**3. Anti VEGF drugs**

and PIGF). These isoforms of VEGF have different effects in ocular pathologies and may dif‐ fer in their neuroprotective abilities [5, 6]. RPE and Müller cells are the major sources of VEGF and they exert their effects through multiple receptors that are mostly expressed on

VEGF-A, has been most strongly associated with angiogenesis and thus consists the target of most anti-VEGF treatments [8, 9]. VEGF-A signals through two receptor tyrosine kinases, VEGFR1 and VEGFR2, and is induced by hypoxia, unlike other VEGF isoforms [7, 10].

Alternative exon splicing of the human VEGF-A gene results in at least four major biologi‐ cally active isoforms, containing 121, 165, 189, and 208 aminoacids (five more are VEG‐

VEGF 121 appears to be essential for normal retinal vascular function [12-13], and VEG‐ FA-165 is the predominant isoform in the human eye. It isa heparin-binding, homodimeric, 45-kDa glycoprotein that is predominantly secreted, although a substantial fraction is bound to the cell surface and to the extracellular matrix[13-14].It appears to be the isoform respon‐

In autopsy studies, VEGF levels were found to be elevated in the retinal pigment epithelium

In summary VEGF-A acts through various pathways which result in promoting pathologic

**•** VEGF is a chemo-attractant for endothelial cell precursors, promoting their differentia‐

**•** It is a powerful agonist of vascular permeability which is particularly important in CNV. Increased vascular permeability in response to VEGF may be due to formation of fenes‐

**•** Leukocytes may amplify the effects of VEGF via their own secretion of VEGF. Further‐ more, VEGF's pro-inflammatory activity, predominantly through the 164 isoform, con‐ tributes to pathological ocular neovascularization [14]. It is therefore a crucial target in combating neovascular and ischemic eye diseases such as: choroidal neovascularization, macular edema secondary to diabetic retinopathy (DME) or retinal vein occlusion and ret‐ inal neovascularisation that may develop in retinal vein occlusion (RVO) or diabetic retin‐

Several anti-VEGF drugs have been studied and have been shown to be effective. However, effective, long-term drug-delivery remains a challenge. Two multi-center, randomized con‐

(RPE) and choroidal blood vessels within the macular area of eyes with AMD [15].

**•** It stimulates angiogenesis by being a potent endothelial cell mitogen [10-11].

**•** It sustains endothelial survival by inhibiting apoptosis [10-12].

trations in microvascular endothelium [12-14].

endothelial cells and are also found on monocytes and macrophages [7].

164 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

FA-145, VEGFA-162, VEGFA-165b, VEGFA-183, and VEGFA-206) [11].

sible for pathological ocular neovascularization.

neovascularization:

tion [12-13].

opathy (DR).

Different VEGF-A isoforms may have different functions in ocular diseases.

Both isoforms are found in CNV tissue excised from patients with AMD.

#### **3.1. Pegaptanib sodium (Macugen) – OSI/Eyetech**

This intravitreal RNA aptamer drug was the first anti-VEGF drug approved by the FDA in 2004 for use in neovascular AMD (nvAMD). It targets VEGFA-165[11]Its efficacy and safety were evaluated in the large VISION trial [16, 17].

Patients with different types of sub foveal CNV secondary to AMD were randomized into four groups. Three groups received an intravitreal injection of pegaptanib sodium at a dose of 0.3mg, 1.0mg, 3.0mg to one eye respectively. The injection was given every 6 weeks for a period of 48 weeks in total. The forth group was the control group and subjects in this group received a sham injection every 6 weeks. Primary outcome was mean change in visual acui‐ ty from baseline.

