BACKGROUND: Cost-effectiveness analyses typically ignore healthcare system resource constraints. Ophthalmology is affected by resource constraints because of increasing disease prevalence and the use of resource-intensive treatments. This study evaluated the impact of resource constraints on the cost-effectiveness of faricimab 6 mg, compared with aflibercept 2 mg and ranibizumab biosimilar 0.5 mg, for treating wet age-related macular degeneration (wAMD) or diabetic macular oedema (DMO) over a 5-year horizon.
METHODS: A microsimulation model estimated the impact of resource constraints on patients visits, delays, costs and quality-adjusted life-year (QALY) losses due to treatment delays at a typical UK National Health Service eye hospital treating 1500 patients with wAMD and 500 patients with DMO. Patient characteristics, treatment regimens and treatment intervals were informed using published literature and expert opinion. Resource constraint was represented by limiting the number of available intravitreal injection appointments per week, with growing demand caused by rising disease prevalence. The model compared outcomes across three scenarios; each scenario involved treating all patients with one of the three treatments.
RESULTS: Over 5 years, in a resource-constrained hospital, compared with aflibercept, faricimab use resulted in the avoidance of 12,596 delays, saved GBP/£15,108,609 in cost and avoided the loss of 60.06 QALYs. Compared with ranibizumab biosimilar, faricimab use resulted in the avoidance of 18,910 delays, incurred £2,069,088 extra cost and avoided the loss of 105.70 QALYs, resulting in an incremental cost-effectiveness ratio of £19,574/QALY.
CONCLUSIONS: Accounting for resource constraints in health economic evaluation is crucial. Emerging therapies that are more durable and require less frequent clinic visits can reduce treatment delays, leading to improved QALY outcomes and reduced burden on healthcare systems. Faricimab reduced the number of delayed injections, leading to improved QALY outcomes for patients in a healthcare system with resource constraints. Faricimab is cost-saving when compared with aflibercept and cost-effective when compared with ranibizumab biosimilar.

BACKGROUND: To evaluate the impact of reimbursement criteria change on the utilization pattern of anti-vascular endothelial growth factor (anti-VEGF) among patients with wet age-related macular degeneration (wAMD) and diabetic macular edema (DME) separately in Taiwan.
METHODS: An interrupted time series analysis (ITSA) was performed using Taiwan\'s National Health Insurance (NHI) database, and patients with wAMD or DME diagnosis at the first injection of anti-VEGF agents was identified from 2011 to 2019. The outcome of interest was treatment gaps between injections of anti-VEGF. This outcome was retrieved quarterly, and the study period was divided into three phases in wAMD (two criteria changed in August 2014 [intervention] and December 2016 [intervention]) and two phases in DME (three consecutive criteria changed in 2016 [intervention]). Segmented regression models adjusted for autocorrelation were used to estimate the change in level and the change in slope of the treatment gaps between each anti-VEGF injection.
RESULTS: The treatment gaps between each anti-VEGF injection decreased from 2011 to 2019. The cancellation of the annual three needles limitation was associated with significantly shortened treatment gaps between the third and fourth needles (wAMD change in level: -228 days [95% CI -282, -173], DME change in level: -110 days [95% CI -141, -79]). The treatment gap between the fifth and sixth needles revealed a similar pattern but without significant change in DME patients. Other treatment gaps revealed considerable change in slopes in accordance with criteria changes.
CONCLUSIONS: This is the first nationwide study using ITSA to demonstrate the impact of reimbursement policy on treatment gaps between each anti-VEGF injection. After canceling the annual limitation, we found that the treatment gaps significantly decreased among wAMD and DME patients. The shortened treatment gaps might further link to better visual outcomes according to previous studies. The different impacts from criteria changes can assist future policy shaping. Future studies were warranted to explore whether such changes are associated with the benefits of visual effects.

Wet age-related macular degeneration (wet AMD) is a primary contributor to visual impairment and severe vision loss globally, but the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells (ECs) is mainly dictated by angiogenic growth factors. Even though treatments targeting vascular endothelial growth factor (VEGF), like ranibizumab, are widely administered, more than half of patients still exhibit inadequate or null responses, suggesting the involvement of other pathogenic mechanisms. With advances in research in recent years, it has become well recognized that EC metabolic regulation plays an active rather than merely passive responsive role in angiogenesis. Disturbances of these metabolic pathways may lead to excessive neovascularization in angiogenic diseases such as wet AMD, therefore targeted modulation of EC metabolism represents a promising therapeutic strategy for wet AMD. In this review, we comprehensively discuss the potential applications of EC metabolic regulation in wet AMD treatment from multiple perspectives, including the involvement of ECs in wet AMD pathogenesis, the major endothelial metabolic pathways, and novel therapeutic approaches targeting metabolism for wet AMD.

