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Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Pegaptanib for Neovascular Age-Related Macular Degeneration Evangelos S. Gragoudas, M.D., Anthony P. Adamis, M.D., Emmett T. Cunningham, Jr., M.D., Ph.D., M.P.H., Matthew Feinsod, M.D., and David R. Guyer, M.D., for the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group N Engl J Med 2004; 351:2805-2816 DOI: 10.1056/NEJMoa042760.

Results In the combined analysis of the primary end point (for a total of 1186 patients), efficacy was demonstrated, without a dose–response relationship, for all three doses of pegaptanib (P. Figure 1 Mean Change in Scores for Visual Acuity.

Panel A shows the mean changes in visual acuity from baseline to week 54 (P. The use of a specific antagonist of an angiogenic factor as a strategy to treat disease was proposed in the Journal more than 30 years ago. Since that time, extensive evidence has suggested a causal role of vascular endothelial growth factor (VEGF) in several diseases of the human eye in which neovascularization and increased vascular permeability occur. In humans, ocular VEGF levels have been shown to rise synchronously with and in proportion to the growth and leakage of new vessels. Animal models of corneal, iridic, retinal, and choroidal neovascularization have shown that neovascularization is dependent on the presence of VEGF. In a complementary fashion, the introduction of VEGF into normal animal eyes resulted in a recapitulation of the pathologic neovascularization that occurs in these tissues during disease. Taken together, these data provided a strong rationale for the targeting of VEGF in human disorders that manifest as ocular neovascularization and increased vascular permeability.

Age-related macular degeneration is the leading cause of irreversible, severe loss of vision in people 55 years of age and older in the developed world, and it remains an area of unmet medical need. The neovascular form of the disease represents approximately 10 percent of the overall disease prevalence, but it is responsible for 90 percent of the severe vision loss. It is expected to develop in almost 1 million people over the age of 55 years in the United States within the next five years, making it a major public health issue in an increasing population of older persons. Neovascular age-related macular degeneration is characterized by choroidal neovascularization that invades the subretinal space, often leading to exudation and hemorrhage.

If the condition is left untreated, damage to photoreceptors and loss of central vision usually result, and after several months to years, the vessels are largely replaced by a fibrovascular scar. Patients in whom a central scotoma develops have difficulty performing critical tasks that are typically associated with central vision, such as reading, driving, walking, and recognizing faces, and the difficulty has a major effect on their quality of life. With greater understanding of the pathogenesis of neovascular age-related macular degeneration, drug therapies targeted at the causal molecular mechanisms have been advanced. Pegaptanib (Macugen), a 28-base ribonucleic acid aptamer (from the Latin aptus, to fit; and the Greek meros, part or region) covalently linked to two branched 20-kD polyethylene glycol moieties, was developed to bind and block the activity of extracellular VEGF, specifically the 165-amino-acid isoform (VEGF 165). Aptamers characteristically bind with high specificity and affinity to target molecules, including proteins. The binding relies on the specific three-dimensional conformation of the properly folded aptamer. To prolong activity at the site of action, the sugar backbone of pegaptanib was modified to prevent degradation by endogenous endonucleases and exonucleases, and the polyethylene glycol moieties were added to increase the half-life of the drug in the vitreous.

We hypothesized that the targeting of VEGF 165 would affect the underlying conditions common to all forms of choroidal neovascularization, including the three angiographic subtypes of neovascular age-related macular degeneration. We conducted two concurrent clinical trials to test the short-term safety and effectiveness of pegaptanib in patients with a broad spectrum of visual acuities, lesion sizes, and angiographic subtypes of lesions at baseline. Study Design We conducted two concurrent, prospective, randomized, double-blind, multicenter, dose-ranging, controlled clinical trials at 117 sites in the United States, Canada, Europe, Israel, Australia, and South America in our study. Patients were eligible for inclusion if they were 50 years of age or older and had subfoveal sites of choroidal neovascularization secondary to age-related macular degeneration and a range of best corrected visual acuity of 20/40 to 20/320 in the study eye and of 20/800 or better in the other eye. The angiographic subtype of a patient's lesion was defined in relation to the visualization of choroidal new vessels (classic) in the fluorescein angiogram. The total area of a predominantly classic lesion includes more than 50 percent classic choroidal neovascularization, the total area of a minimally classic lesion includes less than 50 percent classic choroidal neovascularization, and the total area of an occult lesion includes no classic choroidal neovascularization. Me Without You 2001 Download Itunes on this page.

The total size of a lesion, choroidal neovascularization, or leakage was measured on a frame on the fluorescein angiogram with the optic-disk area as the unit of measure; it is equal to 2.54 mm 2. The size of a lesion, choroidal neovascularization, or leakage is expressed as multiples of this standard optic-disk area. Patients with all angiographic subtypes of lesions were enrolled, and lesions with a total size up to and including 12 optic-disk areas (including blood, scar or atrophy, and neovascularization) were permitted. Details of the method are provided in the, available with the full text of this article at www.nejm.org. Treatment and Outcomes Patients were randomly assigned to receive either sham injection or intravitreous injection of pegaptanib (Macugen, Eyetech Pharmaceuticals) into one eye every 6 weeks over a period of 48 weeks, for a total of nine treatments.

