Purpose: Avacincaptad pegol (ACP) is a pegylated RNA aptamer that inhibits complement C5. The efficacy and safety of ACP 2 mg was investigated in GATHER2, with positive year 1 results published. Herein, 2-year results are reported. Design: Phase 3, randomized, sham-controlled study (ClinicalTrials.gov identifier, NCT04435366). Participants: Patients with non-center point-involving geographic atrophy (GA). Methods: Eligible patients were randomized 1:1 to receive monthly ACP 2 mg (n = 225) or sham (n = 222) for 1 year. At month 12, patients who received ACP 2 mg were randomized again 1:1 to dosing every month (EM; n = 96) or every other month (EOM; n = 93) with ACP 2 mg. Patients who had received monthly sham continued with sham (n = 203). Main Outcome Measures: The safety and efficacy of ACP versus sham administration over 2 years and the effect of ACP EM or EOM dosing in year 2. Results: Overall, 175 and 184 patients in the ACP and sham group completed the study at year 2, respectively. At 2 years, treatment with ACP demonstrated a continued reduction in GA growth (slope) with both ACP EM and EOM versus sham. From baseline to year 2, the mean rate of GA area growth was 4.46 mm2 (standard error [SE], 0.25 mm2) with ACP EM and 5.18 mm2 (SE, 0.17 mm2) with sham, a difference in growth of 0.724 mm2 (95% confidence interval [CI], 0.133-1.315 mm2; P = 0.0165), representing a 14% difference. From baseline to year 2, the mean rate of GA area growth was 4.20 mm2 (SE, 0.25 mm2) with ACP EOM, a difference in growth of 0.976 mm2 (95% CI, 0.377-1.575 mm2; nominal P = 0.0015) versus sham, representing a 19% difference. The incidence of choroidal neovascularization (study eye) was 11.6% with ACP (all treated) versus 9.0% with sham over 2 years. No events of retinal vasculitis, ischemic optic neuropathy, or serious intraocular inflammation occurred over 2 years. Conclusions: Dosing of ACP 2 mg, either EM or EOM, continued to reduce GA growth versus sham therapy over 2 years with no new safety signals compared with year 1. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Ophthalmology 2026;133:451-465 (c) 2025 by the American Academy of Ophthalmology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).
PURPOSE:To assess anatomic and visual function data from 3 randomized, sham-controlled clinical trials of revakinagene taroretcel-lwey in participants with macular telangiectasia type 2 (MacTel). DESIGN:This study pooled data from 1 phase II (NTMT-02) clinical trial and 2 identically designed phase III (NTMT-03-A and NTMT-03-B) clinical trials of revakinagene taroretcel-lwey in MacTel. PARTICIPANTS:In total, 67 participants (99 eyes) from NTMT-02, 115 participants (115 eyes) from NTMT-03-A, and 113 participants (113 eyes) from NTMT-03-B were included in the study. The pooled population included 327 eyes from 295 participants (165 participants who received revakinagene taroretcel-lwey and 162 who underwent sham surgical procedure). METHODS:Assessments were conducted on data from the individual trials as well as on a single pooled population from all 3 trials. MAIN OUTCOME MEASURES:The rate of ellipsoid zone (EZ) area loss over 24 months and changes from baseline in monocular reading speed loss, aggregate retinal sensitivity loss measured by microperimetry, and best-corrected visual acuity (BCVA) were assessed. RESULTS:In the pooled analysis, a 36.2% reduction in the rate of EZ area loss over 24 months was observed with revakinagene taroretcel-lwey (0.118 mm2/24 months; 95% confidence interval [CI], 0.087-0.149) versus sham (0.185 mm2/24 months; 95% CI, 0.154-0.217) (nominal P = 0.003). A 68.2% reduction in monocular reading speed loss at 24 months from baseline was observed with revakinagene taroretcel-lwey (-4.65 words per minute [WPM]; 95% CI, -9.58 to -0.27) versus sham (-14.60 WPM; 95% CI, -20.41 to -8.79) (nominal P = 0.01). Across the 3 trials, a 36.6% reduction in aggregate retinal sensitivity loss was reported over 24 months with revakinagene taroretcel-lwey (28.47 dB; 95% CI, 6.62-50.31) compared with sham (44.85 dB; 95% CI, 36.99-52.72) (nominal P < 0.001). Both treatment groups experienced minimal changes in BCVA over 24 months. CONCLUSIONS:In this pooled analysis, revakinagene taroretcel-lwey reduced the rate of MacTel disease progression and preserved visual function over 24 months, as shown by reductions in the rate of EZ area loss, reading speed loss, and aggregate retinal sensitivity loss. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Purpose:To evaluate the effects of dual angiopoietin-2 (Ang-2)/VEGF-A pathway inhibition with faricimab versus VEGF pathway inhibition with aflibercept 2 mg on pigment epithelial detachment (PED) in patients with neovascular age-related macular degeneration (nAMD). Design:TENAYA/LUCERNE (NCT03823287/NCT03823300) post hoc analysis. Participants:Patients with treatment-naïve nAMD. Methods:Patients were randomized 1:1 to faricimab 6 mg up to every 16 weeks (n = 665) after 4 initial every-4-week (Q4W) doses or aflibercept 2 mg every 8 weeks (n = 664) after 3 Q4W doses. Pigment epithelial detachment was defined as retinal pigment epithelium (RPE) elevation width ≥350 μm and graded as predominantly/purely serous (serous PED) or predominantly/only fibrovascular (fibrovascular PED). Large PED definition: thickness ≥125 μm. Main Outcome Measures:Pigment epithelial detachment thickness change from baseline during initial 12-week head-to-head dosing, proportion of patients with serous PED at the end of head-to-head dosing, and time to first reduction of maximum PED thickness by 50%. Results:Baseline PED characteristics were similar between arms. At week 12, the adjusted mean decrease from baseline in maximum PED thickness was greater with faricimab than aflibercept 2 mg in eyes with large (-119.1 [n = 500] vs. -101.4 μm [n = 496]; nominal P = 0.0028), serous (-136.1 [n = 128] vs. -108.2 μm [n = 114]; nominal P = 0.0147), and any type (-87.9 [n = 644] vs. -74.5 μm [n = 638]; nominal P = 0.0067) PED at baseline. The proportion of eyes with serous PED at baseline remaining serous at week 12 was lower with faricimab than aflibercept 2 mg (4.7% vs. 13.4%; nominal P = 0.0258). In eyes with large PED at baseline, the cumulative incidence of PEDs achieving time to first reduction of maximum PED thickness by 50% at week 12 was 35.3% with faricimab versus 25.7% with aflibercept 2 mg. The corresponding incidence in eyes with serous PED at baseline was 61.1% with faricimab versus 51.8% with aflibercept 2 mg. The incidence of RPE tears was low (faricimab, 2.9%; aflibercept 2 mg, 1.5%). Conclusions:In TENAYA/LUCERNE, dual Ang-2/VEGF-A inhibition with faricimab elicited greater improvements in PED outcomes versus aflibercept 2 mg during head-to-head dosing. These findings are consistent with the greater drying of retinal fluid with faricimab during head-to-head dosing, which may allow for rapid treatment interval extension. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
