**7. Potential complications of anti VEGF agents**

Safety issues with anti VEGF intravitreal injections include local ocular adverse events (AEs) from the drug or the injection, as well as potential systemic AEs of the drug.

Ocular AEs may be categorized as common but not serious and rare but potentially serious. The AEs that are considered common but not serious include subconjunctival hemorrhage, vitreous floaters from medication or vitreous hemorrhage, and discomfort from antiseptic used to prepare the conjunctiva before the injection(9, 20, 21).

Repeated intravitreal injection of ranibizumab or bevacizumab, over extended time periods, has been demonstrated to result in a low incidence of serious ocular adverse events. In the CATT study, endophthalmitis developed after only two of 5449 injections (0.04%) in 599 pa‐ tients treated with ranibizumab, and after only four of 5508 injections (0.07%) in 586 patients treated with bevacizumab. Uveitis, retinal detachment, retinal vascular occlusion or embo‐ lism, retinal tear, and vitreous hemorrhage each also occurred in less than 1% of patients [49, 50]. Efforts are underway in order to further reduce the incidence of these events, with stud‐ ies evaluating the effect of needle type and injection technique on patient pain levels, vitreal reflux, and ocular complications [66].

It is unknown if pretreatment antibiotics for several days prior to injection, or only on the procedure's day is necessary in order to reduce the risk of endophthalmitis. Furthermore, it is unknown if post treatment antibiotics are necessary on the day of the procedure or there‐ after to reduce this risk furthermore. Although the product insert for ranibizumab indicates that the administration of the intravitreal injection should include the use of sterile gloves and a sterile drape, not all physicians agree that these items are necessary to maintain sterile conditions for the injection. However, all agree that the use of a lid speculum and adminis‐ tration of povidone-iodine to the lids, lashes, and conjunctiva are recommended [67].

Another concern is an allergic reaction to the drug. Since ranibizumab is a recombinant monoclonal antibody that contains both mouse and human derived segments, some patients treated with the drug may develop systemic antibodies [8, 20].

In the ANCHOR trial 3.9% of ranibizumab 0.5-mg subjects had developed antibodies to ra‐ nibizumab compared with 0% in the PDT group [20].

In the MARINA trial, after 24 months, 6.3% of subjects treated with ranibizumab 0.5 mg and 1.1% of those in the sham injection group developed antibodies to ranibizumab [8].

Systemic AEs are a concern, since inhibitors of VEGF injected intravitreally, can penetrate the general circulation and compromise functions that rely on VEGF outside of the eye, such as wound healing and the formation of new blood vessels around the heart or brain in cases of ischemia [68, 69]. Patients with AMD already are at higher risk of cardiovascular disease than the general population because of their age and the association of AMDwith systemic hypertension [70], consequently, participants in clinical trialsof VEGF inhibitors were care‐ fully monitored for possible increases in blood pressure, occurrence of myocardial infarc‐ tion/stroke, and nonocular hemorrhages [8, 20].

VA appears to equally improve among all groups, but confidence intervals varied. Of the three combination therapy arms, the triple therapy half-fluence PDT group shared similar mean visual improvement compared with monotherapy and had the fewest retreatments. After 12 months, three retreatments of triple therapy with half-fluence PDT were required compared to 5.1 re-treatments of monotherapy (p<0.001). Adverse event incidence was similar amongst all treatment groups. The final results of the 24-months

Safety issues with anti VEGF intravitreal injections include local ocular adverse events (AEs)

Ocular AEs may be categorized as common but not serious and rare but potentially serious. The AEs that are considered common but not serious include subconjunctival hemorrhage, vitreous floaters from medication or vitreous hemorrhage, and discomfort from antiseptic

Repeated intravitreal injection of ranibizumab or bevacizumab, over extended time periods, has been demonstrated to result in a low incidence of serious ocular adverse events. In the CATT study, endophthalmitis developed after only two of 5449 injections (0.04%) in 599 pa‐ tients treated with ranibizumab, and after only four of 5508 injections (0.07%) in 586 patients treated with bevacizumab. Uveitis, retinal detachment, retinal vascular occlusion or embo‐ lism, retinal tear, and vitreous hemorrhage each also occurred in less than 1% of patients [49, 50]. Efforts are underway in order to further reduce the incidence of these events, with stud‐ ies evaluating the effect of needle type and injection technique on patient pain levels, vitreal

It is unknown if pretreatment antibiotics for several days prior to injection, or only on the procedure's day is necessary in order to reduce the risk of endophthalmitis. Furthermore, it is unknown if post treatment antibiotics are necessary on the day of the procedure or there‐ after to reduce this risk furthermore. Although the product insert for ranibizumab indicates that the administration of the intravitreal injection should include the use of sterile gloves and a sterile drape, not all physicians agree that these items are necessary to maintain sterile conditions for the injection. However, all agree that the use of a lid speculum and adminis‐

tration of povidone-iodine to the lids, lashes, and conjunctiva are recommended [67].

treated with the drug may develop systemic antibodies [8, 20].

nibizumab compared with 0% in the PDT group [20].

