Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

Cardiovascular risk in anti-VEGF treatment of neovascular age-related macular degeneration.

OBJECTIVE: Assess 5-year all-cause mortality (ACM), hemorrhagic stroke, ischemic stroke, and myocardial infarction (MI) risks in nAMD patients receiving anti-VEGF injections compared with controls. DESIGN: Population-based retrospective cohort study using a U.S. federated health research network, containing de-identified data of 96 million patients from 1/1/2003 to 3/6/2023. PARTICIPANTS: nAMD Patients with anti-VEGF injections. Controls included nAMD patients without anti-VEGF injections, non-exudative AMD patients, and patients without AMD. METHODS: Patients were identified using nAMD ICD-10 and anti-VEGF CPT codes and matched for age, sex, and comorbidities. Five-year relative risk of ACM (RR1), hemorrhagic stroke (RR2), ischemic stroke (RR3), and MI (RR4) in nAMD patients receiving anti-VEGF injections were calculated. RESULTS: A total of 27,609 nAMD patients (mean diagnosis age [SD], [78.2 (10.3)]) received anti-VEGF injections; 769 nAMD patients without injections (75.8 [12.2]), 27,599 non-exudative AMD patients (78.2 [10.3]), and 21,902 no-AMD patients (76.1 [10.5]) were identified. After matching, nAMD patients receiving injections did not show increased risk versus nAMD patients without injections (RR1, 0.66; 95% CI [0.53, 0.82]), (RR2, 1.00 [0.42, 2.38]), (RR3, 1.70 [0.92,3.13]), (RR4, 0.63 [0.33, 1.18]). No increased risk was found compared to non-exudative AMD patients (RR1, 0.99 [0.95, 1.03]), (RR2, 0.94 [0.83,1.07]), (RR3, 1.04 [0.96, 1.12]), (RR4, 0.99 [0.91, 1.08]). Increased risk for ACM was observed versus no-AMD patients (RR1, 1.21 [1.15, 1.27]), but no other differences were found (RR2, 0.81 [0.70, 0.93]), (RR3, 1.00 [0.92, 1.09]), (RR4, 0.986 [0.90, 1.09]). CONCLUSION: Anti-VEGF injections were not associated with major cardiovascular events in nAMD patients over 5 years.

Long-term Treatment Patterns for Diabetic Macular Edema: Up to 6-Year Follow-Up in the IRIS® Registry.

OBJECTIVE: To characterize anti-vascular endothelial growth factor (VEGF) intravitreal therapy (IVT) patterns and long-term visual outcomes among patients with diabetic macular edema (DME) in routine clinical practice in the United States. DESIGN: Retrospective analysis of the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS®) Registry.; Participants: Treatment-naïve patients with DME (no previous IVT in the past 12 months) initiating anti-VEGF IVT from 1/1/2015-3/31/2021. METHODS: Baseline characteristics, treatment patterns, and long-term visual acuity (VA) outcomes were reported for up to 6 years of follow-up. MAIN OUTCOME MEASURES: Outcomes included the annualized number of injections, change in VA, and anti-VEGF agents. RESULTS: A total of 190,345 eyes met inclusion criteria. After 1 year of anti-VEGF IVT initiation, eyes received a mean of 3.9 (±2.8) injections and gained +3.2 (±16.4) letters of vision. Of the 1,236 eyes with year 6 data, eyes received a mean of 2.9 (±2.1) injections in year 6 and gained +0.5 (±19.7) letters from baseline. The number of injections decreased, and injection intervals increased year over year up to 6 years regardless of baseline VA initiation. The average injection interval was 10-weeks in year 1, then widened to 13.2 in year 2, before plateauing in years 3-6 (12.6, 12.3, 12.2, and 12.3 weeks respectively). Improvements in VA from baseline were greatest in eyes that received 5 or more injections each year. At the end of follow-up, eyes with good baseline vision (> 20/25) lost vision, whereas those with worse baseline vision (< 20/25) gained vision. Although 51.7% of patients with DME discontinued IVT after a mean of 6 months, 32.8% re-initiated anti-VEGF IVT. Worse VA outcomes were associated with patients of Hispanic ethnicity (-1.08 [-1.34, -0.83] compared to non-Hispanic), Medicaid insurance (-1.15 [-1.48, -0.81] compared to Commercial), and older age (-0.06 [-0.07, -0.05] each additional year) CONCLUSIONS: Patients with DME in the routine clinical settings receive fewer injections than those in clinical trials and fewer than recommended per the label of FDA approved anti-VEGF IVT.

