In choroidal neovascularization anomalous choroidal vessels grow under or through the RPE (Green et al 1993
). Although specific stimuli for CNV growth remain unknown, it generally occurs in the presence of soft drusen, breaks in Bruch membrane, and a pro-inflammatory and pro-angiogenic milieu, characterized by elevated levels of vascular endothelial growth factor A (VEGF) or platelet-derived growth factor (PDGF) (Ambati et al 2003
Choroidal neovascularization has various patterns and configurations of proliferation that have been described based on its appearance with fluorescein angiography (FA). This highly useful diagnostic test allows one to determine the pattern, boundaries, composition and location of the neovascular lesions with respect to the centre of the fovea. These patterns of fluorescence have been shown to be reliable and reproducible in multi-centre clinical trials and in practice (Macular Photocoagulation Study Group 1982
; Macular Photocoagulation Study Group 1986
; Macular Photocoagulation Study Group 1991
; Macular Photocoagulation Study Group 1993
; Macular Photocoagulation Study Group 1994
; Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 2001
; Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 2003
). Classic CNV
refers to a discrete, well-demarcated focal area of hyperfluorescence seen during the early images of the FA that increases in the intensity of fluorescence as the FA images progress in the later phases. The hyperfluorescence not only increases in intensity but also extends beyond the boundary of the initial lesion seen in the early FA images. Occult CNV
refers angiographic patterns lacking the features of classic CNV and is characterized by stippled or speckled hyperfluorescence that is frequently seen in the mid to later FA images. Occult CNV has been divided in to two types, fibrovascular pigment epithelial detachment(FVPED)
and late leakage of an undetermined source(LLUS)
. In FVPED, the lesion has ophthalmoscopic or photographically appreciable thickness or elevation when viewed stereoscopically. The stippled hyperfluorescence may become well defined in the later FA images. In LLUS, the lesion is not elevated when viewed stereoscopically. The choroidal based stippled or speckled hyperfluorescence appears in the mid to late FA images and have no classic or FVPED angiographic qualities. CNV are also described by location. In subfoveal
CNV, any component of the lesion resides underneath the geometric centre of the fovea. In extrafoveal
CNV the edge of the lesion is no closer that 200 micrometers from the foveal centre. Those lesions whose edges reside within 1–199 micrometers from the foveal centre are juxtafoveal
(Macular Photocoagulation Study Group 1991
). When at least 50% of a choroidal neovascular lesion’s composition is of a particular pattern, the qualifier predominantly
is applied, as in predominantly classic, predominantly occult, or predominantly hemorrhagic. When less that 50% of a choroidal neovascular lesion’s composition is of a particular pattern, the term minimally
is applied, as in minimally classic (Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 2003
Thermal laser photocoagulation
The Macular Photocoagulation Study (MPS) compared focal thermal laser photocoagulation of choroidal neovascularization to observation for CNV in AMD patients and consisted of multiple randomized clinical trials. Within 1 year of treatment, 25% of eyes with extrafoveal CNV due to AMD had lost fewer than 6 lines of vision with laser compared to 60% of eyes in the observation group (Macular Photocoagulation Study Group 1982
), with a difference that persisted through 3 years (Macular Photocoagulation Study Group 1986
). Two years after treatment, 21% of eyes with subfoveal CNV lost 6 or more lines of vision compared to 38% of eyes in the observation group (Macular Photocoagulation Study Group 1991
). Unfortunately, eyes lasered for subfoveal CNV initially experience a marked drop in vision due to damage to the macular centre from photocoagulation. This undesirable effect and the advent of newer treatment options, make thermal laser photocoagulation a seldom-used treatment for patients with subfoveal CNV. Today, MPS-style thermal laser photocoagulation for extrafoveal CNV is still considered an effective method of treatment and is used in selected cases.
