Taku Wakabayashi, MD
Retina Research Fellow
Wills Eye Hospital
One of the highlights from the first day of Retina Subspecialty Day was the presentation on the Phase 3 GATHER2 trial moderated by Dr. Diana Do.
Dr. Arshad Khanani from Sierra Eye Associates presented the 12-month results of the Phase 3 GATHER2 trial, which examined the efficacy and safety of intravitreal avacincaptad pegol (Zimura) to sham in patients with geographic atrophy secondary to age-related macular degeneration. Avacincaptad pegol is a pegylated RNA aptamer that inhibits C5. The complement system plays an important role in the pathogenesis of geographic atrophy.
Patients with non-center involving geographic atrophy, which is in part within 1500 µm (≥ 2.5 and ≤ 17.5 mm2 in size), were randomized to 1) intravitreal avacincaptad pegol (2 mg) monthly or 2) sham monthly. The primary endpoint was the mean rate of growth (slope) in the geographic atrophy area from baseline to 12 months.
Avacincaptad pegol met the primary endpoint. The rate of geographic atrophy growth was reduced by 14.3% in the avacincaptad pegol arm, which was statistically significant (P = 0.0064). The mean changes in the geographic lesion area were reduced by 17.3% in the avacincaptad pegol arm, which was also significant (P = 0.0027). A pre-specified subgroup analysis revealed the benefit of avacincaptad pegol in all subgroups, regardless of the baseline geographic area, visual acuity, fundus autofluorescence pattern, age, and gender.
Dr. Khanani emphasized that avacincaptad pegol is the first investigational therapy to achieve the 12-month pre-specified primary endpoint in two pivotal phase 3 trials (GATHER1 and 2).
Dr. Jeffrey Heier, from the Ophthalmic Consultants of Boston, presented the safety results of the GATHER2 trial. Overall, the avacincaptad pegol administered monthly was well tolerated. There were no cases of intraocular inflammation, endophthalmitis, and ischemic optic neuropathy. Intraocular pressure elevation was more common in the avacincaptad pegol arm (9.3%) compared with sham (0.9%); however, most were transient and resolved on the same day. Choroidal neovascularization (CNV) developed in 6.7% in the avacincaptad pegol group and in 4.1% in the sham group. These patients continued their treatment with avacincaptad pegol or sham and received anti-VEGF treatment. A panelist asked how reasonable it is to repeatedly administer avacincaptad pegol, which may pose an increased risk of CNV and may require two different treatments. Dr. Heier answered that the treatment for geographic atrophy may outweigh the risk of CNV, since we already have the treatment for CNV and the risk of geographic atrophy progression is 100%.
Based on the findings of GATHER2, avacincaptad pegol may be a candidate treatment option for geographic atrophy, and FDA submission is planned for the first quarter of 2023.
Dr. Chirag Jhaveri from Retina Consultants of Austin presented data from the DRCR Retina Network Protocol AC, an international multi-center randomized clinical trial comparing bevacizumab with deferred aflibercept and aflibercept monotherapy for diabetic macular edema (DME). Step therapy has been employed by health insurers as a cost-saving approach; this involves first treating patients with lower-cost medication (such as bevacizumab) and then, only if it was ineffective (“fail first”), switching to another more costly medication (such as aflibercept). The potential harm to the patients has been a matter of debate, but no evidence has yet been established regarding the long-term efficacy and safety of step therapy. The protocol AC was designed to answer this important question.
The study included eyes with DME with a visual acuity of 69 to 24 letters (20/320 to 20/50). The primary outcome was the mean change in visual acuity over two years. Eyes were randomly assigned to either aflibercept monotherapy (158 eyes) or bevacizumab first (154 eyes). Over the two-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept. The mean visual improvement was 15.0 letters in the aflibercept monotherapy group and 14.0 letters in the bevacizumab-first group (P = 0.37). The central subfield thickness and the number of patients with complete resolution of edema were also similar between the groups. The ocular adverse events were similar, but systemic serious adverse events and hospitalizations for adverse events were more common in the aflibercept monotherapy group.
Dr. Jhaveri concluded that step therapy with bevacizumab and switching to aflibercept is a safe and effective alternative to aflibercept monotherapy in eyes with center-involved DME.
Dr. Michael Singer from the Medical Center Ophthalmology Associates presented the 24-week results of the Phase 3 BEACON pivotal study, which examined the efficacy and safety of intravitreal KSI-301 (tarcocimab tedromer) for macular edema associated with retinal vein occlusion. Tarcocimab tedromer is an anti-VEGF antibody biopolymer conjugate engineered to increase the durability and efficacy of blocking all VEGF-A isoforms.
Patients with treatment-naïve macular edema associated with retinal vein occlusion with the visual acuity of 80 to 25 letters (20/25 to 20/320) and central subfield thickness of 320 µm or more were randomized to 1) tarcocimab tedromer (5 mg) (Q8W) or 2) aflibercept (2 mg) (Q4W). The primary endpoint was the non-inferiority of tarcocimab to aflibercept, measured by mean changes in visual acuity at 24 weeks.
Tarcocimab (Q8W) was non-inferior to aflibercept (Q4W) and met the primary endpoint. The mean visual improvement in patients with branch retinal vein occlusion was 14.2 letters in the tarcocimab group and 15.6 letters in the aflibercept group. Similarly, the mean visual improvement in all patients was 13.0 letters in the tarcocimab group and 15.5 letters in the aflibercept group. The central subfield change was also non-inferior in the tarcocimab group.
Overall, tarcocimab was well tolerated with comparable ocular and non-ocular adverse events with aflibercept. The rate of intraocular inflammation was 1.4% in the tarcocimab group and 0.4% in the aflibercept group, with no cases of vasculitis or vascular occlusion.
Dr. Singer concluded that tarcocimab is the first anti-VEGF therapy to show visual outcomes comparable to those of monthly aflibercept while doubling the treatment interval. Currently, clinical trials of tarcocimab for DME (GLEAM and GLIMMER studies), AMD (DAYLIGHT study), and NPDR (GLOW study) are also underway. We all look forward to seeing results in the near future.