Results from a combined analysis showed that for all three doses of pegaptanib (P<0.001 for the comparison of 0.3 mg with sham injection; P<0.001 for the comparison of 1.0 mg with sham injection; and P=0.03 for the comparison of 3.0 mg with sham injection) there was a significant difference between the patients receiving treatment and those receiving a sham injection. In the group dosed with pegaptanib 0.3 mg, 70 percent of patients lost fewer than 15 letters of visual acuity (VA), as compared with 55 percent among the controls (P<0.001). The risk of severe loss of VA (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their VA or gained acuity (33 % vs. 23%; P=0.003). As early as six weeks after beginning ther‐ apy with the study drug, and at all subsequent points, the mean visual acuity among pa‐ tients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (P<0.002). During the second year, patients initially assigned to pegaptanib were re-random‐ ized (1:1) to continue or discontinue therapy for 48 additional weeks (8 injections). Those ini‐ tially assigned to sham were re-randomized to continue sham, discontinue sham, or receive 1 of 3 pegaptanib doses. The proportion of patients who lost more than 15 letters or more in vision between week 52 to week 96 was double (14 *vs* 7%), if treatment was discontinued compared to those who continued to receive pegaptanib injections. This suggests that there is a more favorable outcome when continuing treatment for at least two years [18].The Pe‐ gaptanib was found safe and there was no significant difference in serious systemic adverse events or severe ocular inflammation, cataract or glaucoma between the pegaptanib treated groups and the sham treated groups [16, 17].

The VA results of the VISION study are clearly inferior to those of the MARINA and AN‐ CHOR studies evaluating the efficacy of intravitreal ranibizumab for nvAMD (detailed lat‐ er). However, VA efficacy is only one of the clinical considerations that must be taken into account. The safety profile of the drug is not less important. The Macugen was proven to be safe in the VISION study as well as in the smaller study by N. Feucht et al. [19]; in both studies no relevant systemic or ocular adverse effects were noted. Cardiovascular incidents and overall mortality in the Pegaptanib sodium group were comparable to those of the sham injection group.

40.3% in the 0.5mg group, 35.7%in the 0.3mg group, and 5.6% in the verteporfin group. The mean change in VA from baseline to 12months was a gain of 8.5 letters in the 0.3mg group, a gain of11.3 letters in the 0.5mg group, and a loss of 9.5 letters in the vertepor‐ fin group [20]. Rates of serious ocular or systemic adverse events were low in both the

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167

Both studies showed no difference in the percentage of patients losing 15 letters in vision between the 0.3 and 0.5mg. However, the 0.5 mg was statistically significant superior to the 0.3 mg in achieving 15 letters or more in vision. This difference in favor of the 0.5 mg led to

The PIER study [21] evaluated the efficacy of 3 consecutive monthly injections of ranibi‐ zumab followed by fixed re-treatments only every 3 months. Mean changes from base‐ line VA at 12 months were -16.3, -1.6, and -0.2 letters loss for the sham, 0.3 mg, and 0.5 mg groups, respectively (P < or =.0001, each ranibizumab dose vs sham). Ranibizumab reduced the growth and leakage from the CNV. However, the treatment effect achieved following the first 3 consecutive injections declined in the ranibizumab groups during quarterly dosing (e.g., at three months the mean changes from baseline VA was a gain of 2.9 and 4.3 letters for the 0.3 mg and 0.5 mg doses, respectively). Results of subgroups analyses of mean change from baseline VA at 12 months by baseline age, VA, and lesion characteristics were consistent with the overall results. Overall, in this study, the propor‐ tion of gainers of more than three lines was significantly lower than in MARINA or in ANCHOR trials, and this is due to the fact that following the first 3 consecutive injec‐ tions patients were shifted to a significant less frequent dosing of quarterly injections in‐

The EXCITE study evaluated the efficacy and safety of monthly versus quarterly ranibizu‐ mab treatment in nvAMD [22]. Patients were randomized (1:1:1) to 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised of a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either month‐ ly or quarterly injection).In contrast to the PIER study in which patients were examined and injected only every 3 months following the first 3 consecutive monthly injections, in the EX‐ CITE study, patients were followed monthly, but in the 2 quarterly groups they could re‐ ceive an injection only every 3 months. BCVA increased from baseline to month 12 by 4.9, 3.8, and 8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. The noninferiority of a quarterly regimen was not achieved with reference to 5.0 letters, meaning dosing with ranibizumab only every 3 months is inferior than dosing every month, and results in a significant less fa‐ vorable final visual outcome. The safety profile was similar to that reported in prior ranibi‐

Following the results of the PIER and EXCITE study it can be concluded that monthly injec‐ tions is definitely superior to quarterly injections, and that the quarterly regimen should not

its approval by the FDA, and the routine use of 0.5 mg ranibizumab.

MARIMA and the ANCHOR trials[20].

stead of monthly.

zumab studies.

be applied.

Thus, we can conclude that stable vision can be achieved with repeated injections as fre‐ quent as every 6 weeks with pegaptanib. This treatment may still be taken into considera‐ tion especially in subjects suffering from cardiovascular diseases.