Photodynamic therapy with verteporfin
Photodynamic therapy (PDT) involves an intravenous infusion of a photosensitizing agent that selectively binds to the increased number of lipoprotein receptors on the endothelium of abnormal vessels including CNV. The photosensitizing agent is then activated with laser light, usually in the far-red spectrum where light transmission through tissue and blood is higher. Activation of the photosensitizer, which is usually structurally related to porphyrin, results in free-radical formation, endothelial damage, and clotting cascade activation with thrombosis of the affected, abnormal vasculature. Verteporfin®
(Visudyne, Novartis AG, Basel Switzerland) was the first photosensitizer approved for use in exudative AMD. It is administered at a dose of 6 mg/m2
and is activated by 689–691 nanometer laser light. The Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) study demonstrated a particular treatment benefit for patients with predominantly classic subfoveal CNV. At 2 years, PDT with verteporfin prevented loss of 3 or more lines of vision in 67% of these patients, compared to 39% of controls (Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 2001
). However, 33% of patients still lost 3 or more lines of vision over 2 years. In addition, it has been observed that PDT with verteporfin initiates an inflammatory response and up regulates VEGF and other growth factors that contribute to recurrence of CNV (Schmidt-Erfurth et al 2003
). As such PDT with verteporfin is not currently preferred as monotherapy for the management of AMD-related CNV.
The vascular endothelial growth factor family consists of seven members (vascular endothelial growth factors A through F, and placental growth factor), which are secreted polypeptides that share common structural domains but have different biological and physical properties (Ferrara 2004
). VEGF plays a role in normal and pathologic angiogenesis and has at least six known isoforms which are formed through alternative splicing and are named based on their number of amino acids: 121, 145, 165, 183, 189, and 206 (Ferrara 2004
). VEGF165 is a potently pro-angiogenic molecule that has been shown to effect retinal vascular proliferation and increased vascular permeability in the eye (Adamis et al 2005
). Neovascular membranes in patients with AMD contain both isoforms VEGF165 and VEGF121 (Rakic et al 2003
). The 165 isoform can be cleaved by plasmin to form the 110 amino acid fragment (VEGF110) that retains biologic activity (Keyt et al 1996
). Animal models have also suggested that VEGF165 plays a role in inflammation, induction of leukocyte recruitment, and neuroprotection against ischemic injury (Nishijima et al 2007
). This suggests that VEGF blockade may have both deleterious and salubrious effects in eyes with vascular disease. VEGF modulation has therefore been a target of many CNV treatments ().
Figure 1 Mechanisms of inhibition of vascular endothelial growth factor-A (VEGF). Pegaptanib, ranibizumab, bevacizumab, and VEGF trap bind and sequester VEGF, preventing it from binding and activating VEGF receptor. Inhibitors of VEGF receptor tyrosine kinases (more ...) Pegaptanib
The first available anti-VEGF treatment for use in the eye was pegaptanib (Macugen®
, Eyetech Pharmaceuticals, Inc., New York, NY, USA), an aptamer that targets VEGF165. In the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial (VISION), pegaptanib was shown to be safe and effective in preventing vision loss in patients with AMD-related CNV for over 2 years when compared to controls (Gragoudas et al 2004
). However, visual decline occurred over time in a pattern similar to that seen with PDT with verteporfin. This persistent loss of vision despite treatment with pegaptanib may be due to its selective binding to VEGF165 only, leaving all other isoforms uninhibited and available to stimulate neovascularization. Furthermore, its dosing of intravitreal injections every 6 weeks, compared to the less-invasive quarterly dosing schedule of PDT with verteporfin gave pegaptanib treatment of neovascular AMD no competitive advantage.
VEGF antibodies and antibody fragments
Both bevacizumab (Avastin®
, Genentech, Inc., South San Francisco, CA, USA), a full-length humanized antibody against VEGF, and ranibizumab (Lucentis®
, Genentech, Inc.), a humanized antigen-binding fragment against VEGF, are able to bind and inhibit all isoforms of VEGF (Ferrara et al 2004
). Although ranibizumab has one binding site for VEGF compared to bevacizumab’s two, ranibizumab has been affinity matured, exhibiting 3- to 6-fold higher affinity for VEGF than bevacizumab (Presta et al 1997
; Chen et al 1999
Ranibizumab is the first therapy for neovascular AMD to result in a significant improvement in visual acuity (Heier et al 2006
). Two phase III studies of the use of monthly intravitreal injections of ranibizumab, MARINA and ANCHOR have been completed (Brown et al 2006
; Rosenfeld et al 2006a
