A reliable system of continuous anti-vascular endothelial growth factor (VEGF) delivery has the potential to greatly reduce the high treatment burden of monthly eye injections for patients with neovascular age-related macular degeneration (nAMD) and their caregivers. Now, with the Ladder phase 2 trial for a port delivery system (PDS) of ranibizumab now complete, researchers say such an option can maintain both visual acuity and central foveal thickness (CFT), suggesting strong long-term efficacy.
“The benefit is huge, as outcomes are equivalent to monthly gold-standard ranibizumab injections,” said Arshad Khanani, MD, director of clinical research at Sierra Eye Associates, and clinical associate professor at the University of Nevada, Reno and lead author on the study. “PDS can address the unmet need of durability, as well as the treatment burden from frequent injections and visits which leads to non-compliance and vision loss in the real world.”
Dr. Khanani and fellow investigators affirm that continuous VEGF suppression may achieve better long-term outcomes in treating nAMD. The multicenter phase 2 clinical trial measured vision and anatomical outcomes, as well as local and systemic safety.
In total, 220 patients at 49 sites in the United States were randomized into 4 groups; PDS filled with ranibizumab 10 mg/mL, 40 mg/mL, 100 mg/mL, or a control group who received monthly intravitreal ranibizumab 0.5 mg injections. Participants selected were diagnosed with nAMD in the preceding 9 months, and displayed benefit from initial anti-VEGF therapy. Total length of the study was 38 months, and the mean time for PDS participation was 22.1 months.
PDS is a permanent, refillable implant placed by an ophthalmic surgeon in the operating room. Ranibizumab is released continuously into the vitreous through passive diffusion. “The flange rests at the ocular surface under the conjunctiva,” Dr. Khanani explained. “It has a septum through which refill-exchange is performed in the office under topical anesthesia.”
During the trial’s monthly monitoring, if CFT increased or if best-corrected visual acuity (BCVA) decreased by a specified threshold, or a new macular hemorrhage occurred, the need for a refill-exchange was triggered. The median time to first refill was 8.7 months in the PDS 10 mg/mL group, 13.0 months for those receiving 40 mg/mL, and 15.8 months in the 100 mg/mL arm. Further, for subjects receiving the 100 mg/mL dose who received at least 1 refill, the median time from first to second refill was 8.8 months.
Investigators observed a dose-related response with respect to BCVA and CFT at month 22, including the following:
- Baseline vision was maintained in 57.7% of subjects receiving PDS 10 mg/mL, 80.0% in the 40 mg/mL group, and 87.5% with a 100 mg/mL dose.
- Baseline vision was maintained in 88.9% for those receiving monthly intravitreal injections.
- Mean CFT change from baseline measured -0.7 μm in the 10 mg/mL group, -20.9 μm for the 40 mg/mL dose, and -4.0 μm in the 100 mg/mL group.
- Mean CFT change from baseline was -10.9 μm in the monthly injection group.
Because PDS involves implantation, post-surgical adverse events were observed in a number of subjects. These included mild-to-moderate vitreous hemorrhage, cataract, rhegmatogenous and tractional retinal detachment, endophthalmitis, hyphema, and conjunctival effects.
“Most of the risks are associated with conjunctival erosion and retraction and they can be mitigated with good surgical technique,” Dr. Khanani added. As the Ladder trial concluded, 96.6% of eligible participants enrolled in the ongoing Portal extension study.
In the subjects who had their implants removed, investigators found no signs of implant clogging. Limitations of the trial included the variable length of time for which subjects participated, and the smaller sample size of phase 2. “Rates of macular atrophy were similar between all 4 study arms, indicating no increase in macular atrophy with PDS,” Dr. Khanani explained. He and fellow researchers advise further exploration of macular atrophy rates in a larger population sample.
Dr. Khanani noted that the port was generally well tolerated by patients, and the systemic safety was close to equal with monthly intravitreal injections. “Overall, it is a good option for most patients who don’t want (monthly) injections,” he said.
Disclosure: Several study authors declared affiliations with the biotech and pharmaceutical industries. Please see the original reference for a full list of authors’ disclosures.
Khanani A, Callanan D, Dreyer R, et al., End of study results for the ladder phase 2 trial of the port delivery system with ranibizumab for neovascular age-related macular degeneration. Ophthalmol Retina. Published online November 18 2020. doi: https://doi.org/10.1016/j.oret.2020.11.004.