Bevacizumab is a monoclonal antibody to vascular endothelial growth factor developed for the treatment of cancer. Over the past years, it has been used in the management of complicated retinal and choroidal vascular conditions like diabetic retinopathy, retinal venous occlusive disease, retinopathy of prematurity, neovascular glaucoma, and exudative age-related macular degeneration (AMD). The following chapter will address the pharmacology and pharmacokinetics of Bevacizumab and its utility in the management of ophthalmic diseases.

The idea of using antibodies that target malignant tumor cells was originally suggested by Ehrlich at the beginning of the 20th century (1). Creation of somatic hybridization to generate “hybridoma” cell lines brought this idea closer to reality in 1976. Initially the monoclonal antibodies (mAbs) failed to show efficacy in clinical trials mainly due to intrinsic immunogenicity (rodent-derived mAbs). These issues were quickly overcome by newly developed molecular antibody engineering methods that allowed humanization of antibodies. The advance in technology led investigators to develop monoclonal antibodies for specific targets. Antibodies are currently engineered to customize their size, binding specificity, affinity, effectors function, and ability to be produced on a large scale suitable for clinical use.

Bevacizumab is a humanized antibody (IgG1) designed to recognize all isoforms of a diffusible endothelial cell-specific mitogen, the vascular endothelial growth factor (VEGF) with high affinity (Kd, 0.8 nM). Bevacizumab inhibits VEGF-induced proliferation of endothelial cells and VEGF-induced vascular leakage. Angiogenesis is an essential process required for tumor growth, as well as for new vessel formation. The VEGF pathway is well established as one of the key regulators of the angiogenesis process. Elevation of VEGF was found in aqueous humor and vitreous humor in human eyes with proliferative diabetic retinopathy and other retinal disorders. VEGF was also found to be elevated in surgically extracted choroidal neovascular membranes from AMD patients (2,3).

Bevacizumab was Food and Drug Administration (FDA) approved in 2004 for first-line therapy in combination with irinotecan, 5-fluorouracil (5-FU), and leucovorin in metastatic colorectal cancer. This approval was based in the results of a phase III trial (4), where over 800 previously untreated metastatic colon cancer patients were given bolus irinotecan, 5-FU, and leucovorin plus placebo or bevacizumab. The overall response rate was 44.8% in the bevacizumab group and 34.8% in the placebo group, with duration of response of 10.4 and 7.1 months, respectively. The median progression-free survival (PFS) was 10.55 versus 6.24 months, and median survival was 20.34 versus 15.61 months. The main toxicities in the bevacizumab group were grade 3 hypertension (11% versus 2.3%), proteinuria, and arterial thromboembolic events (4.4% vs 1.9%). In 2006, bevacizumab was approved by the FDA for second-line treatment for metastatic colon cancer in combination with intravenous 5-FU-based chemotherapy, and first-line treatment for nonsmall cell lung cancer. In February 2008, the FDA granted accelerated approval of bevacizumab in combination with paclitaxel for first-line treatment of metastatic HER2-negative breast cancer.

Bevacizumab has structural and functional similarities to another anti VEGF agent, ranibizumab. When initial clinical trial data suggested a significant benefit with ranibizumab in AMD, and with ranibizumab unavailable for use because it was awaiting licensing approval by the FDA, ophthalmologists began treating AMD and subsequently diabetic retinopathy and macular edema with bevacizumab, When ranibizumab was eventually licensed for use in America, bevacizumab was already well established in the retina community as a potentially effective and apparently safe therapy. The use of the drug for intravitreous injection increased exponentially without the evidence base that usually guides the rational and safe use of new medicines, namely large randomized controlled clinical trials. The current Comparisons of Age-Related Macular Degeneration Treatments Trials (CATT) is a randomized controlled clinical trial designed to compare the efficacy and safety of two dosing strategies of bevacizumab and ranibizumab.

Bevacizumab (rhuMAb VEGF) is a recombinant humanized IgG1 antibody derived from the murine VEGF monoclonal antibody A4.6.1 (5). It is a full-length antibody of 149 kilodaltons, bigger than ranibizumab (antibody fragment of 48 kilodaltons). Bevacizumab has 93% human and 7% murine protein sequences. The humanization process of bevacizumab was performed by site-directed mutagenesis of a human framework. Several framework residues and the six complementarydetermining regions were changed from human to murine. The final result was a humanized anti-VEGF F(ab), rhuMAb VEGF, agent with the same biochemical and pharmacologic properties as the parental antibody, but with reduced immunogenicity, and a longer biological half-life (5).