). MARINA evaluated 716 patients with minimally classic or occult neovascular AMD. At 2 years, MARINA demonstrated a mean gain of 5.4 letters (0.3 mg group) to 6.6 letters (0.5 mg group) for patients treated with monthly ranibizumab injections compared to a mean loss of 14.9 letters for patients undergoing monthly sham injections (Rosenfeld et al 2006a
). ANCHOR evaluated 423 patients with predominantly classic neovascular AMD. At 1 year, ANCHOR demonstrated a mean gain of 8.5 letters (0.3 mg group) to 11.3 letters (0.5 mg group) for patients treated with monthly ranibizumab injections compared to a mean loss of 9.5 letters for patients treated with verteporfin every 3 months (Brown et al 2006
). The 0.5 mg dose prevented 3 lines of vision loss in 90% (MARINA) to 96.4% (ANCHOR) compared to sham (52.9%) or verteporfin (64.3%). The 0.5 mg dose resulted in 3 or more lines of vision gain in 33.8% (MARINA) to 40.3% (ANCHOR) compared to sham (5.0%) or verteporfin (5.6%). All comparisons were statistically significant (p < 0.001). Serious adverse events for patients treated with ranibizumab included endophthalmitis (1% (MARINA) to 1.4% (ANCHOR)) and uveitis (0.7% (ANCHOR) to 1.3% (MARINA)). Arterial thromboembolic events occurred in 3.8% of the sham group compared to 4.6% in each of the ranibizumab groups (MARINA), and 2.1% of the verteporfin group compared to 2.2% (0.3 mg group) and 4.3% (0.5% group) for the ranibizumab groups (ANCHOR). Although some might consider these data to demonstrate a high level of safety, neither study was powered to evaluate safety concerns. In fact, at a 6-month interim evaluation, the SAILOR study, a phase IV evaluation of the safety and efficacy of 0.3 mg and 0.5 mg doses of as-needed ranibizumab reported a statistically significant increase in the rate of stroke (0.3% compared to 1.2%) with the higher (commercially available) dose whereas for arterial thromboembolic events of myocardial infarction or vascular death, the differences between the doses were not statistically significant [personal communication, Genentech, Inc., January 24, 2007]
The burden of monthly injections of ranibizumab coupled with the appreciable risk of adverse events prompted the PIER and PrONTO studies (Rosenfeld 2006b
; Schmidt-Erfurth 2007
). Each study used less frequent dosing than ANCHOR and MARINA, with PIER using a fixed dosing schedule and PrONTO using an “as needed” schedule. PIER was a phase IIIb randomized, double-masked, sham-controlled study of 184 subjects who received monthly injections of ranibizumab or sham for 3 months, followed by quarterly injections. At 12 months, the sham group lost 16 letters, whereas the ranibizumab group initially gained one line but lost 0.2 letters at 12 months (Schmidt-Erfurth 2007
). Although the study did not include a monthly injection of ranibizumab arm, comparison to ANCHOR and MARINA data would suggest inferiority with the PIER dosing schedule.
The PrONTO study was an open label study of 40 eyes treated with 3 consecutive monthly injections of 0.5 mg ranibizumab followed by further injections based on loss of 5 letters visual acuity or increase of 100 μm of central retinal thickness. Through 1 year, patients required an average of 5.6 injections, 35% gained 3 or more lines, and 95% lost fewer than 3 lines of vision (Rosenfeld 2006b
). Although the criteria for re-treatment have not been systematically evaluated, and some clinicians would support treating based on other factors than those evaluated in PrONTO, decreasing the number of required injections would substantially reduce the burden of AMD treatment on patients.
Bevacizumab is a full-length antibody with similar properties to ranibizumab, and is approved for systemic use in some solid tumours and is therefore available for off-label use in the treatment of AMD-related CNV (Hurwitz 2004
). An open-label uncontrolled clinical study of intravenous infusion of bevacizumab (5 mg/kg) at baseline with 1–2 repeated doses at 2-week intervals in 18 patients reported a statistically significant median gain of 14 letters and decrease of OCT thickness from 379 to 255 μm (Moshfeghi et al 2006
). The only significant ocular or systemic adverse event was hypertension, which occurred or worsened in 10 patients and was readily treated with oral medications.
Concerns about thromboembolic events with use of intravenous bevacizumab in the treatment of cancer prompted investigators to use bevacizumab intravitreally. Multiple retrospective studies have reported on the use of 1.25 mg doses of intravitreal bevacizumab, citing three or more lines of vision improvement in 38.3% (Spaide et al 2006
) to 44% (Rich et al 2006
) of treated patients and median gain of 15 letters (Rich et al 2006
) to 20 letters (Avery et al 2006
) at 8–12 weeks. One prospective study of monthly injections of 2.50 mg bevacizumab reported median gain of 6 lines of vision and normalization of central retinal thickness from 350 to 211 μm using optical coherence tomography (OCT) (Bashshur et al 2006
). Although, the OCT data in these reports are compelling; the visual acuity data did not employ Early Treatment for Diabetic Retinopathy Study (ETDRS) protocol visual acuities and as such may not accurately reflect visual acuity improvement in these patient series.
