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Clinical experience with selective VEGF inhibition in neovascular AMD
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The first treatment strategies for exudative age-related macular degeneration included thermal laser photocoagulation, photodynamic therapy with verteporfin (Visudyne, Novartis), and surgical excision of choroidal neovascular membranes. These treatments offered some benefit to subsets of patients with wet AMD, but most benefit only marginally from these approaches.
Advances in the medical management of AMD now allow physicians to intervene in the pathologic process of AMD with significant safety and efficacy. Inhibition of vascular endothelial growth factor (VEGF), a significant biologic factor in the development of wet AMD, with agents such as pegaptanib sodium (Macugen, Pfizer) can retard the devastating vision loss associated with AMD.
VISION trial data
Pegaptanib selectively inhibits the VEGF165 isoform in the eye and is approved to treat wet AMD in many countries in the European Union and in Brazil, Canada and the United States. The drug is administered by intravitreal injection every 6 weeks, and is typically given for at least 1 year. The approval of pegaptanib was based on outcomes data from the VISION trial.1 The VISION trial consisted of two concurrent, randomized, double-masked, controlled, dose-ranging studies that were designed to be combined for final analyses.
Nearly 1,200 patients at 117 centers worldwide were divided evenly into three treatment groups (each receiving different dosing levels) and one usual-care group that served as a control group. Patients in both treatment and usual-care groups were allowed to receive photodynamic therapy (PDT) with verteporfin at the investigators’ discretion.
Inclusion criteria were broad. Visual acuity ranged from 20/40 to 20/320, and all subtypes of neovascular AMD were included (25% predominantly classic, 39% occult with no classic, and 36% minimally classic). Also, large lesions (up to 12 disc areas) were enrolled, and lesions could have significant hemorrhage (up to 50%) and fibrosis (up to 25%). Finally, patients were allowed to have received PDT prior to pegaptanib.
Response in VISION trial
The primary efficacy endpoint was the percentage of patients losing fewer than three lines of vision. These patients were classified as responders. At 1 year, the responder rate was 70% in eyes treated with pegaptanib compared with 55% in eyes that received usual care, a statistically significant difference. Pegaptanib showed a treatment benefit over usual care regardless of baseline lesion subtype or size, visual acuity, age, gender, or prior and/or baseline PDT usage. Treated eyes also demonstrated an increased rate of visual gain and reduction in severe vision loss. The drug exhibited a good safety profile with no evidence of drug-related ocular or systemic safety signals. The injection safety profile was favorable.
At the end of the first year of the VISION trial, treated patients were randomized to either a second year of pegaptanib or to observation. The second year of the trial demonstrated a significant benefit to continued therapy with an additional year of pegaptanib compared with discontinuing the drug after 1 year. Treated eyes demonstrated a continuation of benefit through 102 weeks, whereas patients who were rerandomized to discontinue pegaptanib after 1 year lost visual acuity. Data over the 2 years of the trial also suggest that pegaptanib should be initiated as early as possible in the disease process.
Secondary endpoints
An important prespecified secondary endpoint in the VISION trial was the proportion of patients who gained or maintained visual acuity. Thirty-three percent of patients who received pegaptanib gained 0 to 15 letters. Six percent of treated eyes achieved a significant visual gain of more than three lines of vision. Another prespecified endpoint examined visual loss. Treated eyes showed a benefit, losing an average of six letters, compared with a 15-letter loss in the usual-care group.
VISION trial researchers also analyzed the proportion of patients who developed legal blindness (20/200 or worse visual acuity) in eyes that were not legally blind at the end of the trial. At 1 year, patients in the pegaptanib group who were not legally blind initially had a 31% risk of developing legal blindness, compared with a 50% risk in the usual-care group, a 38% relative benefit. At the end of the second year, the relative benefit was 36% for the same endpoint in treated eyes vs. eyes in the usual-care group.
Further investigation
A common theme noted by investigators in the VISION trial was that a marked difference between visual acuity results and anatomic responses was often seen. The visual benefit in the VISION trial often did not correlate well with either clinical activity on ophthalmoscopic exam, or fluorescein angiographic (FA) evaluation or by optical coherence tomography (OCT). In many cases, both in the trial and in post-trial experience, visual acuity stabilizes or improves following pegaptanib, despite OCT and FA images that demonstrate increased blood, fluid, or hyperfluorescence.
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Basic science investigations into VEGF and neovascular AMD suggest that choroidal neovascular membranes change over time. In early stages of development, membranes demonstrate a fine, lacy vasculature that is dependent on VEGF. As a result, VEGF blockade in these membranes results in marked involution. In later stages of development, membranes develop vasculature with increased thickness and caliber. These membranes are less VEGF dependent and less responsive to anti-VEGF therapy.
These basic science observations prompted investigators from the VISION trial to perform an post hoc analysis of eyes with newer onset exudative AMD.2 The concept was that eyes with less mature membranes might be more responsive to anti-VEGF therapy with pegaptanib. In one analysis, eyes with lesions that were smaller than two disc areas in size; had a baseline visual acuity of 54 letters or more; and did not have prior PDT, thermal laser, scarring or atrophy were considered to be “early lesions.” A second analysis defined “early lesions” as those having occult CNV without lipid and a baseline visual acuity in the fellow eye that was better than that in the study eye. Subset analysis of these eyes demonstrated enhanced efficacy of pegaptanib therapy. Eyes in the second analysis demonstrated a responder rate of 80%, a 67% rate of visual gain, and a 20% gain of three lines or more.
An independent group of investigators lead by Polly Quiram, MD, PhD, performed a retrospective analysis of 90 patients with newly diagnosed lesions that were treated with pegaptanib.3 These investigators found that initial response in these eyes was significantly better than that in the entire group from the VISION trial, with a responder rate of 90% and visual improvement in 20% of eyes.
The VISION trial established the efficacy and safety of pegaptanib in the treatment of exudative AMD. Clinical utilization after the trial and post-trial analyses4 demonstrates that the exact correlation of visual and anatomic response to pegaptanib is often challenging. In addition, multiple studies have demonstrated enhanced efficacy when pegaptanib is used in eyes with early lesions.
Use of this anti-VEGF approach to AMD greatly benefits patients with AMD. Continued experience with pegaptanib may result in the development of strategies that maximize safety and efficacy and provide patients with even more benefit. An ongoing study called Perspectives will compare early treatment with late treatment with pegaptanib in patients with wet AMD. The study, which is taking place in Europe and Canada will also evaluate other parameters of efficacy, such as ability to read and psychiatric parameters.
References
- Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.
- The VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group. Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis. Retina. 2005;25:815-827.
- Quiram PA. Hassan TS, Williams GA. Vision gainers after early treatment of CNV with Macugen. Abstract presented at: Retina 2005; Jan. 15-20, 2006. Wailea, Hawaii.
- D’Amico DJ for the VISION Clinical Trial Group. Results of the second year of Macugen for the treatment of neovascular AMD (VISION). Abstract presented at: American Society of Retinal Specialists Meeting; July 16-20, 2005. Montreal.