My colleagues and I conducted a phase 1, multicenter, two-dose level comparison, safety, tolerability, and bioeffect study of intravitreal antivascular endothelial growth factor (VEGF Trap-Eye; Regeneron Pharmaceuticals, Tarrytown, NY) in patients with neovascular age-related macular degeneration (AMD).1
VEGF Trap-Eye is a fusion protein of key domains from human receptors 1 and 2 combined with a human IgG Fc fragment and contains all human amino acid sequences. The fusion protein has a high affinity for and binds VEGF more tightly than naive receptors of monoclonal antibodies. The agent blocks all VEGF-A isoforms as well as placental growth factors. In preclinical studies, VEGF Trap-Eye was found to penetrate all retinal layers and prevent development of abnormal blood vessels in animal models of diabetic retinopathy and AMD. Preclinical data also showed that the agent inhibited the growth of new blood vessels when given intravenously, as well as when administered directly into the eye.2
In the second part of the phase 1 CLEAR-IT study, we administered a single intravitreal injection of 0.15 mg or 4 mg of VEGF Trap-Eye to 30 patients with neovascular AMD at day 0. The patients had lesions of any angiographic subtype ≤12 disc areas and BCVA of 20/40 to 20/320 (as per Early Treatment of Diabetic Retinopathy Study [ETDRS] protocol). Safety was assessed with eye examinations, vital signs, and laboratory tests. To measure bioactivity of VEGF Trap-Eye, we performed BCVA, optical coherence tomography (OCT), fluorescein angiography (FA), or clinical criteria.
We found no serious adverse events and no identifiable intraocular inflammation in treated patients. The ocular adverse events were typical of those seen in studies with intravitreal drug administration and did not differ between the two groups.
The analyses we performed at 8 weeks on the first 24 patients who completed the study showed a mean decrease in OCT central retinal/lesion thickness of 67.3 µm for the low-dose group (0.15 mg) and 175 µm for the high-dose group (4 mg) (P=.05). Follow-up injections within 1 week of the 8-week endpoint were administered to 60% of patients assigned to the low-dose group and in 22% of the patients assigned to the high-dose group.
Intravitreal injection of up to 4 mg of VEGF Trap-Eye was well tolerated, and no evidence of ocular inflammation was detected. Although the 0.15- and 4-mg doses intially were comparable in terms of their effectiveness of reducing retinal thickness shown on OCT, the duration of the effect appeared to be longer with the higher dose. This duration of effect resulted in a statistically significant difference between the two groups at week 8.
Fewer patients in the high-dose group required retreatment within 1 week of the study's 8-week endpoint based on objective criteria. The results of this study suggest that higher doses of VEGF Trap-Eye may result in more prolonged suppression of retinal fluid and greater increase in visual acuity among patients with neovascular AMD.
Regeneron is currently conducting a phase 2 study of the VEGF Trap-Eye in patients with neovascular AMD; a small pilot study in diabetic macular edema is also ongoing.
Quan Dong Nguyen, MD, MSc, is Assistant Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine. He may be reached at qnguyen4@jhmi.edu.
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