#### **3.2. Ranibizumab (Lucentis) - Genentech**

Ranibizumab is a small 48kDa recombinant humanized monoclonal antibody fragment. Its small molecular weight enables it to penetrate the inner limiting membrane and reach the subretinal space when injected intravitreally [5,8-9]. It binds all biologically active isotypes of VEGF with high affinity. The half-life of ranibizumab is 2 – 4 days [5, 8], resulting in a rapid systemic clearance and good systemic safety profile.

FDA has approved the use of ranibizumab for treatment of all angiographic subtypes of subfoveal CNV due to AMD. The phase III MARINA trial evaluated the efficacy and safety of ranibizumab for the treatment of minimally classic or occult with no classic CNV associat‐ ed with AMD. This 2-year, prospective randomized, double-masked, sham-controlled trial enrolled 716 patients. Patients were randomized in a 1 : 1 : 1 ratio to receive intravitreal rani‐ bizumab at a dose of either 0.3 mg or 0.5mg or sham injection monthly in one eye for 2 years [9]. The primary outcome was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months.

At 24 months, 92% of patients who received 0.3 mg of ranibizumab and 90% of patients who received 0.5 mg ranibizumab lost fewer than 15 letters, compared with 52.9% in the sham group. The proportion of patients who gained at least 15 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart from baseline to 24 months was 33.3% in the 0.5mg group, 26.1% in the 0.3mggroup, and 3.8% in the sham group. The mean change in ETDRS VA from baseline to 24 months was a gain of 6.6 letters in the 0.5mg group, a gain of 5.4 letters in the 0.3mg group, and a loss of 14.9 letters in the sham-injection group [9].

The ANCHOR study evaluated the efficacy of Ranibizumab for treatment of Predominantly Classic sub foveal CNV due to AMD. The ANCHOR trial was a multicenter, randomized double-blind trial that enrolled 423 patients to compare the efficacy and safety of ranibizu‐ mab vs PDT with verteporfin[20]. Patients were assigned randomly to receive either 0.3 or 0.5mg of ranibizumab plus sham verteporfin, or sham intravitreal injection plus active verte‐ porfin therapy. Ranibizumab or sham intravitreal injections were given monthly, and the verteporfin or sham was administered on day 0 and then as needed at months 3,6, 9, and 12.

At 12 months, 94.3% of patients in the 0.3mg group and96.4% in the 0.5mg group lost fewer than 15 letters from baseline compared with 64.3% in the verteporfin group. The proportion of patients who gained at least 15 letters from baseline to 12 months was 40.3% in the 0.5mg group, 35.7%in the 0.3mg group, and 5.6% in the verteporfin group. The mean change in VA from baseline to 12months was a gain of 8.5 letters in the 0.3mg group, a gain of11.3 letters in the 0.5mg group, and a loss of 9.5 letters in the vertepor‐ fin group [20]. Rates of serious ocular or systemic adverse events were low in both the MARIMA and the ANCHOR trials[20].

er). However, VA efficacy is only one of the clinical considerations that must be taken into account. The safety profile of the drug is not less important. The Macugen was proven to be safe in the VISION study as well as in the smaller study by N. Feucht et al. [19]; in both studies no relevant systemic or ocular adverse effects were noted. Cardiovascular incidents and overall mortality in the Pegaptanib sodium group were comparable to those of the

Thus, we can conclude that stable vision can be achieved with repeated injections as fre‐ quent as every 6 weeks with pegaptanib. This treatment may still be taken into considera‐

Ranibizumab is a small 48kDa recombinant humanized monoclonal antibody fragment. Its small molecular weight enables it to penetrate the inner limiting membrane and reach the subretinal space when injected intravitreally [5,8-9]. It binds all biologically active isotypes of VEGF with high affinity. The half-life of ranibizumab is 2 – 4 days [5, 8], resulting in a

FDA has approved the use of ranibizumab for treatment of all angiographic subtypes of subfoveal CNV due to AMD. The phase III MARINA trial evaluated the efficacy and safety of ranibizumab for the treatment of minimally classic or occult with no classic CNV associat‐ ed with AMD. This 2-year, prospective randomized, double-masked, sham-controlled trial enrolled 716 patients. Patients were randomized in a 1 : 1 : 1 ratio to receive intravitreal rani‐ bizumab at a dose of either 0.3 mg or 0.5mg or sham injection monthly in one eye for 2 years [9]. The primary outcome was the proportion of patients losing fewer than 15 letters from

