Age-related macular degeneration is the leading cause of irreversible visual loss in the
AMD is a bilateral disorder with choroidal neovascularization developing in 26 percent of fellow eyes that were initially free of exudative AMD over a five-year period. As the
Prevention of AMD disease progression is viewed as critical to avoid the severe visual loss commonly associated with exudative AMD.
• AREDS. The only current evidence-based intervention comes from the Age-Related Eye Disease Study. This multicenter,
AREDS concluded that "patients with extensive intermediate-sized drusen, at least one large druse, noncentral geographic atrophy in one or both eyes, or advanced AMD or vision loss due to AMD in one eye should consider taking a supplement of antioxidants plus zinc." The formulation (Ocuvite PreserVision, Bausch & Lomb, and ICaps, Alcon) containing high doses of vitamin C, vitamin E, beta-carotene, copper and zinc lowered the risk of developing advanced AMD by 25 percent in the study. However, in cigarette smokers, another study demonstrated that beta-carotene supplementation increased the risk of developing lung cancer; thus, the antioxidant formulation should exclude beta-carotene in smokers.
• AREDS2. Omega-3 long-chain polyunsaturated fatty acids (fish oils) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), as well as macular xanthophylls (lutein and zeaxanthin) have been suggested to play a protective role in AMD development. AREDS2 is a multicenter, Phase III randomized clinical trial designed to assess the effects of oral supplementation of high doses of lutein and zeaxanthin and/or omega-3 LCPUFAs as a treatment for nonexudative AMD. Patients will be randomized into four groups: placebo; lutein and zeaxanthin only; fatty acids only; and lutein and zeaxanthin plus fatty acids. In this study, nearly 4,000 patients at 100 centers will be followed for five years.
Drug Treatment: Nonexudative AMD
• OT-551. Othera-551 (Othera Pharmaceuticals) antioxidant eye drop is being investigated for chronic treatment of nonexudative AMD. A pilot study of up to 10 eye-drop-tolerant participants with bilateral geographic atrophy is being recruited to characterize the effect of 0.45% concentration of OT-551 eye drops given three times a day on the progression of geographic atrophy area over a two-year period.
• Ciliary Neurotrophic Factor. Certain neurotrophic factors have been demonstrated to retard loss of photoreceptor cells during retinal degeneration. One of these, ciliary neurotrophic factor (CNTF), was found to be effective in retarding vision loss from photoreceptor cell death in 13 animal models of outer retinal degeneration. CNTF has undergone human Phase I safety studies and is currently being assessed in a Phase II study. Neurotech
In the Phase II study, participants will be allocated randomly to one of three arms of the study: sham surgery; a lower dose CNTF implant (NT-501-10.02); and a higher dose CNTF implant (NT-501-6A.02). Based on observations made during a Phase I study of these CNTF implants, the primary outcome will be improvement in best-corrected visual acuity from baseline to week 16. Secondary outcomes will include change in BCVA, change in geographic atrophy and change in area of drusen from baseline to 12 and 18 months.
• Fenretinide. Sirion Therapeutics is sponsoring a Phase II study to determine the efficacy of fenretinide, a retinoic acid derivative, in the treatment of geographic atrophy in subjects. The study will involve 20 centers and recruit 225 patients. Fenretinide has been postulated to decrease the accumulation of lipofuscin and may slow the progression of nonexudative AMD.
• Photodynamic therapy. Verteporfin. The Food and Drug Administration approved verteporfin (Visudyne; QLT Therapeutics and Novartis Ophthalmics) in April 2000 for patients with "predominantly classic" subfoveal CNV caused by AMD. A modified porphyrin with an absorption peak near 689 nm, verteporfin is delivered intravenously for 10 minutes. After a five-minute delay, the CNV complex is irradiated through the pupil with a large-spot diode laser at 689 nm for 83 seconds. The laser energy activates the intravascular compound and stimulates the photodynamic action within the CNV.
In 1999 and 2001, the one- and two-year results of the Treatment of AMD with PDT study were published. TAP consisted of two randomized, prospective, double-blind, placebo-controlled Phase III trials with 609 subjects. First-year data reported that the proportion of eyes with less than 15 letters of visual acuity loss on a standardized eye chart was 67 percent in the treated group versus 39 percent in control group (p< 0.001) when the CNV was predominantly classic; however, no significant differences in VA were demonstrated when the area of classic CNV was less than 50 percent of the entire complex. Also, researchers noted that 90 percent of the subjects required retreatment at three months and an average of more than three retreatments over the first year. Second year follow-up data reported that 59 percent of treated eyes had a favorable visual outcome versus 31 percent in the control group when the lesion was predominantly classic. The TAP trial was unmasked at two years of follow-up.