In each of the reports on intravitreal bevacizumab, negligible adverse events were noted. This was an important finding since numerous concerns were raised with the intravitreal injections of humanized antibody such as the inciting of intraocular inflammation or the promotion of systemic thromboembolic side effects. Acknowledging the bias inherent in a survey based on self-reporting, an internet survey of adverse events of 3810 intravitreal injections in 3034 patients following intravitreal bevacizumab injections reported low rates of treatment-related and drug-related adverse events, citing rates of 0.03% for endophthalmitis and 0.1% for all forms of cerebrovascular events (Fung et al 2006
). Concerns regarding the durability of compounded bevacizumab have been put to rest by in vitro studies of VEGF binding following refrigeration or freezing for up to 6 months (Bakri et al 2006
At this time, efficacy data are superior for ranibizumab than bevacizumab, and each has demonstrated reasonable safety, with the exception of concern for increased rates of stroke demonstrated by SAILOR. In an effort to clarify these issues, the National Eye Institute has agreed to sponsor a multi-centre trial comparing ranibizumab to bevacizumab with fixed monthly versus variable dosing schedules. The Comparison of Age-related Macular Degeneration Treatment Trial (CATT) is scheduled to begin enrolling patients in the fall of 2007. Until this question can be answered by the CATT, we will be forced to treat patients with medication availability and financial feasibility issues in mind. The September, 2006 Preferences and Trends (PAT) survey, administered by the American Society of Retina Specialists (ASRS), in which the response rate was 23.57% of 1667 ASRS members demonstrated that 34.70%–41.75% would recommend bevacizumab for the treatment of subfoveal CNV and 33.42%–41.75% would recommend ranibizumab. (American Society of Retina Specialists 2007
) A follow-up mini survey of the same population of retina specialists (n = 276 responders) specified whether the hypothetical patient was covered by Medicare with or without secondary insurance coverage, without which patients in the United States would be responsible for 20% of the medication bill, or approximately US$400 per injection (American Society of Retina Specialists 2007
). In this survey, 53.11% would recommend bevacizumab for patients with secondary insurance, increasing to 77.01% for patients without secondary insurance.
The VEGF trap (Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA) is a fusion protein of portions of VEGF receptor 1 and 2 and the Fc region of human IgG which binds all VEGF isoforms and does so more tightly than other available VEGF binding agents. The Clinical Evaluation of Anti-angiogenesis in the Retina (CLEAR) study was a randomized, double-masked, ascending dose, placebo-controlled phase I trial of 18 patients with neovascular AMD who received either placebo or 1 of 3 systemic doses of intravenous VEGF trap (0.3, 1.0, and 3.0 mg/kg) (Nguyen et al 2006
). The study found a dose-dependent increase in systemic blood pressure, which was clinically significant above the 1.0 mg/kg dose and further studies of systemic VEGF trap were halted. CLEAR IT-1 was a phase I dose escalation study of a single intravitreal injection of multiple doses VEGF trap (0.05, 0.15, 0.5, 1, 2, and 4 mg). At 6 weeks, mean gain in visual acuity was 4.8 letters and mean OCT central retinal thickness decreased from 298 to 208 μm (Nguyen et al 2006
). The potential benefit of VEGF trap is a sustained effect compared to single injections of other VEGF-binding agents, although this has not been demonstrated in a head-to-head trial. A phase II VEGF trap study (CLEAR-AMD) is currently in the process of enrolling patients.
Small interfering RNA
The 2006 Nobel Prize in Physiology or Medicine was awarded to Andrew Fire and Craig Mello for their work in RNA interference, the process by which small interfering RNA (siRNA) molecules inactivate messenger RNA, thereby suppressing RNA translation. For clinical use, these drugs are administered as double-stranded RNA molecules that are imported across the cellular membrane and processed by an enzyme, Dicer, which shortens the siRNA to 21–24 nucleotides. The processed siRNA is incorporated into a RNA-induced silencing complex (RISC), which, when activated, binds complementary mRNA and digests it. This allows a single molecule of siRNA to degrade multiple copies of mRNA.
