Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors—including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin—have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable.
Our commentary provides a conceptual foundation for the relationship between ocular half-life and treatment durability with respect to intravitreally administered anti-angiogenic therapies typically used for the treatment of retinal diseases, such as neovascular age-related macular degeneration and diabetic macular edema. Of note, we critically examine claims suggesting that increasing the dose of aflibercept can reduce ocular clearance and, consequently, increase ocular half-life. By reviewing the available data and exploring the underlying pharmacokinetic principles, this commentary seeks to provide an evidence-based understanding of the factors influencing treatment durability in this therapeutic area.
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.
Abstract Purpose Timely detection of disease activity in chronic retinal diseases improves visual outcomes but is limited by the lack of validated systems for continuous monitoring and care management. We evaluated the real-world performance of an integrated remote physiologic monitoring and principal care management program (RemoniHealth®) using a self-administered multimodal retinal function test (Macustat®) for home monitoring. Methods This single-arm real-world intervention study was conducted across 33 retina practices. A total of 2,216 adults with chronic retinal diseases performed weekly home retinal function testing with integrated care management support. Primary endpoints included the annualized rate of disease progression detection, time to intervention after first flag, true positive rate, and patient adherence. Descriptive statistics and data analyses were analyzed using chi-square tests and Clopper–Pearson confidence intervals. Results Participants contributed 82,644 encounters and 16,805 patient-months of monitoring. The program generated 241 alerts, including 101 Macustat flags and 135 care management prompts. Among 73 adjudicated flags, 56 were true positives and 17 false positives (PPV 76.7%). The annualized detection rate was 4 per 100 patient-years. Of confirmed events, 93% led to intravitreal injection or other major management change. Mean adherence was 72.1%, and patients with ≥80% adherence had higher odds of true positivity. Discussion This RPM–PCM model achieved high engagement and meaningful detection of asymptomatic progression between visits, supporting the value of home monitoring for timely intervention. Translational Relevance These findings support scalable integration of home vision testing and care management into routine retinal practice to enable earlier intervention and improved continuity of care.
PURPOSE:To compare anatomic biomarkers on spectral-domain OCT between faricimab, a dual angiopoietin-2 (Ang-2)/VEGF-A inhibitor, and aflibercept in a pooled analysis of results from the YOSEMITE/RHINE trials in diabetic macular edema (DME). DESIGN:YOSEMITE/RHINE (NCT03622580/NCT03622593) were identical, randomized, double-masked, active comparator-controlled, 100-week phase III noninferiority trials. PARTICIPANTS:Adults with visual acuity loss due to center-involving DME. METHODS:Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks (Q8W), faricimab 6.0 mg treat-and-extend (T&E), or aflibercept 2.0 mg Q8W for 100 weeks. The T&E up to every 16 weeks dosing regimen was based on central subfield thickness (CST) and best-corrected visual acuity changes. MAIN OUTCOME MEASURES:Post hoc analyses comparing faricimab with aflibercept on CST change; the proportion of eyes with an absence of intraretinal fluid (IRF), subretinal fluid, or both IRF and subretinal fluid or achieving a CST <280 μm at key timepoints during the trials; time to first absence of IRF; and time to first achieving CST <280 μm. RESULTS:In total, 1891 patients were enrolled across YOSEMITE/RHINE (n = 632 faricimab Q8W; n = 632 faricimab T&E; n = 627 aflibercept). There were greater CST reductions from baseline with both faricimab dosing regimens compared with aflibercept over the 100 weeks (adjusted means and area-under-the-curve analysis). Higher proportions of eyes achieved an absence of IRF with faricimab Q8W (58%-63%) and faricimab T&E (44%-49%) versus aflibercept (36%-41%) at weeks 92 to 100. In eyes with IRF at baseline, the median time to first absence of IRF was achieved 40 weeks earlier with faricimab versus aflibercept. The proportion of eyes achieving a CST <280 μm at weeks 92 to 100 was 70% to 74% with faricimab Q8W, 61% to 65% with faricimab T&E, and 61% to 63% with aflibercept. In eyes with CST ≥280 μm at baseline, the median time to first instance of CST <280 μm was achieved 16 weeks earlier with faricimab versus aflibercept. CONCLUSIONS:Dual Ang-2/VEGF-A inhibition with faricimab resulted in greater and faster improvements in anatomic outcomes compared with aflibercept at key timepoints over the pooled YOSEMITE/RHINE trials. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