Longitudinal Trends and Disparities in Diabetic Retinopathy Within an Aggregate Health Care Network.

Importance: Diabetic retinopathy (DR) is a leading cause of blindness in the US, warranting updates on its prevalence and incidence in the setting of advancements in diabetic care over recent years. Objective: To determine recent trends in DR prevalence stratified by baseline demographics to identify those populations at greater risk. Design, Setting, and Participants: This was a cross-sectional epidemiologic evaluation conducted using deidentified data from the large federated TriNetX Analytics health research network composed of 56 health care organizations in the US. Patients from 2015 to 2022 who had an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code of type 1 DR (T1DR) or type 2 DR (T2DR) were included in this analysis. Patients were further stratified by age cohorts (20-29 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, and 70 years or older), race and ethnicity, and sex. Main Outcomes and Measures: Prevalence per 100 000 patients and prevalence odds ratios (ORs) were calculated in Microsoft Excel and Posit (formerly RStudio). Results: A total of 359 126 patients with T1DR or T2DR (mean [SD] age, 67 [14] years; 52% female) were included in this study between January 1, 2015, and December 21, 2022. T1DR increased in prevalence from 2015 to 2022, with T1DR increasing 1.15-fold affecting 70.4 patients per 100 000 in 2022. T2DR increased 1.07-fold affecting 461.7 patients per 100 000 in 2022. For T1DR, the cohort aged 20 to 39 years had the most substantial increase at 4.7 and 1.96 fold. Overall, White males had the largest prevalence ORs of T1DR at 1.41 (95% CI, 1.36-1.47) compared with White females (reference group). In T2DR, patients aged 20 to 39 years again had a 2.5- and 1.6-fold prevalence increase from 2015 to 2022. Regardless of age group, Hispanic males demonstrated larger prevalence OR at 4.08 (95% CI, 3.97-4.19) compared with White females followed by Hispanic females at 2.49 (95% CI, 2.42-2.56), Black males at 2.23 (95% CI, 2.17-2.29), and Black females at 2.00 (95% CI, 1.95-2.05). Conclusion and Relevance: The prevalence of both T1DR and T2DR increased in this network from 2015 to 2022, with individuals aged 20 to 39 years showing large increases. Additionally, T2DR was associated with greater increases in both Hispanic and Black communities. These findings support DR screening in young adults and for T2DR interventions specifically designed for racial and ethnic minoritized patients most affected by disease. Future investigations are warranted to further investigate these trends among young adults.

Melatonin and Risk of Age-Related Macular Degeneration.

