Phase II study results of fusion protein support moving to phase III

April 15, 2008

Outcomes of fluorescein angiography and optical coherence tomography show that patients who received intravitreal injections of a fusion protein (VEGF Trap-Eye, Regeneron Pharmaceuticals) had reductions in retinal thickness, lesion size, and area of choroidal neovascularization. These results support positive visual acuity findings in the same group of patients.

Key Points

Indian Wells, CA-The angiographic and anatomic outcomes from a phase II study of repeated intravitreal injection of three dose levels of a fusion protein at two different intervals support the positive visual changes found in the trial and provide additional support for conducting a phase III trial, said Jason S. Slakter, MD, in a presentation here at the annual meeting of the American Society of Retina Specialists.

The fusion protein (VEGF Trap-Eye, Regeneron Pharmaceuticals) binds all forms of vascular endothelial growth factor-A (VEGF-A) as well as placental growth factor (PLGF). Both VEGF-A and PLGF are proteins that are involved in the abnormal growth of new blood vessels.

Optical coherence tomography (OCT), color fundus photography, and digital fluorescein angiography confirmed reductions in retinal thickness, lesion size, and total area of choroidal neovascularization (CNV) in approximately 150 patients with neovascular age-related macular degeneration in the CLEAR-IT 2 study. Patients were randomly assigned to one of five treatment arms: 0.5 mg every 4 weeks, 2 mg every 4 weeks, 0.5 mg every 12 weeks, 2 mg every 12 weeks, or 4 mg every 12 weeks. Primary and secondary endpoints were measured at week 12; re-dosing occurred at that time.

In the CLEAR-IT 2 study, investigators initially measured central retinal lesion thickness manually and saw a marked and sustained reduction in central retinal thickness and subretinal fluid across the course of the trial, Dr. Slakter said. In a comparison of dosing intervals, patients who received injections of the agent every 12 weeks experienced an initial decline followed by a gradual increase in retinal thickening in both low-dose and high-dose groups. A sustained reduction throughout the entire period, also in both treatment groups, was observed in patients who received injections every 4 weeks.

Because clinicians don't perform this type of time-consuming manual measurement in their offices, Dr. Slakter and colleagues also used mean change in foveal thickness as determined by OCT (Stratus, Carl Zeiss Meditec) to evaluate treatment outcomes.

"Again, the data showed a rapid and consistent, sustained reduction in central foveal thickness as determined by the automated software," he said, adding that the manual and automatic results were very similar.

Angiographic data

Dr. Slakter also discussed the fluorescein angiography data. "There was a reduction in the overall size of the total lesion for all patients. If we break it down, looking at those treated on an every-12-week basis with a single injection, you have a sustained reduction in total lesion size for about 8 weeks and an overall sustained reduction in the monthly therapy arm through the entire course of the follow-up," he said.

In addition, a rapid drop in active CNV area with a sustained effect was seen over 8 weeks in the 12-week dosing groups and a sustained and persistent effect in the every-4-week dosing groups.

A rapid decline in the area of classic neovascularization was observed as well. This decline was persistent for 8 weeks in the 12-week dosing strategy groups and through the entire period in those treated every 4 weeks.

"We can conclude that we've seen visual acuity improvement, which is sustained for a period of at least 8 weeks in all dose groups," Dr. Slakter said. "We also saw that if you look at the OCT, you have a reduction in central retinal lesion thickness, which again is generally reduced over the course of 8 weeks. And finally, we have fluorescein angiographic confirmation that anatomically we have a similar effect, with reduction in the angiographic parameters of the lesion and CNV size, which is persistent and sustained in all those groups for at least 8 weeks." These findings merit further evaluation of the fusion protein in a phase III, randomized, controlled trial, he added. The phase II trial currently is recruiting.