Bevacizumab binds and inhibits all biologically active forms of VEGF, much like ranibizumab (6). It is a full-length, humanized monoclonal antibody, whereas ranibizumab is a humanized antigen-binding fragment. Both proteins were genetically engineered from the same murine monoclonal antibody against VEGF (5). Although bevacizumab has two binding sites for VEGF, ranibizumab has only a single binding site, which has been affinity matured to have an increased binding affinity for VEGF compared with the antigen-binding fragment derived from the original murine antibody (7).

Assays in cynomolgus monkeys (15) and albino rabbits (16) showed that bevacizumab penetrated inner layers of the retina on the first day of injection and reached the choroid during the following days. An active transport mechanism is probably involved in the process.

Following FDA approval of Bevacizumab for treatment of metastatic colorectal cancer, ophthalmologists from around the world extended treatment indications. Currently, bevacizumab is being used for a variety of eye diseases that involve new vessel formation and macular edema.

The first outcomes of bevacizumab in ophthalmology were published in 2006. The encouraging results observed with intravitreal ranibizumab in the earlier phase I/II studies gave the initial impulse to investigate the systemic effect of bevacizumab in neovascular age-related macular degeneration (ARMD) patients.

SANA (Systemic Avastin for Neovascular AMD) was designed to look at the safety, efficacy, and durability of systemic bevacizumab for the treatment of neovascular ARMD. Two cohorts of 9 patients were followed for 24 consecutive weeks following intravenous administration of Bevacizumab at doses of 5 mg/Kg. Improved visual acuity with resolution of leakage from neovascular lesions was observed after 2 or 3 doses of bevacizumab (24). Mild elevation in blood pressure was the only adverse event identified. In spite of the lack of severe adverse events in this first trial, some investigators were concerned with the potential risk for uncontrolled hypertension and thromboembolic events, as had been observed in cancer patients (25,26). With that concern in mind, and because of the pharmacologic similarity with the ranibizumab, intravitreal delivery was tested. It was assumed that, theoretically, a 400-fold lower dose of bevacizumab injected into the eye was safer for the patient than a higher dose given systemically.

Since that first publication in 2006, several studies have been done using bevacizumab for multiple retinal pathologies. New vessel formation, macular edema, choroidal neovascularization, and as an adjuvant in vitreous and glaucoma surgery have been some of the indications for bevacizumab in ophthalmology.

The pathogenesis of macular edema is multifactorial and not completely understood. Disruption in the blood-retinal barrier secondary to inflammatory mediators like VEGF, prostaglandins, cytokines, and other vasopermeability factors, have been involved in the increased permeability of the perifoveal capillaries and the resulting macular edema.

Recent studies show the efficacy of an intravitreal injection of bevacizumab in reduction of pseudophakic cystoid macular edema (27), macular edema secondary to retinal venous occlusions, diabetes (28,29), and other eye diseases like retinitis pigmentosa (30).

The Early Treatment Diabetic Retinopathy Study (ETDRS) (31) established that focal laser photocoagulation for diabetic macular edema (DME) reduced moderate visual loss by 50%. Based on these results, laser treatment for DME has been the only well demonstrated treatment that reduces the risk of vision loss in these patients. However, in the ETDRS, 12% of treated eyes lost ≥15 ETDRS letters at a 3-year follow-up interval. Furthermore, only 3% of the laser-treated eyes gained ≥3 lines of vision. Given that most of the eyes laser-treated for DME do not experience an improvement in visual acuity, alternative management strategies like intravitreal steroids and anti-VEGF are being considered.

Bevacizumab has been used as a treatment for DME since 2006. Several studies have been published showing good results with this new approach (Table 36-1). It has been proposed that the use of intravitreal bevacizumab may reduce the risk of vision loss in eyes with DME by 96% (29). This risk reduction is lower when the investigators include eyes with advanced stages of DME and macular ischemia (32, 33 and 34). The benefit appears evident during the first month of treatment and may continue improving for the next 6 months. Re-injections are often necessary, however, to reach maximum improvement. The optimal treatment schedule is yet to be determined but probably variable, depending on multiple factors. There is evidence that a single injection of bevacizumab lasts for 4 to 6 weeks. Deterioration of visual acuity and recurrence of macular edema are often seen again after 8 to 12 weeks (35).