Importance: Melatonin has been shown to oppose several processes that are known to mediate age-related macular degeneration (AMD), but whether melatonin can confer benefits against AMD remains unclear. Objective: To examine the association between melatonin supplementation and the risk of the development or progression of AMD. Design, Setting, and Participants: This retrospective cohort study accessed data from TriNetX, a national database of deidentified electronic medical records from both inpatient and outpatient health care organizations across the US, between December 4, 2023, and March 19, 2024. Patients aged 50 years or older, 60 years or older, and 70 years or older with no history of AMD (AMD-naive group) and with a history of nonexudative AMD (nonexudative AMD group) were queried for instances of melatonin medication codes between November 14, 2008, and November 14, 2023. Patients were then classified into either a melatonin group or a control group based on the presence of medication codes for melatonin. Propensity score matching (PSM) was performed to match the cohorts based on demographic variables, comorbidities, and nonmelatonin hypnotic medication use. Exposure: The presence of at least 4 instances of melatonin records that each occurred at least 3 months apart. Main Outcomes and Measures: After PSM, the melatonin and the control cohorts were compared to evaluate the risk ratios (RRs) and the 95% CIs of having an outcome. For the AMD-naive group, the outcome was defined as a new diagnosis of any AMD, whereas for the nonexudative AMD group, the outcome was progression to exudative AMD. Results: Among 121 523 patients in the melatonin-naive group aged 50 years or older (4848 in the melatonin cohort [4580 after PSM; mean (SD) age, 68.24 (11.47) years; 2588 female (56.5%)] and 116 675 in the control cohort [4580 after PSM; mean (SD) age, 68.17 (10.63) years; 2681 female (58.5%)]), melatonin use was associated with a reduced risk of developing AMD (RR, 0.42; 95% CI, 0.28-0.62). Among 66 253 patients aged 50 years or older in the nonexudative AMD group (4350 in the melatonin cohort [4064 after PSM; mean (SD) age, 80.21 (8.78) years; 2482 female (61.1%)] and 61 903 in the control cohort [4064 patients after PSM; mean (SD) age, 80.31 (8.03) years; 2531 female (62.3%)]), melatonin was associated with a reduced risk of AMD progression to exudative AMD (RR, 0.44; 95% CI, 0.34-0.56). The results were consistent among subsets of individuals aged 60 years or older (AMD-naive cohort: RR, 0.36 [95% CI, 0.25-0.54]; nonexudative AMD cohort: RR, 0.38 [95% CI, 0.30-0.49]) and 70 years or older (AMD-naive cohort: RR, 0.35 [95% CI, 0.23-0.53]; nonexudative AMD cohort: RR, 0.40 [95% CI, 0.31-0.51]). Conclusions and Relevance: Melatonin use was associated with a decreased risk of development and progression of AMD. Although lifestyle factors may have influenced this association, these findings provide a rationale for further research on the efficacy of using melatonin as a preventive therapy against AMD.

Macular Holes in Tractional Retinal Detachments Secondary to Diabetic Retinopathy.

Purpose: To characterize the visual outcomes and rate of macular hole (MH) closure with tractional retinal detachment (TRD) and proliferative diabetic retinopathy (PDR). Methods: Visit data of patients who had pars plana vitrectomy were retrospectively reviewed; patient demographics, other procedure(s), the MH closure rate, and visual outcomes were also collected. Paired t, Fisher exact, and Mann-Whitney U tests were performed. Results: Ten patients (10 eyes) developed a TRD MH; 3 distinct MH presentations were identified. At the 3-month follow-up, 90% of MHs remained closed without the need for further reoperation (n = 6, type 1 closure; n = 3, type 2 closure). All MHs were closed 12 months after the initial surgery, with 1 eye requiring a single reoperation. The mean visual acuity (VA) at baseline and at 12 months was 20/235 and 20/138, respectively. Conclusions: MHs in the setting of fibrovascular proliferation resulting from PDR present with varied morphology. There is a high rate of MH closure and a trend toward improved VA.

Intraretinal Hyper-Reflective Foci Are Almost Universally Present and Co-Localize With Intraretinal Fluid in Diabetic Macular Edema.

