umbrella association of statutory health insurance companies. The dossier evaluations, on the basis of which the G-BA makes its decisions, are created by the Institute for Quality and Efficiency in Health Care (IQWiG) .

In 2013, aflibercept was first compared with the ACT ranibizumab for the treatment of neovascular age-related macular degeneration . According to the G-BA decision, no additional benefit has been proven for this indication. A benefit assessment of aflibercept for the treatment of patients with metastatic colorectal cancer who had been pretreated with an oxaliplatin-containing regimen followed in the same year; the ACT was the combination chemotherapy of 5-fluorouracil, folinic acid and irinotecan. According to the G-BA decision, there is an indication of a minor additional benefit for such patients. Next, the active ingredient was compared with dexamethasone (intravitreal implant) or ranibizumab in the new application area of macular edema through retinal central vein occlusion. According to the G-BA decision, an additional benefit in this indication is not proven. For patients with visual impairment due to diabetic macular edema, the ACT was again ranibizumab. According to the G-BA decision, an additional benefit has not been proven here either. The same appropriate comparator therapy and the same evaluation result also existed for the treatment of macular edema due to a retinal branch vein occlusion. In 2016, a benefit assessment procedure for the active ingredient aflibercept in the application area of myopic choroidal neovascularization was finally carried out, also in comparison with ranibizumab and also with the result “additional benefit not proven”.

Web links

Public Assessment Report (EPAR) of the European Medicines Agency (EMA) on: Aflibercept

Individual evidence

↑ Eylea® (aflibercept). (PDF) Medicines Commission of the German Medical Association, accessed on May 1, 2015 .
↑ ^a ^b Zaltrap® (aflibercept). (PDF) Medicines Commission of the German Medical Association, accessed on May 1, 2015 .
↑ ^a ^b Collaborations are a key part of Regeneron's strategy and mission. Regeneron, accessed May 1, 2015 .
↑ EYLEA® (aflibercept) Injection Approved for the Treatment of Wet Age-Related Macular Degeneration in Europe. Regeneron, accessed May 2, 2015 .
↑ ^a ^b Assessment Report Eylea. (PDF) EMA, accessed on May 1, 2015 .
↑ ZALTRAP® (ziv-aflibercept) Approved in the EU for Patients with Previously Treated Metastatic Colorectal Cancer. Regeneron, accessed May 1, 2015 .
↑ ^a ^b ^c Summary of Product Characteristics. (PDF) EMA, accessed on May 1, 2015 .
↑ ^a ^b ^c Zaltrap aflibercept. (PDF) EMA, accessed on May 1, 2015 .
↑ EYLEA® (aflibercept) Injection For Intravitreal Injection. Regeneron, accessed May 1, 2015 .
↑ Rote-Hand-Brief on Zaltrap® (Aflibercept) (Sanofi-Aventis Deutschland GmbH from March 2016). (PDF; 1.24MB) (No longer available online.) Sanofi-Aventis Deutschland GmbH, archived from the original on April 8, 2016 ; accessed on August 30, 2019 .
↑ A12-19 Aflibercept - benefit assessment according to Section 35a Social Code Book V (dossier assessment). iqwig.de; accessed on March 23, 2020.
↑ Benefit assessment procedure for the active ingredient aflibercept (neovascular age-dependent macular degeneration). iqwig.de; accessed on March 23, 2020.
↑ A13-08 Aflibercept (Zaltrap) - Benefit assessment according to Section 35a SGB V (dossier assessment). iqwig.de; accessed on March 23, 2020.
↑ Benefit assessment procedure for the active ingredient aflibercept (new area of application: colorectal cancer). g-ba.de; accessed on March 23, 2020.
↑ A13-36 Aflibercept (Eylea) approval extension - benefit assessment according to § 35a SGB V (dossier assessment). iqwig.de; accessed on March 23, 2020.
↑ Benefit assessment procedure for the active ingredient aflibercept (new area of application: macular edema due to retinal central vein occlusion)
↑ A15-05 Aflibercept (Addendum to Commission A14-32). iqwig.de; accessed on March 23, 2020.
↑ Benefit assessment procedure for the active ingredient aflibercept (new area of application: diabetic macular edema). g-ba.de; accessed on March 23, 2020.
↑ A15-11 Aflibercept (new area of application) - Benefit assessment according to Section 35a SGB V (dossier assessment). iqwig.de; accessed on March 23, 2020.
↑ Benefit assessment procedure for the active ingredient aflibercept (new area of application: macular edema as a result of a retinal branch vein occlusion). g-ba.de; accessed on March 23, 2020.
↑ A15-49 Aflibercept (new area of application) - benefit assessment according to § 35a SGB V. iqwig.de; accessed on March 23, 2020.
↑ Benefit assessment procedure for the active ingredient aflibercept (new area of application: myopic choroidal neovascularization). g-ba.de; accessed on March 23, 2020.