At 24 months, 92% of patients who received 0.3 mg of ranibizumab and 90% of patients who received 0.5 mg ranibizumab lost fewer than 15 letters, compared with 52.9% in the sham group. The proportion of patients who gained at least 15 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart from baseline to 24 months was 33.3% in the 0.5mg group, 26.1% in the 0.3mggroup, and 3.8% in the sham group. The mean change in ETDRS VA from baseline to 24 months was a gain of 6.6 letters in the 0.5mg group, a gain of 5.4 letters in the 0.3mg group, and a loss of 14.9 letters in the sham-injection group [9].

The ANCHOR study evaluated the efficacy of Ranibizumab for treatment of Predominantly Classic sub foveal CNV due to AMD. The ANCHOR trial was a multicenter, randomized double-blind trial that enrolled 423 patients to compare the efficacy and safety of ranibizu‐ mab vs PDT with verteporfin[20]. Patients were assigned randomly to receive either 0.3 or 0.5mg of ranibizumab plus sham verteporfin, or sham intravitreal injection plus active verte‐ porfin therapy. Ranibizumab or sham intravitreal injections were given monthly, and the verteporfin or sham was administered on day 0 and then as needed at months 3,6, 9, and 12. At 12 months, 94.3% of patients in the 0.3mg group and96.4% in the 0.5mg group lost fewer than 15 letters from baseline compared with 64.3% in the verteporfin group. The proportion of patients who gained at least 15 letters from baseline to 12 months was

tion especially in subjects suffering from cardiovascular diseases.

166 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

rapid systemic clearance and good systemic safety profile.

**3.2. Ranibizumab (Lucentis) - Genentech**

baseline visual acuity at 12 months.

sham injection group.

Both studies showed no difference in the percentage of patients losing 15 letters in vision between the 0.3 and 0.5mg. However, the 0.5 mg was statistically significant superior to the 0.3 mg in achieving 15 letters or more in vision. This difference in favor of the 0.5 mg led to its approval by the FDA, and the routine use of 0.5 mg ranibizumab.

The PIER study [21] evaluated the efficacy of 3 consecutive monthly injections of ranibi‐ zumab followed by fixed re-treatments only every 3 months. Mean changes from base‐ line VA at 12 months were -16.3, -1.6, and -0.2 letters loss for the sham, 0.3 mg, and 0.5 mg groups, respectively (P < or =.0001, each ranibizumab dose vs sham). Ranibizumab reduced the growth and leakage from the CNV. However, the treatment effect achieved following the first 3 consecutive injections declined in the ranibizumab groups during quarterly dosing (e.g., at three months the mean changes from baseline VA was a gain of 2.9 and 4.3 letters for the 0.3 mg and 0.5 mg doses, respectively). Results of subgroups analyses of mean change from baseline VA at 12 months by baseline age, VA, and lesion characteristics were consistent with the overall results. Overall, in this study, the propor‐ tion of gainers of more than three lines was significantly lower than in MARINA or in ANCHOR trials, and this is due to the fact that following the first 3 consecutive injec‐ tions patients were shifted to a significant less frequent dosing of quarterly injections in‐ stead of monthly.

The EXCITE study evaluated the efficacy and safety of monthly versus quarterly ranibizu‐ mab treatment in nvAMD [22]. Patients were randomized (1:1:1) to 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised of a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either month‐ ly or quarterly injection).In contrast to the PIER study in which patients were examined and injected only every 3 months following the first 3 consecutive monthly injections, in the EX‐ CITE study, patients were followed monthly, but in the 2 quarterly groups they could re‐ ceive an injection only every 3 months. BCVA increased from baseline to month 12 by 4.9, 3.8, and 8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. The noninferiority of a quarterly regimen was not achieved with reference to 5.0 letters, meaning dosing with ranibizumab only every 3 months is inferior than dosing every month, and results in a significant less fa‐ vorable final visual outcome. The safety profile was similar to that reported in prior ranibi‐ zumab studies.

Following the results of the PIER and EXCITE study it can be concluded that monthly injec‐ tions is definitely superior to quarterly injections, and that the quarterly regimen should not be applied.