Purpose: In diabetic macular edema (DME), hyper-reflective foci (HRF) has been linked to disease severity and progression. Using an automated approach, we aimed to investigate the baseline distribution of HRF in DME and their co-localization with cystoid intraretinal fluid (IRF). Methods: Baseline spectral-domain optical coherence tomography (SD-OCT) volume scans (N = 1527) from phase III clinical trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) were segmented using a deep-learning-based algorithm (developed using B-scans from BOULEVARD NCT02699450) to detect HRF. The HRF count and volume were assessed. HRF distributions were analyzed in relation to best-corrected visual acuity (BCVA), central subfield thickness (CST), and IRF volume in quartiles, and Diabetic Retinopathy Severity Scores (DRSS) in groups. Co-localization of HRF with IRF was calculated in the central 3-mm diameter using the en face projection. Results: HRF were present in most patients (up to 99.7%). Median (interquartile range [IQR]) HRF volume within the 3-mm diameter Early Treatment Diabetic Retinopathy Study ring was 1964.3 (3325.2) pL, and median count was 64.0 (IQR = 96.0). Median HRF volumes were greater with decreasing BCVA (nominal P = 0.0109), and increasing CST (nominal P < 0.0001), IRF (nominal P < 0.0001), and DRSS up to very severe nonproliferative diabetic retinopathy (nominal P < 0.0001). HRF co-localized with IRF in the en face projection. Conclusions: Using automated HRF segmentation of full SD-OCT volumes, we observed that HRF are a ubiquitous feature in DME and exhibit relationships with BCVA, CST, IRF, and DRSS, supporting a potential link to disease severity. The spatial distribution of HRF closely followed that of IRF.

Synthesized Gold Nanoparticles with Moringa Oleifera leaf Extract Induce Mitotic Arrest (G2/M phase) and Apoptosis in Dalton's Lymphoma Cells.

The therapeutic potential of chemically synthesized AuNPs has been demonstrated in various types of cancer. However, gold nanoparticles (AuNPs) synthesized using typical chemical methods have concerns regarding their environmental safety and adverse impact on human well-being. To overcome this issue, we used an environmentally friendly approach in which gold nanoparticles were synthesized using Moringa oleifera leaf extract (MLE). The present research was mainly focused on the biosynthesis and characterization of gold nanoparticles (AuNPs) using Moringa oleifera leaf extract (MLE-AuNPs) and explore its anticancer potential against Dalton's Lymphoma (DL) cells. Characterization of the MLE-AuNPs was conducted using UV-Vis Spectroscopy to confirm the reduction process, FTIR analysis to ascertain the presence of functional groups, and XRD analysis to confirm the crystallinity. SEM and TEM images were used to examine size and morphology. After characterization, MLE-AuNPs were evaluated for their cytotoxic effects on Dalton's lymphoma cells, and the results showed an IC50 value of 75 ± 2.31 µg/mL; however, there was no discernible cytotoxicity towards normal murine thymocytes. Furthermore, flow cytometric analysis revealed G2/M phase cell cycle arrest mediated by the downregulation of cyclin B1 and Cdc2 and upregulation of p21. Additionally, apoptosis induction was evidenced by Annexin V Staining, accompanied by modulation of apoptosis-related genes including decreased Bcl-2 expression and increased expression of Bax, Cyt-c, and Caspase-3 at both the mRNA and protein levels. Collectively, our findings underscore the promising anti-cancer properties of MLE-AuNPs, advocating their potential as a novel therapeutic avenue for Dalton's lymphoma.

Incidence of ocular pathology following bariatric surgery for with morbid obesity across a large United States National Database.

BACKGROUND/OBJECTIVES: Bariatric surgery, as indicated for treatment of morbid obesity, has been studied in association with short term effects on ocular pathology. However, effects of surgery on postoperative disease incidence is largely unknown. SUBJECTS/METHODS: In this retrospective cohort study, the TriNetX United States Collaborative Network national database, was queried for patients with an ICD-10 code for morbid obesity and a procedural code for bariatric surgery. Patients were propensity score matched across baseline demographics at the time of surgery and compared to those presenting with an ICD10 code for morbid obesity with no records of a procedural code for bariatric surgery, identifying 42,408 patients per cohort. New diagnoses or procedural codes found after the surgical index date for diabetic retinopathy, age-related macular degeneration, glaucoma, low vision, and blindness along with pertinent treatment metrics were monitored. RESULTS: Bariatric surgery was found to be associated with reduced future risk of diabetic retinopathy (RR: 0.283; 95% CI: 0.252-0.319), macular edema (RR: 0.224; 95% CI: 0.170-0.297), vitreous hemorrhage (RR: 0.459; 95% CI: 0.323-0.653), ocular hypertension (RR: 0.387; 95% CI: 0.387-0.487), glaucoma (RR: 0.360; 95% CI: 0.326-0.399), use of ocular pressure lowering medications (RR: 0.565; 95% CI: 0.496-0.644), age-related macular degeneration (RR: 0.628; 95% CI: 0.447-0.882), cataract surgery (RR: 0.524; 95% CI: 0.448-0.612), and low vision and blindness (RR: 0.328; 95% CI: 0.294-0.365) compared to patients not surgically managed. CONCLUSIONS: The present analysis comprising a large US cohort of patients suggests that bariatric surgery is associated with a decreased risk of future ocular morbidity and mortality.

