Samir Patel, MD
Vitreoretinal Surgery Fellow
Wills Eye Hospital/Mid Atlantic Retina
Drs. Deeba Husain and Vaidehi Dedania moderated this information packed session.
Dr. David Boyer reported outcomes of the Phase II INFINITY study. Based on the promising findings of the OPTIC study evaluating patients with neovascular AMD, the Phase II INFINITY enrolled 34 patients in 3 arms (aflibercept, low dose ADVM-022 [2×1011 vg/eye], and high-dose ADVM-022 [6×1011 vg/eye]) to evaluate the safety, efficacy, and durability of ADVM-022 in patients with diabetic macular edema (DME). The primary endpoint was the time to worsening DME, measured at week 24, and the trial found that 89% of eyes in the control group required rescue aflibercept injections versus 25% and 39% of eyes in the high dose and low dose groups, respectively (p=0.042). Central subfield thickness (CST) improved across all three arms.
From a safety perspective, INFINITY was unmasked due to unexpected adverse ocular events as nearly all of the ADVM-022 treated patients developed dose-dependent anterior and posterior inflammation. Furthermore, nearly all patients receiving gene therapy required steroids by multiple administration routes (ocular, intraocular, oral, or systemic) beyond the 10-week prophylactic period. In three patients, there was severe hypotony with persistent IOP less than 5 mmHg, which necessitated surgical intervention including pars plana vitrectomy, fluocinolone acetonide intravitreal implant insertion, and silicone oil placement. Currently, the etiology and mechanism underlying this dose-limiting toxicity is unknown and remain an avenue for future investigations.
In the second presentation, Dr. Robert Avery, reported data on the subretinal RGX-314 gene therapy trials along with an update on the suprachoroidal delivery trials. RGX-314 uses a AAV8 vector to deliver anti-vascular endothelial growth factor (anti-VEGF) Fab via a subretinal or suprachoroidal approach.
The RGX-314 phase I/IIa dose-escalating trial using a subretinal approach enrolled 42 patients. Most patients enrolled had been receiving treatment for at least four years and typically required over 9 injections in the year prior to enrollment. The mean best-corrected visual acuity (BCVA) was stable to improved in the study cohorts across the two years, and the higher dose cohorts gained more vision. Subretinal RGX-314 was well-tolerated across all doses, and there were no reports of clinically determined immune responses or drug-related ocular inflammation. There was a significant reduction in the retreatment rate with a roughly 60% reduction in the lower dose cohorts and 80% in the higher dose cohorts. Two-year data showed that the RGX-314 protein production level was maintained throughout the study. The promising results of this study have led to the enrollment of the first pivotal clinical trial called ATMOSPHERE with plans for a second pivotal trial by the end of 2021.
Dr. Avery also touched on the AAVIATE Phase II trial evaluating the suprachoroidal delivery of RGX-314 for nAMD, which enrolled 50 patients with dose escalation. Vision was stable at month 6 in the RGX-314 group with a small difference in visual acuity compared to the monthly ranibizumab group. Notably, there was an over 70% reduction in treatment burden in the suprachoroidal treatment group. Furthermore, there was a similar incidence of intraocular inflammation observed among cohorts with dose escalation and events were mild and resolved with topical corticosteroids.
Similarly, the ALTITUDE Phase II trial evaluated the suprachoroidal delivery of RGX-314 for diabetic retinopathy without active DME and enrolled 20 patients with dose escalation. The primary endpoint was a greater than 2 step improvement in ETDRS-DRSS in patients receiving the RGX-314 compared to observation. In general, RGX-314 was well-tolerated without any significant intraocular inflammation and did not require any prophylactic corticosteroid administration. In the 15 RGX-314 treated eyes, 33% achieved a greater than 2 step improvement in DRSS at 3 months. Currently, ALTITUDE is on-going and is enrolling for the dose escalation portion of the study for Cohorts 2 and 3.
For both AAVIATE and ALTITUDE, these results are promising given the ability to provide a durable anti-VEGF treatment via an in-office procedure compared to the subretinal approach, which requires a surgical intervention.