#### **3.3. Bevacizumab (Avastin) - Genentech**

This drug is a full-length recombinant humanized monoclonal antibody (149kDa).It binds to all VEGF-A isoforms. whereas Ranibizumab has only one binding site to VEGF, bevacizu‐ mab has two. Bevacizumab in addition has a longer acting effect *in-vitro*; however, it may penetrate less effectively the retina [23-26]. Its half life time in the vitreous is approximately 8-10 days [24-25].

provement in BCVA to 52 weeks (5.3-letter gain; P<0.0001). The robust improvement and consistent maintenance of VA mainly occurred in patients initially dosed with 2 mg ev‐ ery 4 weeks for 12 weeks, demonstrating a gain of 9 letters at 52 weeks. Overall, a mean of 2 injections was administered after the 12-week fixed-dosing phase, and the mean time to first reinjection was 129 days; 19% of patients received no injections and 45% re‐ ceived 1 or 2 injections. Treatment with VEGF Trap-Eye was generally safe and well tol‐ erated, with few ocular or systemic adverse events. They concluded that PRN dosing with VEGF Trap-Eye at weeks 16-52 maintained the significant anatomic and visual im‐ provements established during the 12-week fixed-dosing phase with a low need for re-in‐ jections. Repeated dosing with VEGF Trap-Eye was well tolerated over 52 weeks of

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VIEW1 was a phase III non-inferiority trial conducted in North America that randomized 1217 patients to VTE 0.5 mg monthly dosing (0.5q4wk), VTE 2 mg monthly (2q4wk),VTE 2 mg every two months following 3 initial monthly doses (2q8wk), or ranibizumab 0.5mg monthly (Rq4wk). The primary endpoint was the proportion of patients who lost fewer than

Secondary endpoints included mean change in BCVA at week 52. The percentage of partici‐ pants in the Rq4wk, 0.5q4wk, 2q4wk, and 2q8wk treatment arms who gained at least 15 let‐

The proportions of patients maintaining vision at 52 weeks were 94.4%, 95.9%, 95.1%, and 95.1% for Rq4wk, 0.5q4wk, 2q4wk, and 2q8wk, respectively. All VTE groups were noninferior to ranibizumab. Mean improvement from baseline to week 52 in ETDRS let‐ ter score was 8.1, 6.9, 10.9, and 7.9 letters for Rq4wk, 0.5q4wk, 2q4wk, and 2q8wk, re‐

There was a small significant difference in visual improvement at 52 weeks, between the 2q4wk and the Rq4weeks in favor of the 2q4weeks, however this was not found in the parallel VIEW 2 trial that will be discussed later. Differences between other VTE groups and Rq4wk were nonsignificant. The difference in the mean reduction in central retinal thickness was not significant among the groups. The incidence of adverse events was

Overall, dosing monthly or every two months with VTE was non-inferior to monthly ranibi‐ zumab and was well tolerated [32]. The VIEW2 study was a parallel study to VIEW 1 that enrolled 1240 patients from Europe, Latin America, Asia, and Australia and yielded similar results [33]. However, minor differences exist. In the VIEW 2 study there was no statistically significant difference between all treatment arms in ETDRS letter score at week 52, and un‐

The VIEW 1 and VIEW 2 results demonstrated non-inferior efficacy of VTE 2mg dosed at a fixed regimen every 8 weeks compared to ranibizumab 0.5mg dosed every 4 weeks. The EY‐ LEA was approved by the FDA for injection every 8 weeks for nvAMD, and therefore may

similar across all treatments, with no increase in blood pressure noted.

lower the injection burden on the patient as well as the medical system.

like VIEW1 the 2q4wk group was not superior to Lucentis.

treatment.

spectively.

15 ETDRS letters from baseline to week 52 [32].

ters in vision were: 31%,25%, 38%, and 31%, respectively.

It was first approved by the FDA for metastatic colorectal cancer and is used off-label in oc‐ ular disease. Although systemic administration of bevacizumab was shown to be associated with increased systemic cardiovascular adverse events, these appear to be rare following in‐ travitreal administration [8, 24].

Many ophthalmologists until recently offered intravitreal bevacizumab to nvAMD patients based on multiple forms of evidence: results from several retrospective case series,[27-30] extrapolation from the outcomes reported in the MARINA and ANCHOR studies, the struc‐ tural similarity between ranibizumab and bevacizumab, and mostly the clinical experience of rapid resolution of morphological abnormalities on optical coherence tomography (OCT) and fluorescein leakage from CNV after treatment with bevacizumab.

