Choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) has a complex pathogenesis that includes inflammatory, angiogenic, and wound-healing components.1-3 One proposed pathologic process begins with impaired diffusion of nutrients to the retina and retinal pigment epithelium (RPE) due to a thickened Bruch's membrane. This leads to oxidative stress and ischemia, as well as an inflammatory response. As a result, RPE and other cells produce cytokines including vascular endothelial growth factor (VEGF). The upregulation of VEGF in turn results in neovascularization.
The multiple factors involved in this complex pathogenesis suggest that there may be a scientific rationale for combining therapies with differing mechanisms of action to treat CNV secondary to AMD. Several agents have recently become available for the treatment of neovascular AMD, including anti-VEGF therapies, steroids, and photodynamic therapy (PDT). Combinations of these therapies may act simultaneously on different elements of the pathogenesis of CNV, resulting in additive or synergistic effects.
Photodynamic therapy with verteporfin (Visudyne, Novartis Pharmaceuticals) inhibits the leakage of choroidal new vessels through selective angio-occlusion. Verteporfin PDT has been shown to safely provide sustained clinical efficacy when administered quarterly in patients with predominantly classic subfoveal CNV in AMD.4
Use of PDT can lead to localized inflammation, and inflammation is also a component of the neovascularization process. Therefore the use of an antiinflammatory agent along with verteporfin PDT has been proposed. Intravitreal injection of a steroid such as triamcinolone acetonide or dexamethasone may decrease inflammation resulting from both PDT- and AMD-related factors, minimizing visual disturbances after PDT administration.
The anti-VEGF agents ranibizumab and bevacizumab address angiogenesis, another key component in the pathogenesis of CNV. Administered intravitreally on a monthly schedule, ranibizumab halted visual acuity loss in 90% to 95% of patients and improved vision in approximately one-third of patients in two randomized clinical trials,5,6 representing an important advance over previously available therapies for CNV.
Recent evidence suggests that monthly monitoring is required to achieve the most effective maintenance of visual improvement with ranibizumab, even if treatment is not needed on every visit.7,8
Because anti-VEGF agents and verteporfin PDT have different modes of action, it is suggested that combining them may optimize the treatment of CNV. Several clinical trials are investigating their use together in combinations. This article reviews results of some of these trials and concludes with a look at other studies still in progress.
REDUCING THE BURDEN OF ANTI-VEGF THERAPY
Two large prospective randomized clinical trials showed that monthly administration of ranibizumab improved visual acuity on the Early Treatment Diabetic Retinopathy Study chart by 6.6 to 11.3 letters at 1 year.5,6
Although monthly treatment is effective, the frequent visits required by this evidence-based approach place significant burdens on patients, physicians, and health-care payers. A regimen that requires fewer visits but provides equivalent efficacy is desirable.
However, less frequent injections of ranibizumab—quarterly after three initial monthly injections—were less efficacious in maintaining visual gains in the PIER (A Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without Classic CNV Secondary to Age-Related Macular Degeneration) study.8
Recent reports from two clinical trials shed further light on the issue of reducing the treatment burden of anti-VEGF therapy.
The SUSTAIN (Study of Ranibizumab in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration) trial7 was a 1-year study evaluating individualized dosing of ranibizumab in patients with CNV secondary to AMD. Patients were initially given three mandatory monthly injections of ran-ibizumab 0.5 mg and then evaluated monthly. Retreat-ments were given if more than five letters of visual acuity were lost or if central retinal thickness (CRT) increased by more than 100 µm.
In a planned 12-month interim analysis of 75 of the 531 patients enrolled in the SUSTAIN trial, mean visual acuity gain was 6.7 letters. A mean of 5.3 injections of ranibizumab were given during the study period, including the three initial mandatory doses.
The SAILOR (Safety Assessment of Intravitreal Lucentis for AMD) study9 also began with three mandatory monthly injections of 0.5 mg ranibizumab, but follow-up in that trial was quarterly, again with retreatment given when more than five letters of visual acuity were lost or CRT increased by more than 100 µm. In 487 patients who were treatment-naïve before enrollment in the SAILOR study, the mean visual acuity gain was 2.3 lines, with a mean 4.6 injections.
Comparison of these results highlights the importance of monthly monitoring when an individualized regimen is used with anti-VEGF treatment.10 Both trials began with three initial mandatory doses followed by as-needed retreatment, but with quarterly follow-up the initial visual gains were not sustained as well as with monthly monitoring (Figure 1).