UNASSIGNED: To evaluate safety and tolerability of EYP-1901, an intravitreal insert containing vorolanib, a pan-VEGF receptor inhibitor packaged in a bioerodible delivery technology (Durasert E™) for sustained delivery, in patients with wet age-related macular degeneration (wAMD) previously treated with anti-VEGF therapy.
UNASSIGNED: Phase I, multicenter, prospective, open-label, dose-escalation trial.
UNASSIGNED: Patients with wAMD and evidence of prior anti-VEGF therapy response.
UNASSIGNED: Patients received a single intravitreal injection of EYP-1901.
UNASSIGNED: The primary objective was to evaluate safety and tolerability of EYP-1901. Secondary objectives assessed biologic activity of EYP-1901 including best-corrected visual acuity (BCVA) and central subfield thickness (CST). Exploratory analyses included reduction in anti-VEGF treatment burden and supplemental injection-free rates.
UNASSIGNED: Seventeen patients enrolled in the 440 μg (3 patients), 1030 μg (1 patient), 2060 μg (8 patients), and 3090 μg (5 patients) dose cohorts. No dose-limiting toxicity, ocular serious adverse events (AEs), or systemic AEs related to EYP-1901 were observed. There was no evidence of ocular or systemic toxicity related to vorolanib or the delivery technology. Moderate ocular treatment-emergent AEs (TEAEs) included reduced visual acuity (2/17) and retinal exudates (3/17). One patient with reduced BCVA had 3 separate reductions of 17, 18, and 16 letters, and another had a single drop of 25 letters. One severe TEAE, neovascular AMD (i.e., worsening/progressive disease activity), was reported in 1 of 17 study eyes but deemed unrelated to treatment. Mean change from baseline in BCVA was -1.8 letters and -5.4 letters at 6 and 12 months. Mean change from baseline in CST was +1.7 μm and +2.4 μm at 6 and 12 months. Reduction in treatment burden was 74% and 71% at 6 and 12 months. Of 16 study eyes, 13, 8, and 5 were injection-free up to 3, 6, and 12 months.
UNASSIGNED: In the DAVIO trial (ClinicalTrials.gov identifier, NCT04747197), EYP-1901 had a favorable safety profile and was well tolerated in previously treated eyes with wAMD. Measures of biologic activity remained relatively stable following a single EYP-1901 injection. These preliminary data support ongoing phase II and planned phase III trials to assess efficacy and safety.
UNASSIGNED: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

OBJECTIVE: To facilitate the assessment of choroid vascular layer thickness in patients with wet age-related macular degeneration (AMD) using artificial intelligence (AI).
METHODS: We included 194 patients with wet AMD and 225 healthy participants. Choroid images were obtained using swept-source optical coherence tomography. The average Sattler layer-choriocapillaris complex thickness (SLCCT), Haller layer thickness (HLT), and choroidal thickness (CT) were auto-measured at 7 regions centered around the foveola using AI and subsequently compared between the 2 groups.
RESULTS: The SLCCT was lower in the AMD group than in the control group (P < 0.05). The HLT was significantly higher in the AMD group than in the control group at the Tparafovea and T-perifovea in the total population (P < 0.05) and in the ≤70-year subgroup (P < 0.05). The CT was higher in the AMD group than in the control group, particularly at the N-perifovea, T-perifovea, and T-parafovea in the ≤70-year subgroup; Interestingly, it was lower in the AMD group than in the control group at the Nparafovea, N-fovea, foveola, and T-fovea in the >70-year subgroup (P < 0.05).
CONCLUSIONS: This novel AI-based auto-measurement was more accurate, efficient, and detailed than manual measurements. SLCCT thinning was observed in wet AMD; however, CT changes depended on the interaction between HLT compensatory thickening and SLCCT thinning.

