248. Results of a Phase 1 and 2a Trial on rAAV. sFlt-1 in Treatment of Wet Age-Related Macular Degeneration

Purpose: To assess safety following subretinal rAAV.sFlt-1 injection at one year. Secondary endpoints were assessed for evidence of biologic activity. Methods: Under the protocol, Phase 1 followed a dose escalation design where eligible subjects received subretinal injection of low dose (LD, N=3, 10E10 vg) and high dose (HD, N=3, 10E11 vg) rAAV.sFlt-1, or control regimen (N=2). In Phase 2a eligible subjects were randomized to receive HD (N=21) rAAV. sFlt-1 or control regimen (N=11). All 40 subjects were assessed using ophthalmic exam and laboratory testing, and received intravitreal ranibizumab retreatment according to protocol-driven criteria for worsening wet Age-related Macular Degeneration (AMD). Results: During the 1-year follow-up to the primary endpoint, no serious adverse events related to rAAV. sFlt-1 were observed. However, transient adverse events such as subretinal hemorrhage, inflammation, and increased intraocular pressure were reported. One LD subject and 11 HD subjects were phakic at baseline; following subretinal injection with vitrectomy all of these subjects experienced cataract progression which was operated by month 10. In the control group, 13 subjects received a mean 3.5 (median 4, range 0-5) ranibizumab retreatments, and had a change in mean Best Corrected Visual Acuity (BCVA) of -8.4 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and a decrease in mean retinal Center Point Thickness (CPT) from 450 µm at baseline (BL) to 355 µm. Subjects in the LD group received a mean 0.33 (median 0, range 0-1) ranibizumab retreatments, and had a mean vision gain of 8.7 ETDRS letters and decreased mean CPT from 449 µm to 315 µm. Retreatment outcomes in the HD group suggested a bimodal distribution: 14 subjects received ≤ 2 ranibizumab retreatments (HD. 1 subgroup) with a mean vision gain of 6.6 ETDRS letters and a mean CPT decrease from 406 µm to 360 µm, and 10 HD subjects received ≥ 3 ranibizumab retreatments (HD. 2 subgroup) with a mean vision change of -2.7 ETDRS letters and increase mean CPT from 407 µm to 456 µm. At BL, serum neutralizing antibodies to AAV were detected in 5/13 (38%) controls, 1/3 LD group (33%), 11/14 HD. 1 subgroup (77%) and 2/10 (20%) HD. 2 subgroup. Five HD group subjects who were seronegative at BL seroconverted after rAAV.sFlt-1 therapy. Conclusions: Subretinal rAAVsFlt-1 was well-tolerated with a favorable safety profile in subjects with wet AMD. Encouraging signs of a response with vision gain and fewer ranibizumab retreatment were observed in the majority of the subjects. Serum neutralizing antibodies to AAV prior to treatment did not adversely affect clinical outcomes.