I recently read this excellent overview of current treatment protocols for anti-VEGF treatments of wet AMD in the April issue of Refractive Eyecare, and asked the author and publishers for permission to reproduce it in this space. Permission was granted, and I hope you find it as interesting and well written as I did.
Dante J. Pieramici, MD
Refractive Eyecare April, 2010
To boost the efficacy and duration of anti-VEGF therapy, researchers are evaluating new dosing regimens, higher drug doses, and new medications.
While current anti-VEGF drugs constitute an effective therapy for neovascular age-related macular degeneration (AMD), they are not a magic bullet. Their main shortcoming is their relatively brief duration of effect, which means that patients must receive monthly intravitreal injections; in addition, the efficacy of current anti-VEGF drugs leaves room for improvement. Clinicians and researchers are therefore continuing to explore the use of new treatment regimens, combination therapies, and higher drug doses. In addition, one new drug is currently in clinical trials and more are undergoing preclinical investigations.
To test these new options, a number of studies are currently underway, including the HARBOR trial, the VIEW 1 and VIEW 2 studies, and the CATT study (See box). While none of these studies is complete, many are fully enrolled and should be providing clinicians with valuable data in the near future.
New Treatment Protocols
Anti-VEGF drugs are effective when administered monthly, but the need for such frequent intravitreal injections places a high treatment burden on the patient and increases the risk of intraocular infections and other complications. For this reason, several studies are examining alternative treatment protocols to see if they can maintain efficacy while decreasing the frequency of injections. (See box 2)
In the PrONTO study, researchers administered ranibizumab (Lucentis) monthly for 3 months and then "as needed" (PRN) for the remainder of the study. During the first year of the study, patients were retreated when optical coherence tomography (OCT) showed an increase in central retinal thickness of at least 100 microns or when visual acuity testing showed a loss of 5 or more letters; during the second year of the study, a qualitative increase in the amount of fluid was also included as one of the retreatment criteria. Using this approach, researchers achieved a mean increase in visual acuity of 11.1 letters and a mean decrease in central retinal thickness of 212 microns with an average of only 9.9 injections over 24 months.(1)
Another way of trying to stretch the interval between intravitreal injections is by using a treat-and-extend protocol. Unlike a PRN dosing schedule, in which patients are monitored monthly even if they are treated less frequently, a treat-and-extend protocol stretches the interval between appointments. Using such a strategy, the patient is treated at every visit, but the time between visits is gradually increased if the patient's condition remains stable – i.e., no signs of vessel leakage, increasing edema, decreasing visual acuity, or blood or lipid on exam. In most cases, this approach reduces the number of injections by approximately 50% over a 1-year period.
[Editors Note: This is a case where the Notal Vision at home monitor, when it becomes available, could prove valuable in extending treatment time for neovascular AMD patients.]
Finally, researchers are also considering the use of photodynamic therapy (PDT) as an adjunct to anti-VEGF injections. Although combination therapy does not seem to improve overall treatment efficacy, early data suggests that combining PDT with anti-VEGF medications may allow clinicians to achieve the same results with fewer injections. Because PDT adds another level of complexity to the treatment, however, it has not been widely adopted by clinicians.
Higher Doses and New Drugs
While PRN dosing, treat-and-extend protocols, and combination therapy can all help to prolong the duration of efficacy for existing anti-VEGF drugs, new drug formulations also hold promise. To test whether using a higher concentration of drug can provide additional benefit, researchers are currently studying high-dose ranibizumab. Other studies are testing novel agents such as VEGF-Trap to see if they provide greater efficacy and/or duration of effect.
In the HARBOR trial, researchers are comparing the standard 0.5 mg dose of ranibizumab with a 2.0 mg dose to see whether injecting more of the drug will improve its efficacy and extend its duration of effect. Both doses are being evaluated using a PRN dosing schedule as well as a fixed monthly schedule, so this trial should also yield information about the interaction between dose and dosing frequency.(2)
In terms of side effects, higher drug doses pose a few potential risks. Injection-related complications are a risk with any intravitreal drug, but these risks should be largely independent of the dose; since the high-dose formulation of ranibizumab is more concentrated than the low-dose formulation, clinicians can inject the same volume for both treatment groups. Thrombotic events such as heart attacks and strokes will be a concern, but the systemic drug levels should be significantly lower than those achieved following systemic administration of Avastin to treat cancer – by a factor of 100.
In addition to the HARBOR trial, other major studies that should soon yield interesting results include the VIEW 1 and VIEW 2 studies, both of which are evaluating a new anti-VEGF agent, VEGF-Trap. Unlike ranibizumab, which is an antibody (Fab) fragment against VEGF, VEGF-Trap is a soluble receptor for VEGF. VEGF-Trap has a higher binding affinity than ranibizumab, which may improve its efficacy and/or duration of effect. VEGF-Trap also blocks platelet-derived growth factor (in addition to all isoforms of VEGF), which may provide some additional anti-angiogenic properties.
Because drug development moves slowly through multiple phases, treatment for neovascular AMD over the next few years will be limited to drugs that are currently available – ranibizumab and bevacizumab – plus VEGF-Trap, which is well along in clinical trials. However, there are numerous agents in the pipeline that are being evaluated in preclinical and phase 1 trials. While we cannot predict which of these agents might prove clinically useful, the range of options undergoing study holds out the promise that one or more of these will prove effective.
Finally, I believe the future of AMD treatment will involve a shift from treatment of neovascular AMD to earlier detection and treatment of non-neovascular AMD. Specifically, researchers are currently examining ways to block inflammation, inhibit oxidation, and rescue photoreceptors. If such treatments are successful, then we might be able to prevent neovascular AMD from occurring.
The Bottom Line
While anti-VEGF drugs are usually effective in the treatment of neovascular AMD, researchers and clinicians are still looking for ways to improve treatment. Since monthly intravitreal injections place a high treatment burden on patients, some studies are examining ways to increase the interval between treatments-such as PRN dosing, treat-and-extend protocols, and combination therapy. In addition, studies are examining the efficacy of other therapies that might offer greater efficacy and/or duration of effect, including high-dose ranibizumab and VEGF-Trap.
Dante J. Pieramici, MD, is a retina specialist at California Retina Consultants, director of the California Retina Research Foundation, and a clinical assistant professor at the University of Southern California's Doheny Eye Institute. He is a consultant for Genentech, Novartis, QLT, and CoMentis.
Refractive Eyecare’s managing editor Kay Downer assisted in the preparation of this manuscript.
1. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 2009 Jul;148(1):43-58.
In addition, the April 25th issue of Ocular Surgery News contains an article on the same subject: Combination Therapy May Augment Anti-VEGF Activity
. It mentions other clinical studies underway for combination therapies and to extend the time between intravitreal injections, including the use of radiotherapy.