Choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) until recently had no efficacious pharmacologic treatment. That changed beginning in 2001 with the introduction of verteporfin photodynamic therapy (PDT) (Visudyne; Novartis, Basel, Switzerland), followed by the approval of two vascular endothelial growth factor (VEGF) inhibitors, pegaptanib (Macugen; OSI/Eyetech, New York, New York) and ranibizumab (Lucentis; Genentech, South San Francisco, California).
The regulatory approvals of these three pharmacologic therapies were supported by prospective randomized trials showing stabilization and/or improvement in visual acuity with repeated treatments.1-5 In addition, investigators have reported promising results with off-label intravitreal injections of corticosteroids6-9 and of the anti-VEGF oncology drug bevacizumab (Avastin; Genentech) for treatment of CNV in AMD.10,11
The availability of multiple pharmacologic therapies has allowed clinicians to begin assessing the efficacy and safety of combinations of two or more agents that address different components of CNV. The goal of these combinations is to achieve synergy or additive effects, either improving the visual acuity results of existing monotherapies or reducing the frequency of treatment they require to maintain vision improvements.
No data from prospective, randomized studies of combination therapies for CNV secondary to AMD have been published, but a number of combinations have shown promise. After a brief review of the rationale for combination therapies, this article describes the results of one ongoing clinical trial comparing two combination treatments.
SEEKING SYNERGIES
AMD is not only an angiogenic disease; it includes three interacting pathologic components: angiogenic, vascular, and inflammatory. The rationale for combination therapy is to address these components with multiple types of treatment, each with a different mode of action. A combination of therapies may potentially improve upon the efficacy of current treatments or reduce the number of treatments needed in eyes with CNV due to AMD.
Inflammatory
Corticosteroids, which have antiinflammatory, antiangiogenic, antifibrotic and antipermeability properties, can be used to address the inflammatory component of CNV. Visual acuity improvements have been seen with intravitreal injection of triamcinolone acetonide alone in small-scale clinical trials and case series.6,7 One randomized, controlled, double-masked clinical study of intravitreal triamcinolone for CNV in AMD has been published.8,9 That study showed a reduction of growth in CNV lesions with classic component in treated eyes. No difference was seen, however, in the amount of severe vision loss at 1 year between treated eyes and controls. Also, a greater risk of elevated intraocular pressure (IOP) and progression of cataract was seen in treated eyes, although the intravitreal injections were in general well tolerated.
Vascular
The vascular component of CNV can be addressed by PDT, in which intravenously injected verteporfin accumulates in the pathologic new vessels in the choroid, where it is then activated with nonthermal laser irradiation. The resulting chemical reaction occludes the new vessels, and often the surrounding normal vessels, which may contribute to the upregulation of VEGF expression seen after PDT.12,13 Two large-scale prospective, randomized clinical trials found verteporfin PDT to be effective in reducing the risk of vision loss in patients with classic1 and occult with no classic2 subfoveal CNV due to AMD.
Angiogenic
VEGF inhibitors can be used to control the angiogenic component of CNV. These drugs interrupt the angiogenic cascade that leads to the formation of new vessels. The inhibition of VEGF and other angiogenic factors reduces the growth of CNV and has also been shown to cause regression of early new vessels.14
Both pegaptanib and ranibizumab, administered intravitreally at regular intervals, have been shown to reduce the risk of vision loss in patients with all types of CNV lesions secondary to AMD.3-5 Bevacizumab seems to have properties similar to ranibizumab when administered intravitreally in patients with CNV due to AMD, but this promise has yet to be evaluated in a prospective randomized clinical trial.
The rationale for combination therapies is to use the different mechanisms of action of these drugs to address the components of CNV with the hope of achieving synergy or additive effects. While the anti-VEGF drugs have shown the ability to improve vision in patients with AMD, the labeling of these drugs mandates retreatment at frequent intervals (every 6 weeks for pegaptanib, every 4 weeks for ranibizumab15,16) based on the protocols of the clinical trials that supported their regulatory approvals. It is hoped that by combining therapies, the intervals between treatments can be lengthened without forfeiting the visual improvements seen with the anti-VEGF agents—or perhaps improving the visual results.
COMBINATIONS WITH PDT
A number of trials have assessed various combinations of PDT with other agents. This article will not review them all. Literature reviews of combinations of verteporfin PDT plus triamcinolone17 and verteporfin PDT plus antiangiogenic drugs18 have been published.
The FOCUS (RhuFab V2 Ocular Treatment Combining the use of Visudyne to Evaluate Safety) study19 showed that verteporfin PDT combined with ranibizumab was more effective than PDT alone. It is not clear from that study whether the combination treatment was more effective than ranibizumab alone. The visual results in the combination group in the FOCUS study were similar to those in the trials that supported regulatory approval of ranibizumab.4,5
A dose-ranging study of pegaptanib plus verteporfin PDT was conducted in 21 patients with subfoveal CNV.20 Ten patients received pegaptanib alone and 11 received pegaptanib plus PDT. Pegaptanib was administered every 4 weeks, with verteporfin given 5 to 10 days before in patient receiving both treatments. At 3 months, 3 lines or more of visual acuity gain more seen in 60% of patients receiving the combination and in 25% of those receiving pegaptanib alone.