Dr. Charlies Wykoff then reported on outcomes of the Phase 3 DERBY and OAKS trials, evaluating the treatment of geographic atrophy secondary to age-related macular degeneration with pegcetacoplan. Pegcetacoplan functions via the complement system with inhibition of C3 as well as downstream C5. In these studies, patients with foveal and extrafoveal GA were randomized to: 1) intravitreal pegcetacoplan monthly, 2) intravitreal pegcetacoplan every other month, 3) sham monthly, or 4) sham every other month. The primary endpoint at 12 months was change in GA lesions as seen on autofluorescence imaging. For the OAKS study, the primary endpoint was met as the rate of GA progression was reduced by 22% in the monthly arm and 16% in the every other month arm, both of which were statistically significant. However, in the DERBY study, the primary endpoint was not met as the rate of GA progression was reduced by 12% in the monthly arm and 11% in the every other month arm, which was not statistically significant. Multiple reasons for inconsistencies between the DERBY and OAKS trials were provided including regional differences in enrollment and differences in baseline demographic/clinical characteristics such as lesion type.
The combined data showed that pegcetacoplan administered monthly and every other month was well tolerated with rates of intraocular inflammation of 2% in the monthly arm and 1% in the every other month arm. The majority of cases were mild and most patients resumed intravitreal pegcetacoplan administration. Furthermore, 6% and 4% of patients developed new-onset investigator determined neovascular AMD in the combined monthly arm and every other arm, respectively.
Based on the study findings of DERBY and OAKS, pegcetacoplan may become the first treatment option for geographic atrophy, and FDA submission is planned for the first half of 2022.
Dr. Arshad Khanani reported data from MERLIN, a phase 3a trial of brolucizumab in patients with neovascular AMD and persistent retinal fluid. The study evaluated continuous q4 week intravitreal brolucizumab compared to aflibercept in patients with nAMD and persistent retinal fluid despite frequent anti-VEGF treatment. In general, these patients had received their first anti-VEGF injection at least 9 months prior to screening and received over 7 injections within the past 9 months. The trial enrolled 535 patients randomized in a 2:1 manner and the primary endpoint was non-noninferiority in BCVA change from baseline to week 52. Brolucizmab met its primary endpoint of noninferiority to aflibercept at week 52 with a mean (95% CI) difference of -0.6 letters (-2.1 – 0.9). However, brolucizumab was superior to aflibercept with regard to change in central subfield thickness at week 52.
Ocular adverse events occurred at a higher rate in those treated with brolucizumab compared to aflibercept. Notably, 4.8% of participants had >15 BCVA letter loss from baseline in the brolicuzmab group compared to 1.7% in the aflibercept group. Furthermore, the rate of intraocular inflammation was 9.3% (including retinal vasculitis and retinal vascular occlusions) in the broluzicumab group compared to 4.5% in the aflibercept group. Based on the study findings, the benefit-risk profile of brolucizumab used in an off-label continuous q4week dose for nAMD was not favorable, and the second year of the study was terminated prematurely in the interest of patient safety.
The final presentation of the session was by Dr. Michael Singer who reported on the final three-year results of the PALADIN study, a Phase IV safety study that evaluated the fluocinolone implant for diabetic macular edema. The objective of this study was to determine the incidence of IOP lowering procedures in patients treated with 0.19mg fluocinolone acetonide implant. Of the 202 eyes enrolled in PALADIN, 94 eyes completed the 36-month study period. In the 2 years prior to study enrollment, most patients received fewer than 4 injections, indicating significant undertreatment, and visual acuity declined with a mean loss of 8.39 letters. After the fluocinolone implant, visual acuity improved with 3.71 letters at 36 months with 65% of eyes receiving 0 – 2 yearly treatments. Retinal thickness was significantly reduced at all timepoints. IOP elevation > 30mmHg occurred in 10.9% of eyes and incisional IOP-lowering surgery was required in 3% of eyes.
Given the promising findings of the study, one wonders whether it would it be possible for better visual outcomes if continuous therapy was initiated as a first line therapy. This is the basis for the NEW DAY study, which is designed to evaluate fluocinolone implant as a baseline therapy in the treatment of DME.