Visual function recovery after bevacizumab treatment in the presence of macular ischemia is not as good as in the absence of ischemia. The foveal thickness may decrease after the injection, but this reduction does not correlate with an improvement in visual acuity (33).

A phase 2 randomized, multi-center clinical trial was conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net) at 36 clinical sites in the U.S. (36). The study was designed to provide data on the short-term effect of intravitreal bevacizumab for DME. The patients were assigned randomly to one of five groups: focal photocoagulation at baseline (N = 19, Group A), intravitreal injection of 1.25 mg bevacizumab at baseline and 6 weeks (N = 22, Group B), intravitreal injection of 2.5 mg bevacizumab at baseline and 6 weeks (N = 24, Group C), intravitreal injection of 1.25 mg bevacizumab at baseline and sham injection at 6 weeks (N = 22, Group D), or intravitreal injection of 1.25 mg bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks
(N = 22, Group E). Although about half of eyes demonstrated an initial positive response to intravitreal bevacizumab (exceeding an 11% reduction in retinal thickness compared with baseline at either the 3-week or 6-week visit), this response was similar to that observed in the laser group after more than 3 weeks. In addition, the magnitude of the response was not large for most subjects. Two doses of bevacizumab are being used: 1.25 mg and 2.5 mg. Both concentrations work in a similar way reducing macular edema and restoring visual acuity in DME. A combination of bevacizumab and laser photocoagulation was tested and no apparent short-term benefit or adverse outcomes were found (36). A large phase 3 randomized clinical trial is important to determine the value of bevacizumab in DME.

Venous occlusions are the second most common retinal vascular disease after diabetic retinopathy. Vision loss in these cases is associated with macular edema and macular ischemia. Laser photocoagulation has been the only evidence-based treatment for patients with macular edema secondary to branch vein occlusions (BRVO) since 1984 when the BRVO Study (37) was published. The BRVO study showed that 63% of laser treated patients had improved ≥2 lines of vision compare with 36% of the control eyes with a mean gain in visual acuity of 1.3 lines in the treated group.

Laser photocoagulation proved not to be useful in macular edema secondary to central retina vein occlusion. The Central Vein Occlusion Study (38) found that initial visual acuity is the best prognostic factor for patients; patients with initial visual acuity of 20/40 or better often retain good vision, patients with initial visual acuity of 20/50 to 20/200 have a variable prognosis (20% may get better), and patients with initial visual acuity worse than 20/200 have a poor prognosis (80% remain 20/200 or worse).

Bevacizumab is being used for macular edema in branch and central occlusions with promising outcomes (Table 36-2) (Figs. 36-1 and 36-2). Investigators reported gain of 2 to 4.8 lines of vision after bevacizumab treatment in patients with macular edema secondary to vein occlusions (39, 40 and 41). Around 67% of the patients gain 3 or more lines of visual acuity after treatment (40,42). The optimum dosing and sequence for treatment is still undetermined. The literature available seems to indicate that multiple injections are required to achieve better visual acuity and to maintain improvement. Two to three injections over the first 6 months appear to be the most common management strategy. (43). Visual improvement and reduction in macular thickness is reported as early as 1 week after treatment and remains stable or improves for up to 2 months after the injection (43,44). Three to four months after treatment visual acuity declined and macular thickness increased in some patients (44). To date no investigators have reported worsening of nonperfusion after treatment with bevacizumab, and some of them reported collateral vessel formation.

Idiopathic macular telangiectasias (IMT) are dilated capillaries that develop in the macula and perifoveolar areas without a known cause. In 1993, Gass and Blodi (50) established a classification of these entities with subgroups and stages. In type 2 (perifoveal telangiectasia) the telangiectatic blood vessel is limited to the perifoveolar area and is associated with leakage and cystic appearance of the fovea. Typical findings in fluorescein angiography are parafoveal ectatic capillaries and late
diffuse leakage, mainly temporal to fovea. Yannuzzi et al. (51

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