To maintain masking of the patients, the patients receiving sham injections and those receiving the study medication were treated identically, with the exception of scleral penetration. All patients (including those receiving sham injection) underwent an ocular antisepsis procedure and received injected subconjunctival anesthetic.

The patients receiving sham injections had an identical syringe — but without a needle — pressed against the eye wall to mimic the active doses that were injected through the pars plana into the vitreous cavity. The injection technique precluded the patient from seeing the syringe. To maintain masking of the investigators, the study ophthalmologist responsible for patient care and for the assessments did not administer the injection. In all cases, a separate, certified visual-acuity examiner masked to the treatment assignment and to previous measurements of visual acuity assessed distance visual acuity.

Owing to ethical considerations, the use of photodynamic therapy with verteporfin was permitted only in the treatment of patients with predominantly classic lesions, as defined in the product label approved by the Food and Drug Administration, and at the discretion of the ophthalmologist, who was masked as to the treatment assignment. The prespecified primary end point for efficacy was the proportion of patients who lost fewer than 15 letters of visual acuity (defined as three lines on the study eye chart) between baseline and week 54.

The trials were designed by the steering committee of the VEGF [Vascular Endothelial Growth Factor] Inhibition Study in Ocular Neovascularization Clinical Trial Group. The data were held and analyzed by the data management and statistics group. The manuscript was prepared by the writing committee. Gragoudas chaired the writing committee, served as the outside academic investigator vouching for the veracity and completeness of the data analyses, had access to the full data set, and was responsible for the decision to submit the manuscript for publication. Results One trial included 586 patients at 58 sites in the United States and Canada and was conducted from August 2001 through July 2002; the other trial included 622 patients at 59 other sites worldwide and was conducted from October 2001 through August 2002. Of the 1208 patients randomly assigned to treatment in the two studies (297 patients assigned to receive 0.3 mg of pegaptanib; 305 patients, 1.0 mg of pegaptanib; 302 patients, 3.0 mg of pegaptanib; and 304 patients, sham injections), 1190 received at least one study treatment (295 patients received 0.3 mg of pegaptanib; 301 patients, 1.0 mg of pegaptanib; 296 patients, 3.0 mg of pegaptanib; and 298 patients, sham injections).

The demographic and ocular characteristics of the patients at baseline were similar among the treatment groups ( Table 1 Demographic and Ocular Characteristics of Patients at Baseline. Four patients were not included in the efficacy analyses, because a sufficiently standardized assessment of visual acuity was not completed at baseline. Therefore, a total of 1186 patients received at least one study treatment, had visual acuity assessments at baseline, and were included in efficacy analyses (294 patients who received 0.3 mg of pegaptanib; 300 patients, 1.0 mg of pegaptanib; 296 patients, 3.0 mg of pegaptanib; and 296 patients, sham injections). A total of 7545 intravitreous injections of pegaptanib and 2557 sham injections were administered. Approximately 90 percent of the patients in each treatment group completed the study. In all the treatment groups, an average of 8.5 injections were administered per patient out of a possible total of 9 injections.

The general health status of the patients entering the trial, calculated for all patients receiving pegaptanib as compared with those receiving sham injection, was as follows: hypertension (55 percent in the pegaptanib groups vs. 48 percent in the sham-injection group), hypercholesterolemia (21 percent vs. 18 percent), diabetes mellitus (10 percent vs. 7 percent), cardiac disorders (35 percent vs. 34 percent), cerebrovascular disease (3 percent vs. 1 percent), peripheral arterial disease (3 percent vs. 3 percent), and electrocardiographic abnormalities (53 percent vs.

In the combined analysis, all three doses of pegaptanib differed significantly from the sham injection in terms of the prespecified primary efficacy end point ( Table 2 Rate of Visual-Acuity Loss, Measured as the Loss of Fewer Than 15 Letters, in 1186 Patients. A loss of fewer than 15 letters of visual acuity was observed at week 54 in 206 (70 percent) of 294 patients assigned to receive 0.3 mg of pegaptanib (P. Discussion Pegaptanib produced a statistically significant and clinically meaningful benefit in the treatment of neovascular age-related macular degeneration.

Overall, a reduced risk of visual-acuity loss was observed with all doses as early as six weeks after treatment was begun, with evidence of an increasing benefit over time up to week 54 ( ). This observation was supported by a variety of findings. Pegaptanib reduced the chance not only of the loss of 15 letters or more of visual acuity (considered a moderate loss), but also of a loss of 30 letters or more (six lines on the study eye chart, which is considered a severe loss). In addition, treatment with pegaptanib reduced the risk of progression to legal blindness in the study eye, promoted stability of vision, and in a small percentage of the patients, resulted in more visual improvement at week 54 than among those receiving sham injections.

