Neil Osterweil

May 06, 2011

May 6, 2011 (Fort Lauderdale, Florida) — An experimental fusion protein was safe and was associated with statistically significant improvements in visual acuity and other parameters, compared with sham injections, in patients with macular edema secondary to central retinal vein occlusion, and also showed efficacy in neovascular age-related macular degeneration, according to investigators here at the Association for Research in Vision and Ophthalmology 2011 Annual Meeting.

VEGF Trap-Eye (Regeneron and Bayer Health) is an intravitreally delivered fusion protein designed to bind to all forms of vascular endothelial growth-factor (VEGF) A and to placental growth factor.

Six-month follow-up results from the phase 3 COPERNICUS (Controlled Phase 3 Evaluation of Repeated Intravitreal Administration of VEGF Trap-Eye In Central Retinal Vein Occlusion: Utility and Safety) trial showed that 56.1% of patients who received the protein gained at least 3 lines of visual acuity (15 or more letters), compared with 12.3% of control subjects who received sham injections (< .0001). The difference between the groups was 43.8% (< .0001), reported Julia A. Haller, MD, ophthalmologist-in-chief at the Wills Eye Institute in Philadelphia, Pennsylvania.

Also presented at the meeting was an analysis of pooled 1-year data from the VIEW (Vascular Endothelial Growth Factor Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration) 1 and 2 trials. Those data showed that a 2 mg dose of the fusion protein injected every 2 months was comparable to once-monthly injections of ranibizumab (Lucentis), and clinically equivalent to once-monthly dosing of the fusion protein, reported Ursula Schmidt-Erfurth, MD, from the Medical University of Vienna, Austria.

COPERNICUS

COPERNICUS was a randomized double-masked trial of 189 treatment-naïve patients with macular edema secondary to central retinal vein occlusion, with central retinal thickness above 250 μm. Disease duration was less than 9 months, and patients had an Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity of 20/40 to 20/320.

A total of 115 patients were assigned to receive 2 mg intravitreal injections of the compound every 4 weeks for 24 weeks, and 74 patients were assigned to received sham injections. The primary end point was the proportion of 3-line visual acuity gainers at 24 weeks. From week 24 on, all patients continued on treatment on an as-needed basis to 1 year.

In addition to the improvements in visual acuity, the fusion protein was associated with a significantly greater decrease in central retinal thickness, at a mean change of –457.8 μm at week 24, compared with –144.8 μm for control subjects (< .001).

"When we look at the percentage of eyes with anterior segment neovascularization at week 24, we see that in the sham-treated group, 6.8% develop neovascular changes in the anterior segment, [compared with] 0% in the drug-treated eyes," Dr. Haller said.

Quality-of-life measures on the National Eye Institute Visual Function Questionnaire, including overall scores and the subcategories of near and distance vision and dependence, were significantly better among patients who received the fusion protein.

Ocular adverse events occurred in 10 (13.5%) of control subjects and in 4 (3.5%) of drug-treated patients. Vitreous hemorrhage occurred in 4 sham-treated subjects and in 0 patients treated with the fusion protein. Similarly, there were 2 cases of neovascular glaucoma, 2 cases of iris neovascularization, and 2 cases of retinal hemorrhage in the control group, but no cases in the drug group.

In contrast, there was 1 case of endophthalmitis and 1 corneal abrasion in the drug group, but none in the control group. There were 2 deaths, both in the sham group: a 74-year-old man died of an arrhythmia 54 days after his last injection; and a 64-year-old woman had an acute myocardial infarction 3 days after her last injection.

2 VIEWS

In both VIEW trials, patients (1217 in VIEW 1 and 1240 in VIEW 2) were randomly assigned to the fusion protein at doses of 2.0 or 0.5 mg every 4 weeks or 2 mg every 8 weeks, or ranibizumab 0.5 mg every 3 weeks.

The primary outcome was maintenance of vision; the secondary end point was mean change in best-corrected visual acuity.

The investigators found that all dose regimens of the fusion protein were statistically noninferior to ranibizumab, with about 95% of patients in each group having a loss of not more than 14 letters over baseline. Similarly, about one third of patients in the ranibizumab and all fusion protein groups had a visual acuity gain of 15 or more letters after 1 year. About 5% of patients in each group gained 30 or more letters.

Changes in mean retinal thickness were also similar among the groups, as was the pattern of anatomical change, with most of the decrease coming in the first 4 weeks, followed by a much more gradual and slight thinning.

Safety data showed low rates of endophthalmitis, all-cause mortality, and primary cardiovascular events, Dr. Schmidt-Erfurth noted.

"Hypertension is one of the most sensitive indicators of systemic anti-VEGF action, and there was no difference among any treatment arm with regard to that parameter," she added.

A retinal specialist who was not involved in trials of the fusion protein said that the drug is emerging as a promising potential addition to the therapeutic arsenal for the wet type of age-related macular degeneration.

"It seems to be equally efficacious as ranibizumab or bevacizumab, and it looks like it can be given at less frequent intervals. From all the data so far, it looks like it will be an attractive alternative," said Ivana K. Kim, MD, from the Retina Service at the Massachusetts Eye and Ear Infirmary, and an assistant professor of ophthalmology at Harvard Medical School, both in Boston.

Dr. Haller reports receiving consulting fees from Genentech in the past, but no longer has a financial relationship with the company. Dr. Schmidt-Erfurth reports being a consultant to and/or doing contract research for Alcon, Bayer Healthcare, and Novartis. Dr. Kim reports serving as an investigator for clinical trials for Eyetech Pharmaceuticals, Alcon, and Genentech.

Association for Research in Vision and Ophthalmology (ARVO) 2011 Annual Meeting: Abstract 1650, presented May 2, 2011; abstract 6643; presented May 3, 2011.

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