The Port Delivery System with Ranibizumab for nAMD: Results from the Phase 2 LADDER Study
September 2019
Campochiaro PA, Marcus DM, Awh CC, et al. The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial. Ophthalmology. 2019 Aug;126(8):1141-1154
Intravitreal anti-vascular endothelial growth factor (VEGF) therapy has revolutionized the treatment of neovascular age-related macular degeneration (nAMD). Despite the remarkable success of anti-VEGF, the frequency of intravitreal injections places a high treatment burden on patients.
The Phase 2 LADDER Clinical Trial investigated the Port Delivery System (PDS), a surgically-implanted, long-acting intraocular delivery system for ranibizumab. The PDS includes a reservoir that can be refilled in the office.
This study enrolled nAMD patients with visual acuity ≥ 20/200 and a positive treatment response to any anti-VEGF agent. Different concentrations of PDS ranibizumab were evaluated, and patients were randomized 3:3:3:2 to treatment with PDS formulations 10-mg/mL, 40-mg/mL, 100-mg/mL or monthly ranibizumab 0.5mg injections.
220 patients were included for analysis. The primary outcome measure was time to first implant refill. The mean time to first refill for all PDS patients was 16.8 months. Between treatment arms, the median time to first refill was 8.7, 13.0 and 15.0 months in the 10-mg/mL, 40-mg/mL, and 100-mg/mL arms respectively. At month 9, the mean BCVA change from baseline in the PDS 10-mg/mL, 40-mg/mL, and 100-mg/mL arms were -3.2, -0.5, +5.0 ETDRS letters respectively. At month 9, the mean BCVA change from baseline in the monthly ranibizumab group was +3.9 ETDRS letter. PDS 100 mg/mL was found to be non-inferior to monthly ranibizumab at 9 months.
In the PDS groups, serious ocular adverse events (AEs) were reported in 16 of 179 patients (8.9%). The most frequent serious AE was vitreous hemorrhage. Initially, vitreous hemorrhage occurred in 11 of the first 22 PDS patients (50%) but the surgical technique was modified to incorporate pars plana laser ablation at the incision site, and the incidence of vitreous hemorrhage decreased to 4.5% (7 of 157) with the modified procedure. There were 3 cases of endophthalmitis and 4 reported rhegmatogenous retinal detachments in PDS-treated patients.
In the LADDER trial, a dose-response was observed across the PDS treatment arms. The greatest clinical benefit was seen in the PDS 100-mg/mL arm where the median time to first refill was 15.0 months, and 79.8% of patients went 6 months or more before requiring their first refill. PDS patients received 80% fewer ranibizumab treatments compared to the monthly intravitreal injection group. The authors point to the comparable vision and OCT outcomes between patients receiving PDS 100-mg/mL and monthly ranibizumab to support that a decreased treatment burden can be achieved without sacrificing clinical efficacy.
The results of LADDER offer support for continuous ranibizumab delivery to decrease treatment burden in nAMD. Future applications may include sustained-release therapy for other VEGF-mediated diseases such as diabetic retinopathy and retinal vein occlusion. However, the surgically implanted device also exposes patients to unique risks inherent to vitreoretinal surgery.