Subsequently, an open-label extension to 36 months of 124 of the 159 original TAP participants with predominantly classic CNV revealed that VA remained nearly constant and required fewer retreatments. Because of the success of the TAP trial, the Verteporfin in Photodynamic Therapy (VIP) trial, another randomized, prospective, double-blind, placebo-controlled clinical trial, was developed to examine many of the patients who fell outside of the inclusion guidelines set by TAP.
VIP was designed to evaluate the treatment efficacy of PDT in 339 subjects with total occult subfoveal CNV, classic CNV with a VA better than 20/40, or CNV secondary to pathological myopia. One-year results of the occult AMD arm showed no significant difference between visual acuity outcomes in exudative AMD patients treated with verteporfin, 51 percent of whom had unfavorable visual outcomes, and placebo (54 percent unfavorable visual outcomes). However, two-year follow up data revealed that 55 percent of the treated subjects with occult CNV had an unfavorable outcome versus 68 percent in the placebo group (p=0.023). On average, the verteporfin-treated patients received five treatments over 24 months of follow-up. Based on this data, the study group recommended verteporfin for purely occult subfoveal CNV that demonstrated recent disease progression in all patients except those with large lesions with good visual acuity. Because the FDA desired additional data before approving verteporfin for occult CNV, the Visudyne in Occult (VIO) trial was developed as a 24-month study to analyze patients with only occult CNV.
Several other trials have evaluated the efficacy of verteporfin in a variety of clinical situations previously lacking sufficient data. Retrospective TAP and VIP data suggested some treatment benefit for smaller, minimally classic lesions. The Visudyne in Minimally Classic Trial (VIM) was thus initiated as a randomized, prospective, double-blind, placebo-controlled clinical trial designed to study the use of verteporfin in patients with minimally classic CNV. Phase II data on 117 patients suggests that small, recently progressive, minimally classic CNV might benefit from verteporfin therapy. Two-year follow-up data revealed fewer verteporfin-treated eyes lost three or more lines of vision on a standard visual acuity chart or converted to a predominantly classic lesion versus placebo. Consequently, a Phase III study (the VMC trial) was started in late 2003 to further evaluate verteporfin in minimally classic CNV.
On April 1, 2004, the Centers for Medicare & Medicaid Services agreed to reimburse physicians for PDT of occult and minimally classic subfoveal CNV (less than 50 percent of CNV complex with early, well-defined hyperfluorescence on rapid sequence fluorescein angiography) from AMD provided that the lesion is four disk areas or less in size at least three months prior to initial treatment and evidence of progression (i.e. loss of five or more letters on standard visual acuity charts, increase of at least 1 disk diameter, or appearance of blood) within three months of treatment.
Because 80 percent of vision loss in verteporfin-treated patients occurs within six months of developing CNV, the Verteporfin Early Retreatment (VER) trial was initiated. The Phase III study of 323 patients compares the benefit of retreatment in six-week intervals versus the standard three months. Twelve-month interim results of the two-year trial did not show improved outcomes versus the standard treatment. Additionally, the Verteporfin with Altered (Delayed) Light in Occult (VALIO) study was developed to evaluate whether delaying the light application to 30 minutes after the initiation of verteporfin infusion (versus the standard 15 minutes) would improve outcomes in occult CNV. Phase II data at six months of follow-up show the group treated at 30 minutes post-infusion lost 1.3 lines of vision while the standard 15-minute post-infusion treatment group lost two to three lines, which was not statistically significant. One year data substantiated the six month findings.
• Rostaporfin. Rostaporfin (Photrex; formerly SnET2, Miravant Medical Technologies) is a purpurin with a similar structure to chlorophyll that absorbs maximally at 664 nm. Like verteporfin, the preconstituted solution is intravenously infused over 10 to 20 minutes. In December 2001, enrollment of 920 patients for a Phase III placebo-controlled, double-masked clinical trial was completed. Two-year follow-up data found that 58 percent of patients receiving a 0.5 mg/kg dose of SnET2 lost less than 15 letters compared to 42 percent of placebo patients (p=0.0045). Rostaporfin was well-tolerated and demonstrated an acceptable safety profile. In September 2004, the FDA requested an additional confirmatory clinical trial before final marketing approval.
