**3. Existing treatments: VEGF inhibitors, corticosteroids, and focal laser**

VEGF proteins contribute to the regulation of vascular permeability and growth through tyrosine kinase receptors called VEGF receptors [12]. Binding of VEGF protein ligands to their VEGF receptors activates the mitogen-activating protein kinase (MAPK) signaling pathway and causes angiogenesis via increased endothelial cell growth and survival [13]. There are multiple VEGF proteins including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PlGF) [14]. VEGF-A primarily targets VEGF receptor 2 (VEGFR2) and increases angiogenesis, vascular permeability, and leukocyte adhesion [15, 16]. See **Figure 1** for a schematic of the relationship between the various VEGF ligands and receptors. Due to its significant role in the pathogenesis of DR/DME, many drugs inhibit the VEGF-A (referred to as simply VEGF for the remainder of this chapter) pathway to halt and decrease angiogenesis and vascular permeability within the disease [17]. Currently, two anti-VEGF medications are approved by the US Food and Drug Administration (FDA) for the treatment of DME: aflibercept (Eylea, Regeneron, Tarrytown, NY, USA) and ranibizumab (Lucentis, Genentech, South San Francisco, CA, UA). In addition, one anti-VEGF agent is frequently used off-label, bevacizumab (Avastin, Genentech, South San Francisco, CA, USA).

Ranibizumab was originally approved for the treatment of neovascular agerelated macular degeneration (nAMD) in the United States in 2006, and it was approved for DME in 2012 based on the phase 3 RISE and RIDE studies [18]. It is administered intravitreally on a monthly basis. Aflibercept was approved in 2011 for nAMD and in 2014 for DME after positive results from phase 3 VIVID and VISTA studies [19]. It can be dosed in longer eight-week intervals, after 5 monthly loading doses. Bevacizumab was approved in 2004 for use in metastatic colorectal

*Angiopoietins as Targets for Diabetic Retinopathy Treatment DOI: http://dx.doi.org/10.5772/intechopen.99749*

#### **Figure 1.**

*Schematic depiction of the major interactions between endothelial-specific growth factors and their receptors. (Reproduced here from https://commons.m.wikimedia.org/wiki/File:Endothelial\_receptors\_and\_growth\_ factors\_01.png, licensed under the creative commons attribution-share alike 4.0 international license).*

cancer; however, it is often used off-label for DME and is dosed intravitreally similarly to ranibizumab [20].

Intravitreal corticosteroids such as triamcinolone acetonide (Triescence, Alcon, Fort Worth, TX, USA), dexamethasone intravitreal implant (Ozurdex, Abbvie/Allergan, Irvine, CA, USA), and fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences, Alpharetta, GA, USA) are also commonly used as a second line treatments for DME, and help reduce exudation by their broad inhibition of inflammatory cytokines. They are often used in combination with anti-VEGF therapy but have potential side effects of cataract progression and ocular hypertension [21]. Focal laser photocoagulation to leaking microaneurysms in the macula has been shown to reduce vision loss compared to no treatment, but does not provide the visual acuity gains achieved with anti-VEGF therapy [19, 22].

Although the use of anti-VEGF agents has greatly improved treatment outcomes in DR/DME patients, these agents have limited durability and require dosing as frequently as monthly, which may be required indefinitely in some cases. Additional treatment barriers include limited treatment efficacy and financial burden, particularly for the branded agents [23]. Anti-VEGF therapy has shown lower efficacy in 'real-world' studies when compared to clinical trial outcomes in DME and in nAMD patients [24–26]. This is partially due to under-treatment in clinical practice, resulting in approximately one line less of visual acuity gains compared to large randomized clinical trials. One real world database study showed that over one year U.S. DME patients received a mean of 7.5, 7.9 and 7.7 injections of aflibercept, bevacizumab and ranibizumab, respectively, which is lower than the 9.2, 9.7, and 9.4 injections received for these same drugs in the DRCR Protocol T Study [25, 27]. For the RISE and RIDE studies, DME patients received monthly ranibizumab injections (12 total), and for the VIVID and VISTA studies patients received bimonthly treatment of aflibercept after 5 monthly doses (8 total). Additionally, it has been shown that blockade of VEGF-A can lead to upregulation of other members of the VEGF family which also have pro-angiogenic effects [28]. For these reasons, there

has been a heightened focus on the development of medications that target alternate pathways, such as the Tie-2/angiopoietin pathway.