The first drug to employ this mechanism in the treatment of neovascular AMD is bevasiranib (formerly Cand5, Acuity Pharmaceuticals, Philadelphia, PA) and is targeted against VEGF mRNA. The Cand5 Anti-VEGF RNA Evaluation (CARE) study was a phase II study of 3 doses of bevasiranib (0.2, 1.5, and 3.0 mg) injected intravitreally 6 weeks apart (n = 127 eyes). At 12 weeks after the initial injection, mean loss of vision was 4.1 letters (0.2 mg dose), 6.9 letters (1.5 mg dose), or 5.8 letters (3.0 mg dose), with 71.8–79.4% losing less than 3 lines. Adverse events included stroke (0.8%), arrhythmia (0.8%), and hypertension (5.5%) (Tolentino 2006
). Compared to improvement in vision seen with other therapies, including ranibizumab, bevacizumab, and VEGF trap, the vision loss in these patients does not bode well for the use of bevasiranib as monotherapy. By targeting a relatively upstream component of the VEGF pathway, it is currently considered that the use of siRNA may have a delayed effect in influencing disease processes. The recent FDA approval of ranibizumab may prompt a design change in the phase III study of bevasiranib to include injection of a VEGF-binding agent at baseline. The combination of VEGF binding by ranibizumab or bevacizumab combined with the mRNA interference of bevasiranib has the theoretic advantage of preventing further vision deterioration by immediately binding existent VEGF while interfering with the upstream production of VEGF.
A second siRNA drug, sirna-027 (Sirna Therapeutics, San Francisco, CA), directed against VEGF receptor 1 (VEGFR1), has demonstrated efficacy in animal models (Shen et al 2006
) and reasonable safety in a Phase I trial and is undergoing phase II evaluation currently.
VEGF receptor tyrosine kinase inhibition
A further method of inhibiting the effect of increased VEGF within the eye with CNV is to inhibit the tyrosine kinase activity of VEGF receptors. Vatalanib®
(formerly PTK-787, Novartis International AG, Basel, Switzerland) is a potent inhibitor of all known VEGF receptor tyrosine kinases, VEGFR1 (sFlt-1), VEGFR2 (KDR), and VEGFR3 (Flt-4). The use of vatalanib is an attractive alternative to intravitreally or intravenously injected medications because of its satisfactory oral bioavailability. Preclinical data have demonstrated inhibition of experimental retinal and choroidal neovascularisation (Maier et al 2005
). Clinical studies in healthy individuals have shown no serious adverse events and adverse events from the use of vatalanib in patients with solid and hematologic malignancies have included nausea/vomiting, fatigue, dizziness, diarrhoea, and hypertension (Joondeph et al 2006
). The Study of Vatalanib and Photodynamic Therapy with Verteporfin in Patients With Subfoveal Choroidal Neovascularization (CNV) Secondary to Age-related Macular degeneration (ADVANCE) is currently enrolling for a phase I/II comparison of PDT to PDT/vatalanib.
Pigment epithelial-derived growth factor (PEDF) is a factor with neurotrophic, neuroprotective, and anti-angiogenic properties (Steele et al 1993
; Mori et al 2002
). The potential benefit of PEDF in preventing damage due to neovascular AMD lies in its multifaceted protection of the retina and retinal pigment epithelium and inhibition of angiogenesis. CDNA encoding human PEDF has been shown to inhibit ocular neovascularization when introduced into the vitreous and subretinal space of animal models via an adenoviral vector (AdPEDF.11, GenVec, Inc., Gaithersburg, MD, USA) (Imai et al 2005
). A phase I study of AdPEDF.11 in 28 patients demonstrated no dose-limiting toxicity and suggested that its anti-angiogenic effect lasts for months (Campochiaro et al 2006
). Furthermore, therapy does not seem to be associated with a systemic immune response, thereby theoretically allowing for repeat injections (Hamilton et al 2006
). The sustained effect and repeatability of this therapy is attractive approach given the relatively short duration of anti-VEGF agents.
Squalamine lactate (Evizon®
, Genaera Corporation, Plymouth Meeting, PA) is an anti-angiogenic amino sterol derived from cartilage of the dogfish shark, Squalus acanthus.