Other PDT Agents
Motexafin lutetium, (Optrin; Pharmacyclics), activated by 732-nm light, can be utilized as both an imaging and photosensitizing agent. It had shown promise in Phase II trials involving 75 patients for the treatment of AMD; however, 77 percent of subjects receiving therapeutic doses developed peripheral extremity paresthesias. In October 2001, Pharmacyclics gained the worldwide rights to develop and market the product from Alcon; however, further development is currently stalled because of the side effects observed in the Phase II trials. Talaporfin sodium (Light Sciences Corp.) is in an early clinical trial in
Although the exact stimulus or, more likely, stimuli that precipitate CNV formation remain speculative, recent evidence indicates that a combination of inflammatory and angiogenic processes is involved in angiogenesis. Circulating endothelial progenitor cells, monocytes, circulating and resident macrophages, endothelial cells and even astrocytes have been implicated as potential cellular sources for cytokine release during CNV formation. One theory proposes that macrophages secrete angiogenic growth factors as an initial response to Bruch's membrane injury.
Whatever initiates CNV formation, angiogenic growth factors are ultimately involved, and an imbalance of angiogenic promoters and inhibitors occurs. Surgically excised and post-mortem CNV tissue, as well as retinal pigment epithelial cells, were immunoreactive for various proangiogenic growth factors including vascular endothelial growth factor, transforming growth factor-beta (TGF-b), platelet derived growth factor (PDGF) and basic fibroblast growth factor (bFGF or FGF-2).
Animal and clinical studies have established VEGF as a key mediator in ocular angiogenesis. Investigators reported up-regulation of VEGF expression in experimentally induced CNV in rats. Another group, which developed a model of retinal and subretinal neovascularization using a transgenic model driven by over-expression of VEGF, showed that excessive VEGF is sufficient for intraretinal and subretinal neovascularization. In human clinical trials, particular attention has focused on the development of pharmaceutical agents to block VEGF expression or neutralize it once expressed. Investigators have inhibited preretinal neovascularization in experimental models with antibodies against VEGF. Others have shown similar effects using VEGF-neutralizing chimeric proteins, which were constructed by joining the extracellular domain of high-affinity VEGF receptors with immunoglobulin G (IgG).
Intravitreal pegaptanib sodium (Macugen, OSI/Eyetech), an RNA aptamer designed to target VEGF165 and larger isoforms, and intravitreal ranibizumab (Lucentis, Genentech), a monoclonal antibody antigen-binding fragment that targets all isoforms of VEGF and their smaller bioactive cleavage products, received FDA approval for the treatment of neovascular AMD in 2004 and 2006, respectively. Bevacizumab (Avastin, Genentech), a full-length humanized monoclonal antibody that targets all isoforms and active cleavage products of VEGF-A, is FDA-approved in combination with chemotherapy for the systemic treatment of metastatic colorectal cancer and lung cancer. Intravitreal bevacizumab has also recently been used off-label for the treatment of neovascular AMD. With their success, these three anti-VEGF agents—pegaptanib sodium, ranibizumab and bevacizumab—have begun to replace thermal laser photocoagulation and PDT as primary treatments for exudative AMD.
• Pegaptanib sodium. The pivotal clinical trials that led to FDA approval of pegaptanib sodium were two concurrent Phase II/III multicenter, randomized, double-blind, sham-controlled, two-year studies (VISION trials) of intravitreal pegaptanib sodium in patients with CNV secondary to AMD. Pegaptanib sodium (0.3, 1.0 or 3.0 mg) was administered every six weeks for 48 weeks. In the second year, a randomized withdrawal study design was implemented to ascertain whether one year of pegaptanib sodium treatment was sufficient to protect patients from a 15-letter loss of VA. Patients in pegaptanib sodium treatment groups were randomized to receive either pegaptanib sodium or usual-care treatment; patients in sham groups were randomized to receive pegaptanib sodium, sham or usual-care treatment.