OBJECTIVE: This study aimed to investigate the potential of microRNAs (miRNAs) in tears, blood, and aqueous humor as biomarkers for predicting treatment response in wet age-related macular degeneration (AMD) patients undergoing anti-vascular endothelial growth factor (anti-VEGF) therapy.
METHODS: In a single-center prospective cohort study, treatment-naïve wet AMD patients and age-matched controls were enrolled. Clinical data and miRNA levels (miR-199a-3p, miR-365-3p, miR-200b-3p, miR-195-5p, miR-335-5p, and miR-185-5p) in tears, blood, and aqueous humor were collected. Treatment response was categorized into responders and non-responders based on visual acuity and central subfield thickness. MiRNA levels were quantified using reverse-transcription PCR. Statistical analyses were performed, including ROC analysis, to evaluate predictive accuracy.
RESULTS: Dysregulated miRNA profiles were observed in wet AMD tears and blood compared to controls. Specifically, miR-199a-3p, miR-195-5p, and miR-185-5p were upregulated, while miR-200b-3p was downregulated in tears. All six miRNAs were elevated in wet AMD blood samples. Notably, responders showed higher tear expression of miR-195-5p and miR-185-5p. Combining these miRNAs yielded the highest predictive power (AUC = 0.878, p = 0.006) for anti-VEGF responders.
CONCLUSIONS: Dysregulated miRNA profiles in tears and blood suggest their potential as biomarkers for wet AMD. MiR-195-5p and miR-185-5p in tears demonstrate predictive value for anti-VEGF treatment responders. This study underscores the non-invasive prediction potential of miRNA tear analysis in wet AMD treatment responses.

At present, the main treatment method for wet AMD is single anti-VEGF therapy, which can require multiple injections, is costly and may have poor efficacy. Studies and clinical experiments have shown that the oral Chinese medicine Xueshuantong combined with anti-VEGF therapy is more effective, and this study aims to explore the molecular mechanism. The TCMSP database was used to identify the main Xueshuantong components. The PubChem database and SWISS Target Prediction data were used to find the SMILES molecular formulas of compounds and corresponding target genes and disease-related genes were searched using the GEO, DisGeNET, and GeneCards databases. Venny was used to identify the intersecting wet AMD-related genes and Xueshuantong targets and Cytoscape software was used to construct direct links between the drug components and disease targets. Then, PPI networks were constructed using the STRING website. R software was used for GO and KEGG enrichment analyses. Cytoscape software was used for topological analyses, and AutoDock Vina v.1.1.2 software was used for molecular docking. 64 compounds corresponding to four drugs were found by the TCMSP database, 1001 total drug targets were found by the PubChem database, 607 wet AMD target genes were found by the GEO, DisGeNET, and GeneCards databases, and 87 Xueshuantong target genes for wet AMD were obtained. Then, by constructing the drug component and disease target network and PPI network, we found that the components closely interacted with VEGF, TNF, caspase 3, CXCL8, and AKT1, which suggested that the therapeutic effects might be related to the inhibition of neovascularization, inflammation, and AKT pathway. Then, GO enrichment analysis showed that the biological processes response to hypoxia, positive regulation of angiogenesis, and inflammatory response were enriched. KEGG enrichment results showed that the HIF-1 and pi3k-akt pathways may mediate the inhibition of wet AMD by Xueshuantong. Topological analysis results identified 10 key proteins, including VEGF, TNF, AKT1, and TLR4. The results of molecular docking also confirmed their strong binding to their respective compounds. In this study, it was confirmed that Xueshuantong could inhibit wet AMD by targeting VEGF, TNF, TLR4, and AKT1, multichannel HIF-1, and the PI3K-AKT pathway, which further proved the therapeutic effects of Xueshuantong combined with single anti-VEGF therapy on wet AMD and provided new insights into the study of novel molecular drug targets for the treatment of wet AMD.