However, treatment with bevacizumab can nowdays be based on the 2-year results of the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) and one year re‐ sults of IVAN study (Inhibit VEGF in Age-related choroidal Neovascularisation)which com‐ pared the efficacy of bevacizumab and ranibizumab for nvAMD and will be discussed in detail later in this chapter.

#### **3.4. Aflibercept (VEGF trap)**

VEGF Trap-Eye (EYLEA; Regeneron, Tarrytown, NY, USA) (VTE) is a soluble fusion pro‐ tein consisting of 2 extracellular cytokine receptor domains and a human Fc region of immunoglobulin G (IgG). This110kDa soluble receptor binds with high affinity to all VEGFA isoforms and VEGF B, and not to VEGF-C and D [5]. The binding affinity of VEGF Trap to VEGF is 10 times higher than bevacizumab. The 2mg dose of VTE at 83days has been proven to have a similar biologic activity to ranibizumab at 30 days [5, 31]. The CLEAR-IT is a phase II trial, which was recently published and evaluated ana‐ tomic outcomes and VA, injection frequency, and safety. The study consisted of 2 phas‐ es; the first was a 12-week fixed dosing period followed by an as-needed (PRN) treatment phase to week 52 with VEGF Trap-Eye for nvAMD [31]. Patients were ran‐ domly assigned to 1 of 5 intravitreal VEGF Trap-Eye treatment groups: 0.5 mg or 2 mg every 4 weeks or 0.5, 2, or 4 mg every 12 weeks during the fixed-dosing period (weeks 1-12). From weeks 16 to 52, patients were evaluated monthly and were retreated PRN with their assigned dose (0.5, 2, or 4 mg). The decrease in CR/LT (central retinal/lesion thickness) at week 12 versus baseline remained significant at weeks 12 to 52 (-130 μm from baseline at week 52) and CNV size regressed from baseline by 2.21 mm2 at 48 weeks. After achieving a significant improvement in BCVA during the 12-week- fixeddosing phase for all groups combined, PRN dosing for 40 weeks maintained the im‐ provement in BCVA to 52 weeks (5.3-letter gain; P<0.0001). The robust improvement and consistent maintenance of VA mainly occurred in patients initially dosed with 2 mg ev‐ ery 4 weeks for 12 weeks, demonstrating a gain of 9 letters at 52 weeks. Overall, a mean of 2 injections was administered after the 12-week fixed-dosing phase, and the mean time to first reinjection was 129 days; 19% of patients received no injections and 45% re‐ ceived 1 or 2 injections. Treatment with VEGF Trap-Eye was generally safe and well tol‐ erated, with few ocular or systemic adverse events. They concluded that PRN dosing with VEGF Trap-Eye at weeks 16-52 maintained the significant anatomic and visual im‐ provements established during the 12-week fixed-dosing phase with a low need for re-in‐ jections. Repeated dosing with VEGF Trap-Eye was well tolerated over 52 weeks of treatment.

**3.3. Bevacizumab (Avastin) - Genentech**

8-10 days [24-25].

travitreal administration [8, 24].

detail later in this chapter.

**3.4. Aflibercept (VEGF trap)**

This drug is a full-length recombinant humanized monoclonal antibody (149kDa).It binds to all VEGF-A isoforms. whereas Ranibizumab has only one binding site to VEGF, bevacizu‐ mab has two. Bevacizumab in addition has a longer acting effect *in-vitro*; however, it may penetrate less effectively the retina [23-26]. Its half life time in the vitreous is approximately

168 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

It was first approved by the FDA for metastatic colorectal cancer and is used off-label in oc‐ ular disease. Although systemic administration of bevacizumab was shown to be associated with increased systemic cardiovascular adverse events, these appear to be rare following in‐

Many ophthalmologists until recently offered intravitreal bevacizumab to nvAMD patients based on multiple forms of evidence: results from several retrospective case series,[27-30] extrapolation from the outcomes reported in the MARINA and ANCHOR studies, the struc‐ tural similarity between ranibizumab and bevacizumab, and mostly the clinical experience of rapid resolution of morphological abnormalities on optical coherence tomography (OCT)

