Fusion protein results promising

Boston-A unique fusion protein (VEGF Trap-Eye, Regeneron/Bayer HealthCare) is being studied to treat age-related macular degeneration (AMD), diabetic macular edema (DME), and macular edema secondary to central retinal vein occlusion (CRVO). Currently, phase II data among a representative cohort of patients are only available in wet AMD. Phase III results in wet AMD and CRVO and phase II data in DME are expected this year and thereafter.

"With currently available vascular endothelial growth factor [VEGF] inhibitor therapy, the [conditions of the] large majority of patients with exudative disease are stable, with 30% to 40% having significant recovery of vision," he said.

The agent is an "interesting" protein composed of key domains from human VEGF1 and VEGF2 and blocks all VEGF-A isoforms and placental growth factor, which may translate into differential activity. It also blocks VEGF-A with higher affinity than native receptors, he said.

AMD

The fusion protein has been under study in the CLEAR-IT 2 Study, a phase II study with two parts. The first was a fixed-dosing phase designed to assess the efficacy and safety of the drug in patients with neovascular AMD. Patients were treated with the assigned doses (0.5 or 2 mg monthly and 0.5, 2, or 4 mg quarterly) for 3 months and then received p.r.n. dosing based on the initial dose assignments from 4 to 12 months. The second phase of the study is an ongoing rollover into an open-label extension study of 2-mg p.r.n. dosing. Results are available from the extension study for a total of 24 months.

Of the 157 patients enrolled at baseline, the mean change in the best-corrected visual acuity (BCVA) was +5.3 letters at 1 year. Of the 117 patients who went on to the extension study, the mean change in BCVA from baseline was +8.4 letters at 1 year and +7.1 letters at 18 months.

An important point, Dr. Heier said, is that the overall increase in VA was sustained out to 24 months with p.r.n. dosing.

The safety profile of the drug generally was consistent with what has been reported with other available agents for the treatment of wet AMD, with most events being related to the injection procedure into the eye. One case of culture-negative endophthalmitis developed that was not related to the study drug. The systemic adverse events (five deaths from pulmonary hypertension, pancreatic carcinoma, and squamous cell lung cancer) also were not related to the drug.

Patients treated with the fusion protein therapy required an average of two additional injections during the 9-month p.r.n. dosing phase and during the extension study the patients needed an average of 3.5 additional injections over months 4 through 18.

"Clinically significant improvements were achieved and maintained over a p.r.n. dosing phase and the drug was well tolerated," Dr. Heier said.

Phase III studies

The phase III studies-VIEW 1 and VIEW 2, each consisting of about 1,200 patients-are ongoing and fully enrolled. In these studies, the fusion protein (0.5 or 2 mg every 4 weeks and 2 mg every 8 weeks) is being evaluated in 4- and 8-week dosing intervals, and the drug is being compared with ranibizumab given every 4 weeks for 1 year. During the second study year, patients are followed monthly with a p.r.n. regimen, with a required treatment at least every 3 months.

DME

A phase II study of the fusion protein for DME is under way and fully enrolled (n = 200). The study has five treatment arms: fusion protein 0.5 and 2 mg every 4 weeks, fusion protein 2 mg every 8 weeks and 2 mg p.r.n., and focal laser treatment. Results are expected mid-year.

Macular edema secondary to CRVO

The COPERNICUS and GALILEO studies are phase III trials of the fusion protein for CRVO. The studies began to enroll patients (n = 165) in the second half of 2009. Patients are randomly assigned 3:2 to the fusion protein 2 mg every 4 weeks or sham treatment for 24 weeks. The primary endpoint is the proportion of patients who gain three lines of vision and the secondary endpoint is the change in the central retinal thickness on optical coherence tomography. At the end of 6 months, all patients will be treated with the fusion protein on a p.r.n. schedule.

"These are all exciting programs," Dr. Heier concluded. "As an investigator and a clinician, I am anxious to see the results of these studies in AMD, DME, and CRVO."

FYIJeffrey S. Heier, MD
E-mail: jsheier@eyeboston.com

Dr. Heier is an investigator and consultant to Regeneron.