Article Date: 8/1/2004

Pegaptanib Sodium Therapy for Exudative Age-Related Macular Degeneration

Recent clinical trials have shown that the investigational drug pegaptanib sodium (Macugen) is effective in reducing the risk of vision loss due to neovascularization in age-related macular degeneration (AMD). The drug is an antivascular endothelial growth factor (VEGF) aptamer that is injected into the vitreous.


VEGF binds to cell receptors on endothelial cells and plays a critical role in inducing blood vessel growth and permeability. Research in humans has shown that the concentration of VEGF is elevated in eyes with exudative AMD or diabetic macular edema and that inhibiting VEGF is associated with a reduction in blood vessel growth and leakage. Research also indicates that a VEGF isoform, VEGF165, is responsible for pathological ocular neovascularization.

Aptamers are synthesized short strands of oligonucleotides that bind to specific molecular targets. The shape of the pegaptanib sodium aptamer provides it with a high specificity and affinity for VEGF165. By binding with VEGF165, pegaptanib sodium blocks it from binding with the endothelial cell receptors, thereby preventing angiogenic stimulation of the cell.

Pegaptanib sodium is a pegylated aptamer to which a polyethylene glycol molecule has been added to increase the half-life of the drug and consequently lengthen the time between treatments. Published human pharmacokinetic data are not yet available; a clinical trial of the drug's pharmacokinetics in humans recently completed enrollment. Preclinical studies in rhesus monkeys, however, showed that the average half-life of pegaptanib sodium was approximately 94 hours, and the drug was fully active in the vitreous humor after 28 days.1


Preliminary results from clinical trials using pegaptanib sodium to treat AMD-related choroidal neovascularization were promising. A phase I study of a single injection demonstrated the safety of the drug. Subsequently, a phase II study was done in 2 parts, both with multiple injections. This study assessed safety as well as vision stabilization and improvement associated with pegaptanib sodium as a standalone treatment and in combination with photodynamic therapy (PDT) with verteporfin. Although these studies had relatively few patients, results showed that 87.5% of patients treated with pegaptanib sodium alone had stabilized or improved vision 3 months after treatment, and 25% had 3 or more lines of improvement.2 In the group of patients who received both pegaptanib sodium and PDT, 90% had stabilized or improved vision, and 60% had an improvement of 3 lines of vision 3 months after treatment. No related serious adverse events were reported.


  • Eyelash washes and topical broad-spectrum antibiotic for 3 days prior to injection OR 10 cc flush with 5% povidone iodine to entire ocular surface immediately prior to injection
  • Single-use bottles
  • 3 applications of topical broad-spectrum antibiotic and 5% povidone iodine 1 hour prior to injection
  • Sterile preparation and drape
  • Sterile speculum, gloves and sterile technique
  • No prophylactic paracentesis


On the basis of the initial results of the phase I/II studies, 2 phase II/III clinical trials, known collectively as the VEGF Inhibition Study In Ocular Neovascularization (VISION), were begun.* VISION comprised 2 randomized, double-masked, controlled, dose-ranging studies performed at 117 investigational sites throughout the world. Entry criteria were broad and included any subtype of CNV (preread at the Wilmer Ophthalmological Institute), visual acuity 20/40 to 20/320, and lesion size of 12 disc areas or less. Study subjects were randomly assigned to 0.3 mg, 1 mg, or 3 mg of pegaptanib sodium or to sham treatment. Treatment was given every 6 weeks, in most cases for a total of 9 treatments, and subjects were followed for 54 weeks. At the investigator's discretion, PDT was allowed for predominantly classic lesions, which was then accepted as usual care.

Full results of this trial cannot yet be reported; however, a summary of top-line results has been made available and can be reviewed here. As reported at the 2004 Aspen Retinal Detachment Society Meeting, the American Academy of Ophthalmology 2003 Annual Meeting, the Macula Society 2004 Annual Meeting, and the Association for Research in Vision and Ophthalmology 2004 Annual Meeting, the broad entry criteria and the number of clinical centers participating in VISION led to rapid completion of the enrollment of 1186 subjects.3-8 The primary efficacy endpoint, the proportion of patients losing <15 letters (3 lines) of visual acuity by 54 weeks of follow-up, was met. Pegaptanib sodium showed evidence of efficacy at all 3 dosage levels. In the 0.3-mg group, 70% lost <3 lines of vision (P = .0001); in the 1-mg group, 71% (P = .0003); in the 3-mg group, 65% (P = .0310); and in the sham group, 55% (NS). The 0.3 mg dose of pegaptanib sodium was subsequently chosen as the lowest efficacious dose.

The treatment effect of pegaptanib sodium manifested early and was sustained through 54 weeks of follow-up. The treatment group also had a significantly greater likelihood of preservation of vision at 54 weeks. Pegaptanib sodium was also effective in reducing the risk of severe (>= 6-line) vision loss. Subjects in the sham group were about twice as likely as those in the treatment group to have this degree of loss. The use of PDT was more frequent in the sham group than in the treatment group.

The rate of patients completing the study was >90% in both the treatment group and the sham group. In addition, the vision outcomes showed that the overall treatment benefit of pegaptanib sodium was not driven by any one subtype of CNV; the results were similar in the predominantly classic, minimally classic, and occult with no classic subgroups.