Its mechanism of action includes blockade of cell membrane ion transporters that regulate cell function by controlling pH and metabolism. When bound to calmodulin, squalamine also blocks the action of VEGF and integrin expression, thereby inhibiting angiogenesis. Squalamine is ineffective when administered intravitreally and therefore requires intravenous dosing. However, systemic dosing has yielded promising results in rats (Ciulla et al 2003
) as well as humans (Kaiser 2007
). In a phase I/II clinical trial of 40 patients who had received 25 or 50 mg/m2 weekly for 4 weeks, no patients lost vision and 26% gained 3 or more lines. Genaera has abandoned this product and is no longer in clinical development.
Anecortave acetate has also been used in patients with AMD-related CNV. In these patients, Anecortave acetate produced similar visual acuity results to PDT with verteporfin in the C-01-99 study (Slakter et al 2006
). With improved therapies and outcomes, anecortave acetate is not appropriate monotherapy for active CNV. However, the NEI is sponsoring the BRIDGE study that will evaluate combination therapy of anecortave acetate and ranibizumab.
The suggestion that surgical removal of CNV before the development of subretinal fibrosis would allow for reapposition of healthy RPE and photoreceptors, thereby improving visual acuity is an attractive one. Multiple techniques and modifications have been tried to improve visual acuity outcomes in patients with CNV, including submacular surgical removal of CNV (Hawkins et al 2004
), pneumatic displacement of large subretinal haemorrhage (Hassan et al 1998
), and macular translocation (deJuan et al 1998
; Mruthyunjaya et al 2004
). To date, none of these therapies has proven effective, and with rare exception, none are appropriate primary treatment strategies for AMD-associated CNV.
As with many therapies, which have been borrowed from oncology for use in the treatment of neovascular AMD, the concept of “induction and maintenance” is one employed in several combined management approaches in an effort to improve therapeutic efficacy and reduce treatment frequency. As indicated previously, PDT has been implicated in having the undesirable observation of increasing inflammation and VEGF levels (Schmidt-Erfurth et al 2003
). By combining treatment modalities, an opportunity exists to refine the blockade of angiogenesis and vascular permeability. For example combination of PDT, intravitreal anti-VEGF agent and steroid could in theory allow for blockade of CNV at multiple levels. The FOCUS study is a phase I/II trial comparing as-needed dosing of verteporfin followed by monthly dosing of either ranibizumab or sham injection. At 2 years, the ranibizumab/PDT group gained a mean of 4.6 letters whereas the sham/PDT group lost a mean of 7.8 letters. The number of treatments through 2 years averaged 1.4 in the ranibizumab/PDT group compared to 4.0 in the sham/PDT group (Heier, Antoszyk, et al 2006
; Heier, Boyer, et al 2006
In a prospective, non-comparative, interventional case series, 104 patients underwent triple therapy using intravitreal dexamethasone (800 μg) and bevacizumab (1.5 mg) administered within a mean of 16 hours after PDT (Agustin et al 2007
). All 104 patients received one triple therapy cycle while 5 patients received a second triple treatment due to remaining CNV activity. The triple therapy was complemented in 18 patients (17.3%) by an additional intravitreal injection of bevacizumab. The mean follow-up period was 40 weeks (range, 22–60 weeks). Mean increase in visual acuity was 1.8 lines (p < 0.01). Mean decrease in retinal thickness was 182 micrometers (p < 0.01). No serious adverse events were observed. The authors concluded that triple therapy results in significant and sustained visual acuity improvement after only one cycle of treatment in patients with AMD associated CNV. In addition, the therapy offered a good safety profile and potentially lower cost compared with therapies that must be administered more frequently, and convenience for patients (Agustin et al 2007
). The PDT was performed with a reduced time of light delivery (70 seconds) in an effort to theoretically reduce choroidal damage (Michels et al 2006
The Neovascular Age-related macular degeneration, Periocular corticosteroids and Photodynamic therapy (NAPP) trial evaluated 67 patients with AMD and subfoveal CNV. Thirty-four patients were given a single periocular injection of corticosteroid, followed immediately by PDT with verteporfin, and 33 patients were given PDT alone. No difference in visual acuity or angiographic leakage between the groups was observed at 6 months (NAPP Trial Research Group et al 2007
Several other studies are combining therapeutic modalities, including the BRIDGE study (ranibizumab plus anecortave acetate), PROTECT study (ranibizumab plus PDT with verteporfin), VISION phase IV study (pegaptanib plus PDT) are currently underway.