Another concern is an allergic reaction to the drug. Since ranibizumab is a recombinant monoclonal antibody that contains both mouse and human derived segments, some patients

In the ANCHOR trial 3.9% of ranibizumab 0.5-mg subjects had developed antibodies to ra‐

In the MARINA trial, after 24 months, 6.3% of subjects treated with ranibizumab 0.5 mg and

1.1% of those in the sham injection group developed antibodies to ranibizumab [8].

from the drug or the injection, as well as potential systemic AEs of the drug.

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

trial were not published yet.

reflux, and ocular complications [66].

**7. Potential complications of anti VEGF agents**

used to prepare the conjunctiva before the injection(9, 20, 21).

Among participants in the MARINA trial, approximately16% in both the ranibizumab 0.5 mg and sham injectiongroups developed hypertension [8] and in the ANCHOR treatment related hypertension was higher in the PDT group (8.4%) than in the ranibizumab group (6.4%) [20].

In the CATT trial there was no evidence that ranibizumab0.5 mg was associated with in‐ creases in either diastolic or systolic blood pressure [49, 50].

Nonocular hemorrhages include events such as cerebral or gastrointestinal bleeding. In the ANCHOR trial, non ocular hemorrhage was more frequent in the 0.5-mg ranibizumab group (6.4%) than in the PDT group (2.1%) [20]. In the MARINA trial, the cumulative fre‐ quency of nonocular hemorrhage by month 24 was 5.5% in the sham injection group com‐ pared with 8.8% in the 0.5-mgranibizumab group [8].

Among participants in the MARINA trial, approximately 16% in both the ranibizumab 0.5 mg and sham injection groups developed hypertension [3].

In the CATT trial Gastrointestinal disorders (e.g., hemorrhage, hernia, nausea, and vomit‐ ing), occurred in 11 (1.8%) ranibizumab-treated and in 28 (4.8%) bevacizumab-treated pa‐ tients (*P* = 0.005) [51].

With respect to cardiovascular or cerebrovascular events, during the ANCHOR trial, 1 sub‐ ject in the PDT group (0.7%) and 3 subjects in the ranibizumab 0.5-mg group (2.1%) devel‐ oped nonfatal myocardial infarctions, although the events did not occurshortly after treatment. [20]. The frequency of stroke (1 in each group) and cerebral infarction (0 in each group) in the ANCHOR trial were too low to draw meaningful conclusion [20].

At 24 months, the overall frequency of cardiovascular systemic events in the MARINA trial was similar in the0.5-mg ranibizumab and sham injection groups [8]. Therewere only small differences in the frequency of thromboembolic events between the sham injection group (3.8%) and the ranibizumab 0.5-mg group (4.6%) [8]. The frequency of death (2.5%) was the same in the ranibizumab 0.5-mgand sham injection groups [8]. Two individuals in each group died of stroke.

There was no significant difference in the frequency of myocardial infarction between the 2 treatment groups in the SAILOR trial [36].

In the CATT trial at 2 years, 5.3% assigned to ranibizumab and 6.1% assigned to Bevacizu‐ mab had died (*P* = 0.62). The proportion of patients with arteriothrombotic events was simi‐ lar in the ranibizumab-treated patients (4.7%) and in the bevacizumab-treated patients 5.0%; (*P* = 0.89). Venous thrombotic events occurred in 3 (0.5%) ranibizumab-treated patients and in 10 (1.7%) bevacizumab-treated patients (*P* = 0.054) [51].

**8. New anti VEGF agents under investigation**

SIRNA stands for short interfering RNA. SIRNAs are 21 to 25 nucleotide-long double-stranded RNA molecules capable of destroying a corresponding target messenger RNA with high selec‐

Anti VEGF Agents for Age Related Macular Degeneration

http://dx.doi.org/10.5772/54198

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SIRNAs work intracellularly, where they are incorporated into a protein complex called RNA-induced silencing complex (RISC) [71]. The RISC has RNA helicase activity, which un‐ winds the two strands of RNA. The strand of the siRNA that becomes associated to the RISC leads the complex to selectively cleave and degrade messenger RNA molecules containing a complementary sequence. The siRNA is engineered to match the protein encoding nucleo‐ tide sequence of the target messenger RNA. Since the translation of messenger RNA into proteins is an amplification step, destroying it is a very potent method of inhibiting protein

SIRNA-027 (SIRNA Therapeutics, Inc.) is a short interfering RNA that targets the VEGF re‐ ceptor 1 (VEGFR-1).Animal experiments have shown that both intravitreous and periocular injections of siRNA directed against VEGFR1 lead to a substantial reduction of VEGFR1

The siRNA suppressed the development of CNV at rupture sites in Bruch's membrane and de‐ creased retinal neovascularizationin mice with oxygen-induced ischemic retinopathy [72-73].