COMBINATION TREATMENT
Although anti-VEGF monotherapy has shown greater efficacy against neovascular AMD than any previous treatment option, it carries some disadvantages. As noted above, it requires intensive follow-up and frequent retreatment. In addition, there is currently no defined endpoint for anti-VEGF therapy; patients with neovascular AMD potentially face monthly evaluations and injections for the rest of their lives. Furthermore, there is evidence that anti-VEGF therapy may become less effective as neovascularization develops over time.11
Combination of anti-VEGF therapy and verteporfin PDT may overcome some of these drawbacks. The two therapies target different components of CNV.12 Addition of PDT to anti-VEGF therapy might help to achieve more sustained absence of vascular leakage. And combination therapy might allow a less frequent dosing schedule for intravitreal injections while still maintaining the visual improvements seen with anti-VEGF monotherapy.
Ranibizumab in combination with verteporfin PDT was evaluated in a phase 2 investigator-sponsored trial, the FOCUS (RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety) study. In FOCUS, 162 patients with predominantly classic CNV were randomized 2:1 to receive verteporfin PDT followed by ranibizumab 0.5 mg or sham injection. Injections were given monthly, with PDT administered quarterly if needed, for 23 months.
At 24 months, mean gain in visual acuity in eyes receiving the combination treatment (n=105) was 4.6 letters. Patients receiving PDT and sham injection (n=56) lost a mean 7.8 letters—a 12.4 letter difference between treatment groups (P<.0001). In addition, the combination treatment produced greater reduction in the area of CNV leakage and staining of the retinal pigment epithelium than PDT alone (P<.001). The mean number of PDT treatments at 24 months was 4.0 in the PDT-alone arm and 1.4 in the PDT-plus-ranibizumab arm.
A multicenter open-label safety study of ranibizumab and verteporfin PDT in patients with CNV secondary to AMD recently reported 9-month results.13 Patients with predominantly classic (n=13) or occult (n=19) CNV received standard fluence PDT at baseline and at months 3, 6, and 9 if needed based on fluorescein angiography. Ranibizumab was given at baseline (1 hour after PDT) and at months 1, 2, and 3.
Twenty-two of 32 patients (68.7%) needed only the mandatory four injections of ranibizumab and one baseline verteporfin treatment during the course of the study. One additional PDT treatment was given in 21.8% of patients, and two additional treatments in 9.4%.
Mean retinal thickness decreased from 403.6 µm at baseline to 231.8 µm at 9 months. Retinal thickness changed little from month 1 through month 9 (Figure 2). The mean area of leakage decreased from 8.2 mm² at baseline to 1.9 mm² at 9 months. At 9 months, there were no active lesions and no recurrent leakage on fluorescein or optical coherence tomography. Macular edema and subretinal fluid also resolved. No severe vision loss due to inflammation was seen.
Mean visual acuity improved by 6.9 letters at month 4 and by 2.4 letters at month 9. Vision was stable or improved in 90% of patients (Figure 3).
ONGOING STUDIES
Combination therapy is being further investigated in the ongoing SUMMIT clinical program, which includes the DENALI trial in the United States, MONT BLANC in Europe, and EVEREST in Asia. Enrollment is complete in both the DENALI (N=323) and MONT BLANC (N=255) trials. These 2-year studies will evaluate the safety and efficacy of verteporfin therapy combined with ranibizumab in comparison with ranibizumab alone in patients with subfoveal CNV secondary to AMD. Initial results of these trials are expected some time this year. Enrollment is ongoing in the EVEREST trial, which will investigate the use of combination therapy in patients with symptomatic polypoidal choroidal vasculopathy.
In addition, a Visudyne patient registry14 now has a database of approximately 1,200 patients with AMD who have been treated with verteporfin plus bevacizumab (93%) or verteporfin plus bevacizumab plus a steroid (7%). Mean age of patients in the registry is 79 years, and 56% were not treated for AMD prior to enrollment in the registry.
With a mean follow-up of 15 months, the mean vision change in patients in the registry is a gain of four letters. The mean number of retreatments with verteporfin PDT is 0.6, and mean number of ranibizumab retreatments is 2.2. In addition, 27% of patients have received no retreatments. Patterns of retreatment will be evaluated in subsequent analyses.
CONCLUSIONS
There is a rationale for combining anti-VEGF therapy and verteporfin PDT in the treatment of CNV secondary to AMD. The rationale is based on the potential for additive benefits due to the distinct mechanisms of action of these two therapies, respectively targeting the angiogenic and vascular components of CNV. In addition, there is the potential to sustain the absence of leakage from CNV, and to allow the creation of individualized treatment regimens.
Further analysis of this combination is warranted and is being carried out in the ongoing SUMMIT series. These trials will show whether combination therapy can provide sustained visual acuity benefits and extended treatment-free intervals.
Peter K. Kaiser, MD, is in the Vitreoretinal Department at the Cole Eye Institute, Cleveland Clinic. Dr. Kaiser disclosed 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.
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