[AKDAE_1-1] Eylea® (aflibercept). (PDF) Medicines Commission of the German Medical Association, accessed on May 1, 2015 .

[AKDAE_2-2] Zaltrap® (aflibercept). (PDF) Medicines Commission of the German Medical Association, accessed on May 1, 2015 .

[Regeneron-3] Collaborations are a key part of Regeneron's strategy and mission. Regeneron, accessed May 1, 2015 .

[Regeneron_2-4] EYLEA® (aflibercept) Injection Approved for the Treatment of Wet Age-Related Macular Degeneration in Europe. Regeneron, accessed May 2, 2015 .

[EMA-5] Assessment Report Eylea. (PDF) EMA, accessed on May 1, 2015 .

[Regeneron_3-6] ZALTRAP® (ziv-aflibercept) Approved in the EU for Patients with Previously Treated Metastatic Colorectal Cancer. Regeneron, accessed May 1, 2015 .

[EMA_3-7] Summary of Product Characteristics. (PDF) EMA, accessed on May 1, 2015 .

[EMA_2-8] Zaltrap aflibercept. (PDF) EMA, accessed on May 1, 2015 .

[Regeneron_4-9] EYLEA® (aflibercept) Injection For Intravitreal Injection. Regeneron, accessed May 1, 2015 .

[10] Rote-Hand-Brief on Zaltrap® (Aflibercept) (Sanofi-Aventis Deutschland GmbH from March 2016). (PDF; 1.24MB) (No longer available online.) Sanofi-Aventis Deutschland GmbH, archived from the original on April 8, 2016 ; accessed on August 30, 2019 .

[11] A12-19 Aflibercept - benefit assessment according to Section 35a Social Code Book V (dossier assessment). iqwig.de; accessed on March 23, 2020.

[12] Benefit assessment procedure for the active ingredient aflibercept (neovascular age-dependent macular degeneration). iqwig.de; accessed on March 23, 2020.

[13] A13-08 Aflibercept (Zaltrap) - Benefit assessment according to Section 35a SGB V (dossier assessment). iqwig.de; accessed on March 23, 2020.

[14] Benefit assessment procedure for the active ingredient aflibercept (new area of application: colorectal cancer). g-ba.de; accessed on March 23, 2020.

[15] A13-36 Aflibercept (Eylea) approval extension - benefit assessment according to § 35a SGB V (dossier assessment). iqwig.de; accessed on March 23, 2020.

[16] Benefit assessment procedure for the active ingredient aflibercept (new area of application: macular edema due to retinal central vein occlusion)

[17] A15-05 Aflibercept (Addendum to Commission A14-32). iqwig.de; accessed on March 23, 2020.

[18] Benefit assessment procedure for the active ingredient aflibercept (new area of application: diabetic macular edema). g-ba.de; accessed on March 23, 2020.

[19] A15-11 Aflibercept (new area of application) - Benefit assessment according to Section 35a SGB V (dossier assessment). iqwig.de; accessed on March 23, 2020.

[20] Benefit assessment procedure for the active ingredient aflibercept (new area of application: macular edema as a result of a retinal branch vein occlusion). g-ba.de; accessed on March 23, 2020.

[21] A15-49 Aflibercept (new area of application) - benefit assessment according to § 35a SGB V. iqwig.de; accessed on March 23, 2020.

[22] Benefit assessment procedure for the active ingredient aflibercept (new area of application: myopic choroidal neovascularization). g-ba.de; accessed on March 23, 2020.