Association of serum neutralizing antibodies with safety and efficacy outcomes in a Phase 2a trial of rAAV.sFlt-1 in the treatment of wet AMD

Abstract

Purpose : Purpose: To explore relationship between safety and efficacy outcomes and immunological status following subretinal rAAV.sFlt-1 injection at one year post-treatment.

Methods : Subjects were randomized to receive subretinal rAAV.sFlt-1 (10E11vg, n=21) or control (n=10). All subjects were able to receive intravitreal ranibizumab (RBZ) retreatment according to protocol-driven criteria for worsening wet AMD. Ophthalmic safety, immune response to AAV2, and routine laboratory safety tests were assessed.

Results : No serious adverse events (AE) related to rAAV.sFlt-1 were observed at one year. Transient AEs were: subretinal hemorrhage, inflammation, and increased IOP. Ten of eleven phakic subjects developed post vitrectomy cataract which was treated by extraction and lens implantation. In the rAAV.sFlt-1 treated group the mean BCVA increased by +2.2 ETDRS letters and mean CPT increased by +27μm from baseline (BL). Eleven of 21 rAAV.sFlt-1 treated subjects required ≤2 RBZ rescue injections. Of these, 10 had AAV2 neutralizing antibodies (nAb) present at BL. For these 11 subjects, mean CPT remained unchanged (BL 338μm vs 1 yr 343μm) and mean BCVA increased by +6.7 ETDRS letters. The rAAV2.sFlt-1 treated subjects requiring >2 RBZ injections (n=10) lost a mean of -2.7 ETDRS letters, while mean CPT increased by +51μm (BL 406μm vs 1 yr 456μm), and two had nAb present at BL. Controls showed a mean -9.3 ETDRS letter loss and -85μm CPT decrease (BL 418μm vs 1 yr 333μm). They received a mean of 3.6 (median=4) rescue RBZ injections compared to a mean of 3.1 (median=2) injections for the rAAV.sFlt-1 treated group. Three controls had nAbs present at BL. Of the 21 rAAV.sFlt-1 treated subjects, 5 demonstrated transient and 3 showed sustained increases in nAb titer.

Conclusions : In this phase 2a study, subretinal rAAV.sFlt-1 was well-tolerated with a favorable safety profile. At one year following rAVV.sFlt-1, a subset of subjects had encouraging signs of a response with vision gain and fewer injections received while mean foveal thickness showed minimal change. Presence of pre-existing serum neutralizing antibodies did not appear to affect clinical outcomes.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.