At the recent World Congress of Ophthalmology in Brazil, ophthalmologists from all over the world shared their positive experiences with the off-label use of intravitreal Avastin for the treatment of retinal and choroidal vascular diseases. Few innovations in medicine have been adopted throughout the world as rapidly as the off-label use of intravitreal Avastin. To date, the global ophthalmic community has found no evidence of ocular or systemic toxicity, and Avastin appears to be effective. However, the long term safety of intravitreal Avastin is still unknown and needs to be studied. Although most of the clinical experience to date is anecdotal, there is a growing belief that these early observations will be predictive of future success when intravitreal Avastin is studied prospectively. This article will describe the scientific and clinical rationale for the use of intravitreal Avastin in the treatment of ocular exudative diseases.
Vision Improvement with Anti-VEGF Therapy: Lucentis (Ranibizumab)
Recent phase III clinical trials involving Lucentis (ranibizumab) for the treatment of neovascular age-related macular degeneration (AMD) have demonstrated that improved visual acuity can be achieved by inhibiting vascular endothelial growth factor (VEGF). VEGF has been implicated as a major angiogenic factor responsible for vision loss from ocular neovascularization and macular edema in AMD, diabetes, and other vasoproliferative diseases (Endocr Rev. 2004;25(4):581-611). Lucentis, a humanized antigen binding fragment (Fab) against VEGF derived from a full length murine anti-VEGF monoclonal antibody, is able to bind and inhibit all the biologically active molecular forms of VEGF.
According to data from the phase III trials, monthly intravitreal injections of Lucentis at doses of 0.3 mg and 0.5 mg resulted in an overall improvement in visual acuity and the prevention of neovascular growth. Such findings in a phase III study involving neovascular AMD patients are unprecedented. Moreover, the phase III trials faithfully reproduced the beneficial effects shown in the earlier phase I/II studies with Lucentis (Ophthalmology. 2006;113(4):642 and Ophthalmology. 2006;113(4):632).
While the benefits seen with Lucentis in these early trials were unambiguous, uncertainty existed as to whether patients and clinicians would acquiesce to monthly intraocular injections and whether the low-grade inflammation associated with Lucentis would limit its acceptance because of the concern that it would be confused with endophthalmitis. It was within the context of these uncertainties that subsequent investigations of systemic Avastin (bevacizumab) for the treatment of neovascular AMD were undertaken.
Systemic Avastin (Bevacizumab)
Avastin was approved by the FDA for the intravenous treatment of metastatic colorectal cancer in February 2004. Shortly thereafter, Michels and associates proposed that Avastin, a humanized full-length antibody against VEGF derived from the same murine monoclonal as Lucentis, would be able to leak from a neovascular lesion, bind VEGF, and improve macular anatomy and vision in patients with neovascular AMD (Ophthalmology. 2005;112(6):1035-1047). This hypothesis proved to be correct in all 18 patients enrolled in the SANA Study. After just 2 or 3 Avastin infusions at 2 week intervals, researchers observed effects nearly identical to the benefits observed with intravitreal Lucentis. Moreover, these benefits occurred in both eyes of patients with bilateral neovascularization, and the duration of these benefits lasted 6 months or longer in 12 of the 18 patients (Ophthalmology. 2005;112(6):1035-1047 and Ophthalmology. 2006. In press). When additional therapy was necessary, a single retreatment was able to eliminate recurrent neovascularization.
While the visual acuity and anatomic outcomes after 2 or 3 systemic Avastin infusions appeared similar to monthly intravitreal injections of Lucentis, the systemic approach had some disadvantages. Each treatment was expensive, costing an average $2200 per infusion. In addition, the potential systemic risks included hypertension and thromboembolic events, most notably heart attack and stroke. While no thromboembolic events were observed in the aforementioned study, the risk of these events in an elderly population without cancer was unknown, and the threat that such events could develop as a result of high-dose systemic Avastin therapy was sufficient to dampen the enthusiasm for using Avastin in a large clinical trial. However, the SANA Study proved to be an essential step towards the use of intravitreal Avastin.
The Road to Intravitreal Avastin
It was theoretically possible to decrease the systemic risks associated with Avastin by lowering the systemic dose of Avastin 2 to 3 fold or by injecting 400-fold less Avastin directly into the eye. While an intravitreal injection of Avastin in humans had not yet been performed, there were several reasons to suspect that intravitreal Avastin would be safe and effective. We knew from the SANA Study that the anti-VEGF properties of Avastin and Lucentis were similar because both drugs resulted in nearly identical anatomic and visual acuity outcomes. A review of the literature demonstrated that the overall affinity of both molecules for VEGF was similar and the original mouse monoclonal antibody against VEGF had been injected injected into monkey eyes without sequellae. In this monkey model of neovascular glaucoma, multiple injections of the mouse anti-VEGF antibody resulted in prevention of iris neovascularization without any inflammation observed (Arch Ophthalmol. 196;114(1):66-71). The lack of inflammation was remarkable in this cross-species experiment (mouse monoclonal in monkey eyes) suggesting that the humanized mouse monoclonal (Avastin) would be associated with little if any inflammation if injected into human eyes.
However, one limitation of intravitreal Avastin was thought to be its size. In the 1990s Genentech published a study concerning the retinal penetration of an anti-VEGF Fab and a full-length antibody after an intravitreal injection (Toxicol Pathol. 1999;27(5):536-544). While the Fab appeared to penetrate better than the full-length antibody, the study was flawed due to the fact that the two molecules recognized different antigens: the Fab was directed against VEGF, and the full-length antibody was directed against an antigen expressed within the inner retina known as HER2. This was problematic, because one possible explanation for the limited penetration of the full-length antibody after intravitreal injection was that it became bound to the antigen expressed in the inner retina. In addition, the notion that better penetration would result in increased efficacy for the treatment of choroidal neovascularization was never tested. This same study also demonstrated that a full-length antibody had an intravitreal half-life nearly twice as long as that of a Fab. This observation suggested that an antibody with a longer half-life might be dosed less frequently than a Fab, resulting in fewer intravitreal injections.
Intravitreal Avastin was also inexpensive. Compared with Macugen (pegaptanib sodium), which OSI Pharmaceuticals sells for about $1000 an injection or $3300 per milligram, the proposed dose of Avastin at 1.25 mg costs $6.88 ($5.50 per mg). If dispensed by a licensed pharmacist directly from the vial to the syringe under sterile conditions, the cost of Avastin rises to between $17 and $50 a syringe, which is still substantially less than other treatments for neovascular AMD. The volume of Avastin necessary to achieve a dose of 1.25 mg is only 50 microliters (0.05 mL) of the undiluted, commercially available drug. This volume is easily injected the eye and is the same volume used for Lucentis in the clinical trials. Pharmacists currently dispense Avastin into tuberculin syringes in accordance with Chapter 797 of the U.S. Pharmacopeia (USP) guidelines.
Current Practices
At present, intravitreal Avastin is offered as salvage therapy to patients failing other approved therapies. However, there is a growing consensus among ophthalmologists that intravitreal Avastin should be offered as frontline therapy. Patients all over the world have experienced short-term anatomic and visual acuity improvements that appear very similar to those observed with Lucentis in neovascular AMD (Figure 1).