However, treatment with bevacizumab can nowdays be based on the 2-year results of the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) and one year re‐ sults of IVAN study (Inhibit VEGF in Age-related choroidal Neovascularisation)which com‐ pared the efficacy of bevacizumab and ranibizumab for nvAMD and will be discussed in

VEGF Trap-Eye (EYLEA; Regeneron, Tarrytown, NY, USA) (VTE) is a soluble fusion pro‐ tein consisting of 2 extracellular cytokine receptor domains and a human Fc region of immunoglobulin G (IgG). This110kDa soluble receptor binds with high affinity to all VEGFA isoforms and VEGF B, and not to VEGF-C and D [5]. The binding affinity of VEGF Trap to VEGF is 10 times higher than bevacizumab. The 2mg dose of VTE at 83days has been proven to have a similar biologic activity to ranibizumab at 30 days [5, 31]. The CLEAR-IT is a phase II trial, which was recently published and evaluated ana‐ tomic outcomes and VA, injection frequency, and safety. The study consisted of 2 phas‐ es; the first was a 12-week fixed dosing period followed by an as-needed (PRN) treatment phase to week 52 with VEGF Trap-Eye for nvAMD [31]. Patients were ran‐ domly assigned to 1 of 5 intravitreal VEGF Trap-Eye treatment groups: 0.5 mg or 2 mg every 4 weeks or 0.5, 2, or 4 mg every 12 weeks during the fixed-dosing period (weeks 1-12). From weeks 16 to 52, patients were evaluated monthly and were retreated PRN with their assigned dose (0.5, 2, or 4 mg). The decrease in CR/LT (central retinal/lesion thickness) at week 12 versus baseline remained significant at weeks 12 to 52 (-130 μm from baseline at week 52) and CNV size regressed from baseline by 2.21 mm2

weeks. After achieving a significant improvement in BCVA during the 12-week- fixeddosing phase for all groups combined, PRN dosing for 40 weeks maintained the im‐

at 48

and fluorescein leakage from CNV after treatment with bevacizumab.

VIEW1 was a phase III non-inferiority trial conducted in North America that randomized 1217 patients to VTE 0.5 mg monthly dosing (0.5q4wk), VTE 2 mg monthly (2q4wk),VTE 2 mg every two months following 3 initial monthly doses (2q8wk), or ranibizumab 0.5mg monthly (Rq4wk). The primary endpoint was the proportion of patients who lost fewer than 15 ETDRS letters from baseline to week 52 [32].

Secondary endpoints included mean change in BCVA at week 52. The percentage of partici‐ pants in the Rq4wk, 0.5q4wk, 2q4wk, and 2q8wk treatment arms who gained at least 15 let‐ ters in vision were: 31%,25%, 38%, and 31%, respectively.

The proportions of patients maintaining vision at 52 weeks were 94.4%, 95.9%, 95.1%, and 95.1% for Rq4wk, 0.5q4wk, 2q4wk, and 2q8wk, respectively. All VTE groups were noninferior to ranibizumab. Mean improvement from baseline to week 52 in ETDRS let‐ ter score was 8.1, 6.9, 10.9, and 7.9 letters for Rq4wk, 0.5q4wk, 2q4wk, and 2q8wk, re‐ spectively.

There was a small significant difference in visual improvement at 52 weeks, between the 2q4wk and the Rq4weeks in favor of the 2q4weeks, however this was not found in the parallel VIEW 2 trial that will be discussed later. Differences between other VTE groups and Rq4wk were nonsignificant. The difference in the mean reduction in central retinal thickness was not significant among the groups. The incidence of adverse events was similar across all treatments, with no increase in blood pressure noted.

Overall, dosing monthly or every two months with VTE was non-inferior to monthly ranibi‐ zumab and was well tolerated [32]. The VIEW2 study was a parallel study to VIEW 1 that enrolled 1240 patients from Europe, Latin America, Asia, and Australia and yielded similar results [33]. However, minor differences exist. In the VIEW 2 study there was no statistically significant difference between all treatment arms in ETDRS letter score at week 52, and un‐ like VIEW1 the 2q4wk group was not superior to Lucentis.

The VIEW 1 and VIEW 2 results demonstrated non-inferior efficacy of VTE 2mg dosed at a fixed regimen every 8 weeks compared to ranibizumab 0.5mg dosed every 4 weeks. The EY‐ LEA was approved by the FDA for injection every 8 weeks for nvAMD, and therefore may lower the injection burden on the patient as well as the medical system.