At one year, 70 percent of patients receiving 0.3-mg pegaptanib sodium had lost <15 letters of VA, compared with 55 percent of control patients (p<.001). Also at one year, 10 percent of patients receiving 0.3-mg pegaptanib sodium lost >30 letters of VA, compared with 22 percent of control patients (p<.001). However, only 6 percent of pegaptanib sodium-treated patients had gained ≥15 letters. The two-year data demonstrate that patients treated with 0.3-mg pegaptanib sodium for two years were more likely to maintain VA than were patients who received usual care for two years or patients who stopped pegaptanib sodium treatment after one year.
• Ranibizumab. The two pivotal Phase III trials that led to FDA approval of ranibizumab were
ANCHOR is a multicenter, randomized, double-masked, two-year comparison study of monthly intravitreal ranibizumab (0.3 or 0.5 mg) with sham verteporfin PDT versus PDT with sham ranibizumab injection in patients with predominantly classic CNV secondary to AMD. At one year, 94 percent and 96 percent of ranibizumab-treated patients had lost <15 letters of VA, compared with 64 percent of PDT-treated patients (p<.0001); and 36 percent and 40 percent of ranibizumab-treated patients had gained ≥15 letters of VA, compared with 6 percent of PDT-treated patients (p<.001). Two-year data are currently being analyzed. Together, the
Additional clinical studies of alternative dosing strategies of ranibizumab have also provided data supporting the benefits of ranibizumab in patients with neovascular AMD. An alternative dosing schedule of intravitreal ranibizumab (0.3 or 0.5 mg monthly for three months followed by once every three months thereafter) is being examined in a Phase IIIb multicenter, randomized, double-masked, sham-controlled, two-year efficacy and safety study (PIER). First-year data showed that 83 percent of patients treated with 0.3 mg ranibizumab and 90 percent of patients treated with 0.5 mg ranibizumab had lost <15 letters of VA, compared with 49 percent of control patients. Also after one year, 12 percent and 13 percent of treated patients (0.3 and 0.5 mg, respectively) had gained ≥15 letters of VA, compared with 10 percent of control patients; and the mean change in VA was -1.6 in the 0.3-mg treatment group and -0.2 letters in the 0.5-mg group, compared with -16.3 letters for control patients.
PrONTO is a Phase I/II open-label, unmasked, uncontrolled, two-year study of an optical coherence tomography-guided, variable dosing regimen of ranibizumab (monthly intravitreal ranibizumab at a dose of 0.5 mg for three months followed by intravitreal ranibizumab as needed based on OCT-defined retreatment criteria for all subtypes of subfoveal CNV secondary to AMD). At one year, 95 percent of treated patients had lost <15 letters of VA; 35 percent of treated patients had gained ≥15 letters of VA, compared with 10 percent of control patients; and the mean change in VA was +9.3 letters for treated patients.
• Bevacizumab. The
In the first reported case study of intravitreal bevacizumab, a patient with recurrent CNV secondary to AMD, previously treated with PDT in combination with triamcinolone acetonide and with pegaptanib, experienced resolution of visual distortion within one week in association with resolution of subretinal fluid and a reduction in central retinal thickness following a single injection of 1.0 mg bevacizumab.
Subsequent retrospective and prospective studies of monthly intravitreal administration of bevacizumab (1.25 to 2.5 mg) demonstrated that intravitreal bevacizumab significantly improved mean VA and reduced central retinal thickness in patients with subfoveal neovascular AMD. A large prospective, randomized trial comparing bevacizumab to ranibizumab for exudative AMD is currently being planned.
• VEGF Trap. VEGF Trap (Regeneron Pharmaceuticals and Aventis) is a high-affinity recombinant fusion protein that consists of the immunoglobulin domain 2 of the VEGF-R1 receptor and the domain 3 of the VEGF-R2 receptor, fused to the crystallizable fragment of human IgG. This antigen selectively binds and neutralizes all exogenous VEGF-A molecular isoforms as well as placental growth factor. Administration can be either local or intravenous.
A Phase I randomized, multicenter, placebo-controlled study of VEGF Trap demonstrated a dose-dependent decrease in retinal thickness two weeks following a single intravenous injection in patients with neovascular AMD (12 percent for 0.3-mg VEGF Trap, 10 percent for 1-mg, 66 percent for 3-mg, and 60 percent for placebo, p<.02) Dose-limiting toxicities, including hypertension and proteinuria, were reported for the 3-mg dose. A Phase I/II study of intravitreal VEGF Trap (CLEAR IT-1) is ongoing.