In the VISION (VEGF Inhibition Study in Ocular Neovascularization) trial,3 PDT could be administered at the discretion of the investigator in patients receiving pegaptanib. The small sample sizes and confounding factors in this and in the dose-ranging study, however, make drawing conclusions about relative efficacy of PDT in combination with pegaptanib difficult.
The combination of intravitreal triamcinolone plus verteporfin PDT was evaluated in several small case series, including one of the first with 13 patients who had previously been treated with PDT and 13 treatment-na•ve patients.21,22 Investigators reported a mean improvement of 2.5 lines of visual acuity in treatment-naïve patients at 12 months after combination therapy. The previously treated patients showed an improvement of 0.44 lines (2 letters) at 12 months. The frequency of retreatment over the course of the year in this study was less than half the frequency in the two trials for regulatory approval of PDT.1,2 However, these studies had different sizes and different entry criteria, making comparisons between them difficult.
Concerns have been raised about increased risks of complications with the combination of PDT and intravitreal steroids. In a retrospective series in which patients received intravitreal triamcinolone within 6 weeks of PDT, 29% of eyes experienced IOP elevation, and 50% of phakic eyes experienced progression of cataract.23 IOP should be monitored regularly when intravitreal steroid treatment is used.
VERITAS STUDY
No large-scale prospective randomized clinical trials have been published evaluating either the combination of PDT plus intravitreal corticosteroids or the combination of PDT plus an anti-VEGF agent.
The VERITAS (A Safety and Efficacy Study Comparing the Combination Treatments of Verteporfin Therapy Plus One of Two Different Doses of Intravitreal Triamcinolone Acetonide and the Verteporfin Therapy Plus Intravitreal Pegaptanib) trial is an ongoing prospective randomized clinical trial evaluating both of these types of combination therapies in patients with CNV due to AMD.
The study, which began in September 2005, enrolled 111 patients before halting recruitment because of the results of clinical trials evaluating ranibizumab, and it is not currently recruiting. A companion study, the DENALI study, is currently recruiting and is evaluating the combination of PDT and ranibizumab versus ranibizumab alone.
VERITAS is an active-controlled phase 3 trial in which patients with subfoveal exudative AMD receive one of three treatment regimens on an as-needed basis: verteporfin PDT plus triamcinolone (1 mg or 4 mg) intravitreal injection or verteporfin plus pegaptanib intravitreal injection.
The primary outcome measure is loss of less than 15 letters of visual acuity from baseline at 1 year. Secondary outcome measures include the following: gain of 5, 10, or 15 letters of visual acuity or more from baseline at 6 months and 1 and 2 years; loss of less than 15 letters of visual acuity from baseline at 6 months and 2 years; need for verteporfin treatment throughout the study after baseline; change in BCVA at months 3, 6, and 12; and change in total size of lesions at months 3, 6, and 12.
Patients eligible for the study were 50 years of age or older at time of enrollment, with untreated subfoveal CNV lesions secondary to AMD. Lesions of any type and smaller than 5,400 µm in the greatest linear dimension were included. Exclusion criteria were history of prior PDT, external beam radiation, subfoveal focal laser photocoagulation, submacular surgery, or transpupillary thermotherapy; known allergy to verteporfin, triamcinolone or pegaptanib; and eye surgery within the past 2 months).
At 1 year, there was no significant difference between the three groups in terms of the primary outcome of loss of less than 15 letters. Further analysis of the study results is ongoing.
While a number of combination therapies for CNV in AMD have been evaluated in case series and small clinical trials, the results of large-scale prospective randomized studies are needed to guide clinicians in their treatment decisions for patients losing vision to AMD. Currently there are several randomized studies evaluating various combination treatments. Hopefully, these studies will allow us to realize the magnitude of the benefits as well as safety of these combination treatments.
Peter K. Kaiser, MD, is in the Vitreoretinal Department at the Cole Eye Institute, Cleveland Clinic. Dr. Kaiser states that The Cole Eye Institute has received research grant support from Alcon Laboratories, Allergan, Eyetech Pharmaceuticals, Genentech, Regeneron, Novartis, QLT, and Sirna Therapeutics. Dr. Kaiser disclosed that he is a member of the scientific advisory boards and/or a consultant for Alcon, Allergan, Novartis, and TargeGen. He is a member of the Retina Today Editorial Board. Dr. Kaiser may be reached at pkkaiser@aol.com; phone +1 216 444 6702.
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