The visual results are further supported by angiographic measurements obtained by personnel masked to the treatment assignments, which suggested a reduction in the growth of the total size of the lesion or of choroidal neovascularization and in the severity of leakage ( ). These data provide indirect biologic evidence of the mechanism of action of pegaptanib. Although fluorescein angiography is a time-honored method of assessing neovascular age-related macular degeneration, the quantitative measurements of the size of a lesion and of choroidal neovascularization may have been confounded by changes in permeability that accompanied pegaptanib therapy. Any conclusions about the extent of choroidal neovascularization and lesion size must be made, therefore, with this caveat in mind. The inhibition of permeability by pegaptanib may have played an important role in the visual outcomes observed. A reduction in vascular permeability probably accounted for the improved outcome at six weeks, because the data indicate there was little likelihood of a meaningful change in choroidal neovascularization or lesion size at that point. Because all forms of choroidal neovascularization have been associated with elevated levels of VEGF, it was hypothesized that a broad spectrum of patients might benefit from anti-VEGF therapy with pegaptanib.

Indeed, there was no evidence that any one baseline characteristic, including angiographic subtype, lesion size, or initial level of visual acuity, precluded a treatment benefit. The beneficial responses observed with pegaptanib probably imply that a common underlying disease process was treated. These data support the hypothesis that pegaptanib is effective in a broad population of patients with neovascular age-related macular degeneration. Since approximately 90 percent of the patients enrolled completed the two trials, the intravitreous-injection regimen also appeared to be accepted by both patients and physicians. The per-injection rates of endophthalmitis (0.16 percent), retinal detachment (0.08 percent), and traumatic lens injury (0.07 percent) in the current trial were similar to rates identified in a comprehensive review of more than 15,000 intravitreous injections.

Therefore, the risks associated with intraocular injection of pegaptanib are probably no different from those associated with intraocular injection of other drugs. Because this treatment requires multiple injections, the risk of endophthalmitis was 1.3 percent per patient during the first year of the trials. For comparison, the range of the reported risk of endophthalmitis associated with cataract surgery is 0.06 percent to 0.4 percent. Our data show that, despite this risk, the majority of patients fare better with eight to nine injections over the course of a year than with no treatment. However, in order to maximize the benefit of treatment, it is critical that all treating ophthalmologists carefully adhere to an appropriate aseptic technique for each injection, educate patients regarding worrisome symptoms, and closely monitor patients after each injection.

Careful attention to the technique of the procedure can probably minimize the risk of endophthalmitis after intravitreous injection. For ethical reasons, sham injection was used as a control in these studies.

Preclinical experiments have shown that it is unlikely that control intravitreous injections would have resulted in a visual improvement. Endogenous VEGF-induced retinal vascular permeability in a rat model was not inhibited when phosphate-buffered saline or an inactive control (e.g., polyethylene glycol) was given by intravitreous injection. Only intravitreous injections of pegaptanib reduced vascular permeability. Similarly, studies in primates have shown that intravitreous injections of a VEGF inhibitor effectively suppressed neovascularization in the iris and the choroid, whereas intravitreous injections of inactive control substances such as phosphate-buffered saline or nonimmune antibody did not appear to alter the natural course of the disease.

In summary, treatment with pegaptanib provided a statistically significant and clinically meaningful benefit in a broad spectrum of patients with neovascular age-related macular degeneration, regardless of the size or angiographic subtype of the lesion or the baseline visual acuity. The rate of injection-related adverse events represents a potentially modifiable risk but necessitates vigilance. Because age-related macular degeneration tends to progress over years, long-term data will be required for a full characterization of the safety and efficacy of pegaptanib therapy. Our results provide validation of aptamer-based therapy in the treatment of human disease and support ongoing investigations into the use of VEGF antagonists in patients with diabetic retinopathy and retinal-vein occlusion, which are other disorders associated with elevated levels of intraocular VEGF. References • 1 Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186 • 2 Adamis AP, Miller JW, Bernal M-T, et al.

Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994;118:445-450 • 3 Aiello LP, Avery RL, Arrigg PG, et al.

Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480-1487 • 4 Malecaze F, Clamens S, Simorre-Pinatel V, et al. Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy. Download Free Software Last Chaos German Setup Ooma more. Arch Ophthalmol 1994;112:1476-1482 • 5 Amano S, Rohan R, Kuroki M, Tolentino M, Adamis AP.

Requirement for vascular endothelial growth factor in wound- and inflammation-related corneal neovascularization. Invest Ophthalmol Vis Sci 1998;39:18-22 • 6 Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol 1996;114:66-71 • 7 Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A 197-10461 .