Acuity Pharmaceuticals has also produced a siRNA called Cand5 or Bevasiranib that targets the messenger RNA of the VEGF protein itself. Animal models have shown prevention of

Bevasiranib sodium was developed for intravitreal administration. Following intravitreal in‐ jection, bevasiranib is well distributed within the eye and localizes to the retina [72, 73].

Preliminary results of Phases I and II clinical trials of bevasiranib have shown promising re‐ sults for the treatment of nvAMD and diabetic macular edema. There are various studies of different phases underway (the COBALT studies although recruitment was stopped). A phase III study evaluating the combination of bevasiranib and ranibizumab in nvAMD (the

The purpose of this study is to compare intravitreal bevasiranib sodium as maintenance therapy for AMD following initiation with three monthly doses of ranibizumab. Preliminary clinical results indicate that the effects of bevasiranib do not appear until six weeks after the initiation of treatment, which suggests that combination therapy with anti VEGF drug might be justified. The late effect of bevasiranib might be linked to its mechanism of action, since bevasiranib inhibits the synthesis of new VEGF, and does not eliminate existing VEGF, a di‐ rect anti-VEGF agent may be required to neutralize VEGF already present in the eye before inhibition of new VEGF synthesis. Preliminary results of the carbon and cobalt studies sug‐ gested that over 30% of patients on combination ranibizumab-bevasiranib achieve an im‐

tivity and efficacy [71]. This leads to post transcriptional gene silencing (PTGS).

**8.1. RNA Interference (SIRNA)**

messenger RNA levels [71-72].

CNV development after laser-induced injury [72].

CARBON study) is currently underway.

function.

One or more serious systemic adverse events occurred in 255 patients (21.5%), with 53 (17.6%) in the ranibizumab-monthly group, 64 (22.4%) in the bevacizumab-monthly group, 61 (20.5%) in the ranibizumab-as-needed group, and 77 (25.7%) in the bevacizu‐ mab-as-needed group (P = 0.11 by the chi-square test). Hospitalizations accounted for 298 of the 370 individual serious systemic adverse events (80.5%). When dosing-regimen groups were combined, the proportions of patients with serious systemic adverse events were 24.1% for bevacizumab and 19.0% for ranibizumab (P = 0.04). After adjustment for demographic features and coexisting illnesses at baseline, the risk ratio for bevacizumab, as compared with ranibizumab, was 1.29 (95% confidence interval, 1.01 to 1.66; P = 0.04). Patients treated as needed had higher rates than patients treated monthly (risk ratio, 1.20; 95% CI, 0.98 −1.47; *P* =0.08). After excluding all events previously associated with systemic treatment with anti–vascular endothelial growth factor drugs, 170 (28.4%) of ra‐ nibizumab-treated patients and 202 (34.5%) of bevacizumab-treated patients had experi‐ enced events (*P* = 0.02) [51].

Although event rates for these cerebrovascular or cardiovascular events seem to be low with ranibizumab, ophthalmologists should ensure that patients understand the theoretic poten‐ tial for these risks. Additional studies over time may help to refine understanding of the magnitude, if any, of this risk.

In the recently published IVAN trial at 12 months, 6 participants (1.9%) in the ranibizu‐ mab group and 5 (1.7%) in the bevacizumab group (*P* = 0.81) had died; 5 (1.6%) had re‐ ceived continuous and 6 (2.0%) discontinuous treatment (*P* = 0.74) [52]. Fewer participants treated with bevacizumab compared with ranibizumab had an arteriothrom‐ botic event or heart failure (0.7% vs. 2.9%; odds ratio, 0.23; 95% CI, 0.05to 1.07; *P* = 0.03), but no difference between treatment regimens was found (*P* = 0.34). One or more serious systemic adverse events occurred in 30 (9.6%) in the ranibizumab group and 37 (12.5%) in the bevacizumab group (*P* = 0.25). Similarly, 30 (9.7%) in the continuous and 7 (12.3%) in the discontinuous group had ≥1 serious systemic adverse events (*P* = 0.32). More than 10 participant-specific events occurred in 3 MedDRA categories: cardiac disorders, surgi‐ cal or medical procedure, and any other class (available at http://aaojournal.org). Com‐ parisons by drug and regimen for cardiac disorders and surgical or medical procedure showed no differences (*P*≥0.46). One case of severe uveitis developed after 1 injection; there was 1 reported traumatic cataract and 3 retinal pigment epithelial tears. Five "oth‐ er" ocular events were each reported once.

#### **7.1. Safety of Bevacizumab**

Data on the safety of intravitreal bevacizumab are more limited than data on Ranibizumab safety, due to the lack of large multicenter trials performed with Bevacizumab. The results of the CATT and IVAN trials were previously presented.