• siRNA. RNA interference (RNAi) is a method of post-transcriptional gene silencing that uses double-stranded RNA to target a specific messenger RNA transcript. Small interfering RNA (siRNA) destroys targeted mRNAs thereby silencing the expression of the target gene. One siRNA can destroy hundreds of mRNAs resulting in the suppression of thousands of proteins, such as VEGF. Instead of antagonizing the VEGF once it is produced, siRNA can stop the production of VEGF altogether. Small interfering RNA agents designed to silence the VEGF gene and the VEGF receptor have been shown in preclinical studies to inhibit ocular neovascularization and vascular permeability effectively in animal models. Bevasiranib sodium (formerly called Cand5; Acuity Pharmaceuticals) and Sirna-027 (Sirna Therapeutics) are currently being studied in early phase clinical trials.
In a Phase II, randomized trial, bevasiranib (single injections at baseline and week six) was shown to be well-tolerated after 12 weeks of follow-up, with mild adverse events related primarily to the injection procedure and with no systemic exposure. Bevasiranib ultimately stabilized VA in most patients and led to improvement in VA in more than one-third of patients. Data from a Phase I study of Sirna-027 in patients with neovascular AMD indicated that after three months of follow-up, single injections of Sirna-027 stabilized VA in 24 of 26 (92 percent) patients and improved vision in five of 26 (19 percent) patients with neovascular AMD.
Steroids and Related Compounds
Researchers have long known that corticosteroid compounds possess angiostatic properties via alteration of extracellular matrix degradation, as well as inhibition of inflammatory cells, which invariably participate in neovascular responses. Researchers have started favoring intravitreal administration of corticosteroids because the blood-ocular barrier is bypassed, more constant therapeutic steroid levels are achieved, and systemic side effects are minimized. These injections have demonstrated efficacy in subretinal and preretinal neovascularization in animal models.
• Triamcinolone acetonide. In early clinical studies, triamcinolone acetonide, an antiangiogenic corticosteroid, helped stabilize and to a lesser extent improve VA when used in combination with PDT in patients with neovascular AMD. However, triamcinolone acetonide was unable to prevent visual loss in a substantial portion of tested patient populations, although most studies assessed only single-dosing regimens, unlike the periodic-dosing regimens used for the anti-VEGF agents discussed above. Studies to date suggest that triamcinolone acetonide appears to be most useful in reducing the need for retreatment of patients with PDT.
• Implantable Corticosteroids. Because intraocular corticosteroids have shown antiangiogenic effects with repeated intravitreal administration, the development of sustained-release intraocular implants has achieved near constant intraocular steroid concentrations without repeated injections. Further, researchers at Bausch & Lomb and Control Delivery Systems have developed Retisert (formerly Envision TD), a non-biodegradable intravitreal implant that releases fluocinolone acetonide for up to three years.
Phase III studies involving diabetic macular edema were promising for resolution of retinal leakage compared to placebo. However, the study also reported that 58.5 percent of subjects receiving the 0.5-mg implant developed serious side effects such as increased intraocular pressure, vitreal hemorrhage and cataracts at one year versus 10.7 percent of the standard care group. Meanwhile, a biodegradable dexamethasone implant (Posurdex, Allergan) has shown safety and benefit in recent Phase II trials for macular edema from diabetes mellitus, branch or central retinal vein occlusion, uveitis or surgery. These implantable corticosteroids will be tested in exudative AMD.
• Anecortave Acetate. In 1985, a class of steroid with minimal glucocorticoid or mineralocorticoid activity was developed. It is now undergoing evaluation in human trials as anecortave acetate (Retaane; Alcon). The lack of corticosteroid activity minimizes commonly encountered IOP elevation and accelerated cataract formation. In addition, anecortave acetate was formulated for injection into the sub-Tenon's space with a specially designed cannula.
Early animal models suggested that administration of this compound inhibited growth of a highly vascularized intraocular tumor in a murine model and retinal neovascularization in a retinopathy of prematurity rat model. A study of 128 patients involved in a Phase II/III randomized, prospective, placebo-controlled trial, designed to evaluate the clinical safety and efficacy of juxtascleral injection of anecortave acetate versus placebo for the treatment of subfoveal CNV, found that baseline vision (p=0.01), stabilization of vision (p=0.03), and prevention of severe vision loss (p=0.02) were statistically superior to baseline at 12 months. The dropout rate, however, was nearly 50 percent.