In studies of systemically administered anti-VEGF drugs used at much higher doses to treat cancer, potential systemic adverse effects have included hypertension, proteinuria, and peripheral thromboembolic events. None of these complications occurred with greater frequency in patients who received pegaptanib sodium; the rates of systemic events were the same in both the treatment and the sham groups.

The treatment group did not have an increased rate of ocular complications, e.g., cataract formation or progression, glaucoma, or changes in the retinal or choroidal vasculature. Some transient increases in intraocular pressure (IOP) after injection were noted, but in the vast majority of patients the mean IOP returned to normal by the week 1 follow-up visits, and there was no evidence of a sustained increase in IOP over the first year of the study. Mild, transient intraocular inflammation was slightly more common in the pegaptanib sodium group, which was attributed to the procedure. Endophthalmitis is a concern in any intravitreous injection procedure. In 7545 injections, 12 patients developed endophthalmitis (1.3% per patient/year); 75% of the patients with endophthalmitis stayed in the study, and only 1 developed severe vision loss ­ a rate of 0.1% compared with a 22% risk of severe vision loss associated with exudative AMD. The endophthalmitis was thought to be related to the injection technique, and, after discussion with several retina experts, the injection technique was changed (Table). In the subsequent 9 months, there were no cases of endophthalmitis; the change in technique appears to have reduced the risk.

Several factors may contribute to pegaptanib sodium's safety profile. With its specificity for the VEGF165 pathologic isoform, it affects the underlying cause of neovascularization and spares normal vasculature. Aptamers are nonimmunogenic, with little risk of evoking an adverse immune response. Because the drug is injected into the vitreous, the risk of systemic effects is minimized.

In summary, VISION comprised 2 positive, replicate, pivotal phase II/III trials that used a clinically significant primary endpoint with wide entry criteria for the 0.3-mg dose. With the use of multiple, clinically meaningful endpoints, the combined data suggest that pegaptanib sodium helps prevent vision loss. Of note, the overall treatment benefit was not driven by any one lesion subtype or composition. There were very few systemic or ocular adverse events.


Data from the VISION trials indicate that pegaptanib sodium may help to preserve vision in patients with neovascular AMD, a leading cause of visual loss in the western world. Its efficacy appears to be independent of lesion size, lesion composition, and patient age. Although it is not likely that this treatment will allow patients who have lost the ability to read or drive do so again, it may provide a valuable treatment option for many people who previously did not have any options, for example, those with larger exudative AMD lesions.

The pilot study that evaluated pegaptanib sodium in combination with verteporfin PDT raises the intriguing prospect that this new agent may be more efficacious when given in concert with other therapeutic modalities. In the phase II AMD trial, 25% of patients treated with pegaptanib sodium alone had 3 or more lines of visual improvement, whereas 60% of those treated with pegaptanib sodium and PDT had this degree of improvement. Assuming FDA approval, many investigators and clinicians may use pegaptanib sodium in conjunction with PDT. When other effective treatments are identified and approved, especially those that may attack the complicated sequence of events in the pathogenesis of CNV at stages other than vascular endothelial growth, the synergies between these treatments and pegaptanib sodium may present an important breakthrough in AMD therapy.

Address correspondence to: Lawrence J. Singerman, MD, FACS, Retina Associates of Cleveland, 3401 Enterprise Parkway, Suite 300, Cleveland, OH 44122. Telephone: (216) 831-5700. E-mail:

From Retina Associates of Cleveland, Cleveland, Ohio, Dr. Singerman is a consultant and a member of the Scientific Advisory Board for Eyetech Pharmaceuticals, Inc. Retina Associates of Cleveland receives grant support from Eyetech Pharmaceuticals, Inc. for clinical trials.

* VISION is the largest clinical trial ever performed for exudative AMD, and it was completed expeditiously. The design called for a 1-year endpoint. With 117 participating centers, enrollment was completed rapidly, and the dissemination of study results followed shortly thereafter. The efficacy and safety analysis was finalized on October 16, 2003, and the analysis was disseminated to the investigators on November 14, 2003.



1. Drolet DW, Nelson J, Tucker CE, et al. Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys. Pharm Res. 2000;17:1503-1510.

2. Eyetech Study Group. Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. Ophthalmol. 2003; 110:979-986.

3. Eyetech Pharmaceuticals presents Macugen(TM) (pegaptanib sodium) data at the Aspen Retinal Detachment Society Meeting in Aspen, Colorado. Available at: Accessed 30 June 2004.

4. Nichols ER. AAO: Experimental drug may benefit patients with age-related macular degeneration. Available at: Accessed 30 June 2004.

5. Realini Tony. New therapies for AMD coming soon, speakers say. Available at: Accessed 30 June 2004.

6. D'Amico DJ, Bird AC. VEGF Inhibition Study in Ocular Neovascularization-1 (VISION-1): safety evaluation from the pivotal MacugenTM (pegaptanib sodium) clinical trials. ARVO Abstract 2363; 2004.

7. Gragoudas ES. VEGF inhibition study in ocular neovascularization-1 (VISION-1): efficacy results from Phase II/III MacugenTM (pegaptanib sodium). ARVO Abstract 2364; 2004. Accessed 30 June 2004.

8. Singerman LJ. VEGF inhibition study in ocular neovascularization (VISION): efficacy outcomes from the pivotal Phase II/III Macugen (pegaptanib sodium) clinical trials. Abstracts. 27th Annual Meeting of the Macula Society, February 26 ­ March 1, 2004, Las Vegas, Nevada. Abstract p. 200.


Retinal Physician, Issue: August 2004