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.
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).
Figure 1. Optical coherence tomography (OCT) scans.
However, follow-up is limited to less than 1 year because the first case reports were published only in July 2005 (Ophthalmic Surg Lasers Imaging. 2005;36(4):331-335). Intravitreal Avastin was also reported to cause resolution of the macular edema associated with a central retinal vein occlusion (Ophthalmic Surg Lasers Imaging. 2005;36(4):336-339). In this case report, the patient had responded favorably to intraocular steroids, but subsequently developed steroid-induced ocular hypertension, and intravitreal Avastin was offered as salvage therapy. Following the presentation and publication of these case reports, clinicians all over the world started using intravitreal Avastin.
Dr. Robert Avery was at the forefront of this movement, and his recent publication documents the short-term safety and efficacy of intravitreal Avastin for neovascular AMD (Ophthalmology. 2006;113(3):363-372). In addition, Dr. Richard Spaide and colleagues have recently reported their extensive positive experience with off-label intravitreal bevacizumab for the treatment of neovascular AMD (Retina. 2006;26(4):383-390). Avery also teamed up with Dr. Anat Loewenstein in another study to show that Avastin penetrates the full thickness of the retina (Retina. 2006;26(3):262-269). In addition, researchers using electrophysiologic testing have demonstrated that no Avastin-induced retinal toxicity was observed in rabbit eyes and human eyes (Retina. 2006;26(3):262-269, Retina. 2006;26(3):257-261, and Retina. 2006;26(3):270-274). In vitro toxicity studies by Dr. Baruch Kuppermann confirmed the absence of Avastin toxicity in a well-defined series of experiments in a controlled tissue culture environment (Retina. 2006. In press). Finally, Dr. Anne Fung, who has logged more than 7000 injections in more than 5000 patients from 12 countries through an internet-based safety survey, reports that the use of intravitreal Avastin appears to be safe (2006 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 4, 2006; Fort Lauderdale, Fla).
As a result of these observations, clinicians all over the world have been using intravitreal Avastin, and at the most recent annual ARVO meeting in Fort Lauderdale during the first week in May 2006, the vast clinical experience in treating neovascular AMD and other exudative diseases with intravitreal Avastin became apparent. Aside from the fact that Avastin is perceived to be safe and effective, the drug’s growing popularity is due to its low cost and a huge unmet need to affordably prevent blindness from neovascular diseases. As the news spread by word of mouth, the global ophthalmologic community openly shared their knowledge and experience in the best interests of patient care. The rapid accumulation of scientific and clinical data on intravitreal Avastin also demonstrates how a global network of ophthalmologists and vision scientists can make enormous progress, each contributing expertise to help fill in the details about safety and efficacy. Numerous papers will undoubtedly be published over the next few months, and while most of these clinical reports will be retrospective clinical reviews, prospective clinical studies are underway and more are being planned. While Avastin will likely never carry a formal label indicating its use in ophthalmic diseases, the power of a global clinical consensus should not be underestimated. The lack of regulatory approval will not prevent clinicians from using Avastin, especially when there are so many patients and governments unable to afford the high price of approved therapies.
||Phase III Study Shows Lucentis Improved Vision In Patients With Wet Age-Related Macular Degeneration [press release]. Montreal, Canada: Genentech, Inc.; July 18, 2005.
||Preliminary Phase III Data from Head-to-Head Study of Lucentis Shows Lucentis Improved Vision Compared to Visudyne in Patients with Wet Age-Related Macular Degeneration [press release]. Montreal, Canada: Genentech, Inc.; January 14, 2006. |
||Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581-611.|
||Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006;113(4):642. |
||Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N. Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology. 2006;113(4):632. |
||Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005;112(6): 1035-1047.|
||Mordenti J, Cuthbertson RA, Ferrara N, et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol. 1999;27(5):536-544.|
||Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol. 1996;114(1):66-71. |
||Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2005;36(4):336-339.|
||Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36(4):331-335. |
||Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006;113(3):363-372. |
||Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina. 2006;26(4):383-90.|
||Shahar J, Avery RL, Heilweil G , et al. Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin). Retina. 2006;26(3):262-269. |
||Manzano RP, Peyman GA, Khan P, Kivilcim M. Testing intravitreal toxicity of bevacizumab (Avastin). Retina. 2006;26(3):257-261. |
||Maturi RK, Bleau LA, Wilson DL. Electrophysiologic findings after intravitreal bevacizumab (Avastin) treatment. Retina. 2006;26(3):270-274. |
||Davidorf FH, Mouser JG, Derick RJ. Rapid improvement of rubeosis iridis from a single bevacizumab (avastin) injection. Retina. 2006;26(3):354-356. |
||Spaide RF, Fisher YL. Intravitreal bevacizumab (avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina. 2006;26(3):275-278. |
||Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina. 2006;26(3):279-284. |
||Mason JO 3rd, Albert MA Jr, Vail R. Intravitreal Bevacizumab (Avastin) For Refractory Pseudophakic Cystoid Macular Edema. Retina. 2006;26(3):356-357. |
||Fung AE, Rosenfeld PJ, Reichel EZ. Intravitreal Avastin safety survey: results from the World Wide Web. Poster presented at: 2006 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 4, 2006; Fort Lauderdale, Fla.|
The author discloses a financial interest as a recipient of current clinical research funding from Genentech, Inc., Alcon Laboratories, Inc., and Eyetech/OSI Pharmaceuticals. He also participates on the ad hoc scientific advisory boards for Genentech, Novartis Ophthalmics, and Allergan. Dr. Rosenfeld has no proprietary interest in any of the drugs discussed in this article.