Anti-VEGF Agents

PEGAPTANIB

The preclinical data suggesting that VEGF165 was especially pathogenic, and that its inhibition with pegaptanib could reverse BRB breakdown, provided the basis for a proof-of-concept Phase 2 double-masked, multicenter, randomized, controlled trial enrolling 172 patients with DME (105). Patients received intravitreous pegaptanib (0.3 mg, 1 mg, or 3 mg) or sham injections at study entry, Week 6, and Week 12, with additional injections and/or focal photocoagulation given at the investigator’s discretion through 30 weeks; final assessments were made 6 weeks later. In this dose-ranging study, no additional benefit was conferred at doses above 0.3 mg. This dose proved significantly superior to sham for all prespecified endpoints (median visual acuity, change in mean central retinal thickness, and need for photocoagulation therapy), and the drug was well-tolerated (105).

In a subsequent retrospective analysis of 16 patients who entered the trial with retinal neovascularization, 8 of 13 who received pegaptanib showed complete regression of neovascularization or regression at 36 weeks (106). None of the three patients with neovascularization in the sham group and none of four with neovascularization in the fellow eye showed complete regression. Among the eight patients whose neovascularization regressed with pegaptanib, three experienced progression at Week 52 following pegaptanib cessation at Week 30 (106). Similar encouraging results, demonstrating regression in response to pegaptanib treatment, have since been reported in an open-label case series in patients with high-risk proliferative DR (107).

RANIBIZUMAB AND BEVACIZUMAB

Ranibizumab and bevacizumab, two nonselective agents that bind all VEGF isoforms, have been studied in small-scale trials as intravitreous treatments for DR and DME. Ranibizumab, a humanized antibody fragment engineered for high-affinity binding to VEGF (108), has been examined in two pilot open-label studies, each involving 10 patients with DME (109, 110). Both studies reported improvements in visual acuity and reductions in macular thickness; Nguyen et al. (109) reported no adverse events, while Chun et al. (110) encountered five cases of mild to moderate ocular inflammation.

Bevacizumab, a full-length monoclonal antibody related to ranibizumab that is approved for treatment of cancer (108), was shown to be effective in small studies in inducing regression of iris (111) and retinal (112) neovascularization in patients with DR. In a case series involving patients with retinal and/or iris neovascularization, all 44 eyes with angiographically defined neovascularization that were treated with intravitreous bevacizumab (with doses ranging from 6.2 g to 1.25 mg) showed a reduction in leakage within 1 week of injection; complete resolution of leakage was seen in 9 of the 11 cases of iris neovascularization and in 19 of 26 cases involving neovascularization of the disk (113). In two patients receiving 1.25 mg, there was also some decrease in the leakage of retinal or iris neovascularization of the untreated fellow eye, indicating that systemic exposure may have occurred (113).

These findings suggest that strategies targeting VEGF hold promise in treating DR and DME. Both pegaptanib and ranibizumab are clinically approved reagents for neovascular age-related macular degeneration after demonstrating acceptable tolerability