Investigators announced 12-month data of another 530-patient, Phase III, two-year, randomized, prospective clinical study that directly compared anecortave acetate with verteporfin PDT. No statistical difference was found in subjects with less than three lines of vision loss. Alcon applied for an FDA New Drug Application, but the approval was not granted with this data.
Two additional Phase III studies of Retaane will study the effects of anecortave acetate on slowing the progression of high-risk, nonexudative AMD patients. The studies began enrollment of 2,500 patients at 100 sites worldwide in February 2004 with a planned follow-up of four years. In addition, a study called BRIDGE is in the planning stages, in which anecortave acetate will be administered after a series of initial induction doses of intravitreal ranibizumab to determine if decreased frequency of ranibizumab administration is feasible.
• Squalamine. Squalamine (Genaera), an antiangiogenic aminosterol originally found in the body tissues of the cancer-resistant dogfish shark, acts as an inhibitor of growth factor signaling, including VEGF, integrin expression and cytoskeletal formation. Systemic intravenous administration has inhibited iris neovascularization in primate models, oxygen-induced retinopathy in murine models, and laser-induced CNV in a rat model. A Phase I/II trial of 40 patients in Mexico revealed that once-weekly intravenous injections of squalamine for four consecutive weeks preserved vision in 100 percent of subjects and improved visual acuity by three lines or more in 26 percent of subjects at four months. Three Phase II clinical trials suggested some benefit, but the larger Phase III was halted recently.
• AdPEDF. Researchers have attempted to stimulate intravitreal production of native pigment epithelium-derived factor (PEDF), a naturally occurring, potent antiangiogenic protein deficient in eyes with CNV, using gene therapy. PEDF inhibits angiogenesis by inducing apoptotic death of endothelial cells stimulated to form new vessels. In a laser-induced CNV murine model, CNV was reduced after intravitreal PEDF was produced from an adenoviral vector. One study demonstrated that increased intravitreal PEDF has shown up to 85 percent inhibition of neovascularization in laser-induced CNV, transgenic VEGF and retinopathy of prematurity models. GenVec Inc. has developed a PEDF-producing adenovirus vector, AdPEDF (PEDF on an adenovirus vector), and completed recruitment of 51 patients in five states for Phase I human trials in August 2004. Interim, 12-month results of 24 patients revealed no dose-limiting toxicities or related severe adverse events.
Combretastatin A4-phospate Prodrug
Combretastatin A4-phosphate Prodrug (CA4P; OXiGENE), an analog of colchicine that binds tubulin (intracellular structural protein necessary for cell division), was originally derived from the root bark of the South African willow tree Combretum caffrum. Murine models overexpressing VEGF and laser-induced CNV demonstrated that CA4P was effective in prevention and treatment of CNV. A Phase I/II trial of 20 patients to study the safety and efficacy of intravenous CA4P administration once a week for four weeks with six-month follow-up is under way. Preliminary results of seven subjects found that CA4P was well-tolerated in doses up to 36 mg/m2 with the only side effects being mildly increased pulse and blood pressure. OXiGENE is currently exploring local and nonsystemic methods of administration of CA4P.
Combination Therapy Trials
A variety of combination therapies are undergoing clinical trial currently. Studies of Visudyne PDT, e.g., to rapidly close CNV, or combined with steroids and/or other anti-VEGF therapies to limit additional growth of and leakage from CNV, are in planning or in progress already. Studies are also being planned or are in progress using combinations of anti-VEGF agents such as bevacizumab or ranibizumab to cause rapid resolution of exudation, followed by maintenance of stability with agents that can be administered less frequently, such as pegaptanib or anecortave acetate.
With these new therapies, we have entered into a new era in the treatment of AMD and eye disease in general. We can now very elegantly target molecular processes, including RNA production and specific protein expression, instead of pursuing destructive therapies such as laser photocoagulation. In the near future, many additional clinical trials will be conducted with combinations of these therapies to maximize efficacy. Clinical trials assessing preventive therapies, prior to the development of CNV, however, will ultimately yield the most important means to minimize debilitating vision loss from AMD, which has the potential to be a significant public-health issue in the
Dr. Ciulla practices in the Vitreoretinal Service, Midwest Eye Institute,
Age-Related Eye Disease Study Research Group. Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11. Arch Ophthalmol 2003;121:1621-4.
Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: One-year results of two randomized clinical trials—TAP report. Arch Ophthalmol 1999;117:1329-45.
Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: Two-year results of two randomized clinical trials—TAP report 2. Arch Ophthalmol 2001;119:198-207.
Verteporfin in Photodynamic Therapy (VIP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: Two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization - Verteporfin in Photodynamic Therapy Report 2. Am J Ophthalmol 2001;131:541-60.
Bressler N. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization - Verteporfin in Photodynamic Therapy Report 2. Am J Ophthalmol 2002;133:168-9.
Bressler N, Rosenfeld P, Lim J, VIM Study Group. A phase placebo-controlled, double-masked, randomized trial—verteporfin in minimally classic CNV due to AMD (VIM). Invest Ophthalmol Vis Sci 2003;44:E-abstract 1100.
Rosenfeld P, VIM Study Group. Verteporfin in minimally classic CNV due to AMD (VIM) - two-year results from a phase II controlled clinical trial. Invest Ophthalmol Vis Sci 2004;45: E-abstract 2273.
Gragoudas ES, Adamis AP, Cunningham ET Jr., et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805-2816.
Chakravarthy U, Adamis AP, Cunningham ET Jr., et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology 2006;113:1508-1525.
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY. Ranibizumab for Neovascular Age-Related Macular Degeneration: 2-Year Results of the MARINA Study. N Engl J Med 2006;355:1419-1431.
Rosenfeld PJ, Fung AE, Lalwani GA, et al. Visual acuity outcomes following a variable-dosing regimen for ranibizumab (Lucentis) in neovascular AMD: The PrONTO Study. Invest Ophthalmol Vis Sci 2006;47:E-Abstract 2958.
Michels S, Rosenfeld PJ,
Moshfeghi AA, Rosenfeld PJ,
Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331-335.
Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383-390.
Costa RA, Jorge R, Calucci D, et al. Intravitreal bevacizumab for choroidal neovascularization caused by AMD (IBeNA Study): Results of a phase 1 dose-escalation study. Invest OphthalmolVis Sci 2006;47:4569-4578.
Geitzenauer W, Michels S, Prager F, et al. Early effects of systemic and intravitreal bevacizumab (Avastin) therapy for neovascular age-related macular degeneration [article in German]. Klin Monatsbl Augenheilkd 2006;223:822-827.
Ladewig MS, Ziemssen F, Jaissle G, et al. Intravitreal bevacizumab for neovascular age-related macular degeneration [article in German]. Ophthalmologe 2006;103:463-470.
Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363-372.e5.
Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006;142:1-9.
Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495-511.
Nguyen QD, Shah SM, Hafiz G, et al. A Phase I trial of an IV-administered vascular endothelial growth factor trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2006; 113:1522.e1-1522.e14.
Reich SJ, Fosnot J, Kuroki A, et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol Vis 2003;9:210-216.
Tolentino MJ, Brucker AJ, Fosnot J, et al. Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization. Retina 2004; 24:132-138.
Ciulla T, Criswell M, Danis R, Hill T. Intravitreal triamcinolone acetonide inhibits choroidal neovascularization in a laser-treated rat model. Arch Ophthalmol 2001;119:399-404.
Penfold P, Gyory J, Hunyor A, Billson F. Exudative macular degeneration and intravitreal triamcinolone. A pilot study. Aust N Zeal J Ophthalmol 1995;23:293-8.
Danis R, Ciulla T, Pratt L, et al. Intravitreal triamcinolone acetonide in exudative age-related macular degeneration. Retina 2000;20:244-50.
Ruiz-Moreno JM, Montero JA, Barile S, Zarbin MA. Photodynamic therapy and high-dose intravitreal triamcinolone to treat exudative age-related macular degeneration: 1-year outcome. Retina 2006;26:602-612.
Ergun E, Maar N, Ansari-Shahrezaei S, et al. Photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide in the treatment of neovascular age-related macular degeneration. Am J Ophthalmol 2006;142:10-16.
Schmidt-Erfurth U, Michels S, Augustin A. Perspectives on verteporfin therapy combined with intravitreal corticosteroids. Arch Ophthalmol 2006;124:561-563.