The September issue of Ophthalmology published a study that compared the efficacy of intraocular injections of bevacizumab (Avastin; Genentech, Inc.) with ranibizumab (Lucentis; Genentech, Inc.) in a mouse model of neovascular age-related macular degeneration (AMD). In this model, human vascular endothelial growth factor (VEGF) was produced in retinal cells by transgenic mice.1 The study concluded that in this model, bevacizumab is not inferior to ranibizumab for the treatment of subretinal neovascularization and is superior in severe cases. These data may be relevant to treatment of patients with neovascular AMD.
Peter A. Campochiaro, MD, one of the study's investigators, said in an interview with Retina Today that the results suggest that ranibizumab may not be more effective than bevacizumab in the treatment of neovascular AMD, but he cautions that these results should not be generalized to other disease processes such as diabetic macular edema (DME) and macular edema due to retinal vein occlusion (RVO). Dr. Campochiaro is the George S. and Dolores Doré Eccles Professor of Ophthalmology and Neuroscience at the Wilmer Ophthalmological Institute of the Johns Hopkins Hospital School of Medicine. Researchers, including Dr. Campochiaro and Dante Pieramici, MD, stress that these hypotheses—that ranibizumab is more efficacious than bevacizumab or vice versa for any disease process—are just that, hypotheses and the true answer may depend on the disease being treated.
CLINICAL IMPRESSIONS
Currently, comparisons between the two similar anti-VEGF therapies are based purely on clinical impressions rather than firm clinical data. The ongoing Comparison of AMD Treatments Trial (CATT), which is comparing the effects of intraocular injections of 0.5 mg ranibizumab and 1.25 mg bevacizumab, will provide the clinical data to determine if there is a measurable difference in efficacy in treatment of neovascular AMD; however, the findings will not apply to other disease processes. It is possible that ranibizumab has no advantage over bevacizumab in neovascular AMD treatment but does in the treatment of macular edema due to diabetic retinopathy or RVO, as some anecdotal evidence has suggested. Some retina specialists have been disappointed in the effects of bevacizumab in patients with DME and feel that ranibizumab may provide more benefit, Dr. Campochiaro said. Likewise, there is a perceived difference in treating macular edema due to RVO, although probably not as much difference as is felt to be the case in DME, he added.
Good data are not available to support or refute such observations, Dr. Campochiaro stressed. There are positive data from small studies in which ranibizumab was used to treat DME or RVO,2,3 and these impressive results are being confirmed by larger studies including the 6-month results of the BRAVO and CRUISE studies, he said. Case series reporting results using bevacizumab in patients with macular edema do not seem as impressive, but patient populations in these studies may differ, making it difficult to draw firm conclusions. Understanding that it is not proven that ranibizumab is superior to bevacizumab in treatment of macular edema, it is still useful to ask if there are any characteristics of ranibizumab that could potentially provide advantage.
MOLECULAR SIZE
One possible explanation as to why ranibizumab is said by some to be more effective than bevacizumab in DME and RVO is related to the molecule's size. Dr. Campochiaro speculates that diseases such as DME, in which the retinal vessels are leaking deep in the retina, may require more penetration than was originally believed.
"The transgenic mice study showed that there is a much greater systemic effect from bevacizumab compared with ranibizumab. Bevacizumab is a fairly large molecule, and yet it appears to get out of the eye and maintain levels in the circulation to a greater extent than ranibizumab," Dr. Campochiaro said. A longer half-life in the circulation is well-documented and understandable because bevacizumab contains an Fc domain while ranibizumab does not. The Fc domain may also allow bevacizumab to be transported out of the eye to a greater extent, because there are Fc receptors in the ciliary body which seem to function to transport immunoglobulin-G out of the eye into the circulation, Dr. Campochiaro explained. "However, while bevacizumab may get out of the eye as well as or better than ranibizumab and thus access the subretinal space through the circulation, it may not penetrate into the retina as well as ranibizumab," he said.
BINDING AFFINITY
Dr. Pieramici, of California Retina Consultants in Santa Barbara, CA, is doubtful that there is a clinically significant difference in effectiveness between ranibizumab and bevacizumab in neovascular AMD. Dr. Pieramici said in an interview with Retina Today that his clinical impression is that, for patients with DME as well as macular edema secondary to RVO, ranibizumab may work better than bevacizumab. A Diabetic Retinopathy Clinical Research Network (DRCR.net) study that evaluated intravitreal bevacizumab for DME4 produced disappointing results, Dr. Pieramici said, with intravitreal bevacizumab reducing DME in only some eyes. However, data are still needed to definitively prove that ranibizumab is the more effective treatment for DME.
"It is possible that edema may respond more rapidly and to a greater extent with ranibizumab due to its high-binding affinity for VEGF," Dr. Pieramici said.
Ranibizumab is five to twenty times more potent on a molar basis in binding VEGF-A than bevacizumab.5 Furthermore, there may be may have higher levels of VEGF in the eye in DME and RVO compared with AMD, Dr. Pieramici pointed out. In AMD, ischemia, with resulting upregulation of VEGF, is localized and occurs in the outer retina. In comparison, ischemia is much more diffuse in diabetic and retinal vascular disease such as RVO and occurs in the inner retina. In the latter case, ranibizumab, with its potent ability to bind to and inactivate more VEGF, would, in theory, be more effective than bevacizumab in disease states with more diffuse ischemia and higher levels of VEGF, Dr. Pieramici speculated.
This observation is counterintuitive to ranibizumab's original purpose, Dr. Pieramici added, "because the molecule was developed to penetrate the retina and treat neovascular macular degeneration, but my impression is that ranibizumab works better in diseases of the inner retina where penetration would be less of an issue, such as for DME and RVO".
_1773249222.png?auto=compress,format&w=75)