UNASSIGNED: Retrospective, real-world study to evaluate visual acuity (VA), anti-vascular endothelial growth factor (anti-VEGF) injection intervals, and central macular thickness (CMT) in neovascular age-related macular degeneration (nAMD) eyes switched to brolucizumab only or to brolucizumab alternating with another anti-VEGF.
UNASSIGNED: The overall study population comprised eyes that were given ≥1 brolucizumab injection between 1 October 2019 and 30 November 2021. The brolucizumab-only (BRO) cohort consisted of prior anti-VEGF-treated eyes treated exclusively with ≥3 brolucizumab injections over ≥12 or ≥18 months; the alternating brolucizumab (ALT) cohort comprised prior anti-VEGF-treated eyes treated with ≥2 brolucizumab injections and ≥1 other anti-VEGF over ≥12 or ≥18 months.
UNASSIGNED: A total of 482 eyes received ≥1 brolucizumab injection during the study period. Mean VA changes from baseline were -1.1±15.1 letters (BRO cohort; n = 174) and 1.3±13.0 letters (ALT cohort; n = 47) at Month 12, and 0.0±13.5 letters (BRO cohort; n = 95) and -7.3±17.2 letters (ALT cohort; n = 29) at Month 18. Mean changes in injection intervals were +26.9±48.1 days (BRO cohort) and +11.1±17.3 days (ALT cohort) at Month 12 and +36.3±52.3 days (BRO cohort) and +14.0±19.9 days (ALT cohort) at Month 18. Mean changes in CMT were -35.2±108.1 μm (BRO cohort) and -31.5±91.2 μm (ALT cohort) at Month 12 and -38.9±75.0 μm (BRO cohort) and -9.0±59.9 μm (ALT cohort) at Month 18. Intraocular inflammation-related adverse events were recorded in 22/482 (4.6%) eyes.
UNASSIGNED: Treatment with either brolucizumab alone or brolucizumab alternating with another anti-VEGF can preserve vision, reduce CMT, and extend anti-VEGF injection intervals in patients with nAMD.

Periodontitis causes low-grade systemic inflammation and has been associated with elevated active-matrix metalloproteinase (aMMP-8) levels, blood-ocular barrier breakdown and a risk of wet age-related macular degeneration. To assess the association between aMMP-8 levels and macular status among patients with wet age-related macular degeneration (AMD).
Patients on anti-VEGF treatment for wet AMD were enrolled for oral aMMP-8 rinse test in Mehiläinen Private Hospital, Helsinki, Finland. Macular status was examined from spectral-domain optical coherence tomography (SD-OCT) scans by a medical retina specialist and aMMP-8 levels were analyzed with chairside point-of-care oral rinse (PerioSafe®) test and real-time quantitated by a dentist using the ORALyzer®- reader with a 10 ng/ml cut-off for aMMP-8 activity.
Elevated aMMP-8 levels were found in 10 out of 32 patients. Age, gender, anti-VEGF (bevacizumab or aflibercept) distribution, cumulative number of anti-VEGF injections and treatment interval were comparable between patients with aMMP-8 levels below and above the point-of-care level. Macular status differed in regard to aMMP-8 activity; among patients with aMMP-8 levels below the point-of-care subretinal fibrosis was found in 6 out of 22 eyes, whereas among patients with aMMP-8 levels above the point-of-care subretinal fibrosis was found in 8 out of 10 eyes (p = 0.005). Respectively, the mean thickness of subretinal fibrosis at fovea was 19.5 ± 44.1 and 92.3 ± 78.3 µm (p = 0.018). No differences were found in the presence and in the area of geographic atrophy, or fluid distribution, whereas thicknesses of serous pigment epithelial detachment (65.5 ± 99.5 and 12.9 ± 27.9 µm, p = 0.038) and neuroretina (204.2 ± 57.8 µm and 143.0 ± 43.7 µm, p = 0.006) were greater in the eyes of patients with physiological aMMP-8 levels compared to those with elevated aMMP-8 levels.
Elevated aMMP-8 levels may account for subretinal fibrosis formation in wet AMD.

Several chronic eye diseases affect the posterior segment of the eye. Among them age-related macular degeneration can cause vision loss if left untreated and is one of the leading causes of visual impairment in the world. Most treatments are based on intravitreally injected therapeutics that inhibit the action of vascular endothelial growth factor. However, due to the need for monthly injections, this method is associated with poor patient compliance. To address this problem, numerous drug delivery systems (DDSs) have been developed. This review covers a selection of particulate systems, non-stimuli responsive hydrogels, implants, and composite systems that have been developed in the last few decades. Depending on the type of DDS, polymer material, and preparation method, different mechanical properties and drug release profiles can be achieved. Furthermore, DDS development can be optimized by implementing mathematical modeling of both drug release and pharmacokinetic aspects. Several existing mathematical models for diffusion-controlled, swelling-controlled, and erosion-controlled drug delivery from polymeric systems are summarized. Compartmental and physiologically based models for ocular drug transport and pharmacokinetics that have studied drug concentration profiles after intravitreal delivery or release from a DDS are also reviewed. The coupling of drug release models with ocular pharmacokinetic models can lead to obtaining much more efficient DDSs for the treatment of age-related macular degeneration and other diseases of the posterior segment of the eye.