Comparing Three-Dimensional Digitally Enabled Intraoperative OCT With Conventional Microscope-Integrated OCT in Vitreoretinal Surgery: A Post Hoc Analysis of the DISCOVER Study.

BACKGROUND AND OBJECTIVE: This study compared the surgeon experience between conventional microscope-integrated intraoperative optical coherence tomography (iOCT) and digitally enabled microscope-integrated iOCT in vitreoretinal surgery. PATIENTS AND METHODS: This is a post hoc case-control analysis of the DISCOVER study. Conventional microscope-integrated iOCT (Rescan 700, Zeiss) was compared with digitally enabled iOCT (Artevo 800, Zeiss). Compared variables included surgical field-based visualization (ie, ocular heads-up display in the conventional group; three-dimensional screen-based visualization in the digital iOCT group) and non-surgical field-based visualization (ie, review on the external two-dimensional monitor). RESULTS: A total of 200 patients were included. Surgical field-based visualization of iOCT was significantly higher in the digitally enabled group (P < 0.0001). Required endoillumination level was significantly lower in the digital iOCT group (P < 0.0001). Surgeons reported "significant" back discomfort and headache more frequently when using conventional iOCT (P = 0.003 and P = 0.001, respectively). CONCLUSIONS: Digitally enabled iOCT resulted in greater surgical visualization efficiency, appeared to require a lower illumination level, and may provide advantages for ergonomic-related discomfort. [Ophthalmic Surg Lasers Imaging Retina 2024;55:270-277.].

Real-world effects of anti-vascular endothelial growth factor injection frequency on visual outcomes in patients with diabetic macular oedema.

BACKGROUND AND OBJECTIVE: Anti-vascular endothelial growth factor (VEGF) injections are often administered less frequently in real-world treatment of diabetic macular oedema (DMO) than what was studied in clinical trials. This study aims to characterise real-world DMO treatment patterns and the effect of treatment intervals on patient outcomes. STUDY DESIGN/PATIENTS AND METHODS: This was a retrospective study of 291 patients with DMO treated with anti-VEGF therapy. 12- and 24-month best visual acuity (BVA) and central subfield thickness (CST) were compared between injection interval groups, which were determined by averaging the two most recent injection intervals. Multiple linear regressions were performed to identify factors associated with injection interval, BVA, and CST. RESULTS: 48.8% of patients received injections less than or equal to every 8 weeks (≤ q8w), 27.5% between every 8 to 12 weeks (q8-12w), and 23.7% greater than every 12 weeks (> q12w). Baseline CST was similar (p = 0.32), but BVA differed significantly in q8-12w patients (p = 0.0095). BVA and CST at 12 months were similar, but q8-12w patients experienced greater 12-month BVA improvement (7.36 ± 12.4 letters) than > q12w patients (1.26 ± 12.3 letters; p = 0.0056). 24-month BVA and CST changes were similar between groups (p = 0.30 and 0.87). Baseline BVA, HbA1c, and sex were associated with 12-month BVA, and baseline BVA and CST were associated with 12-month CST. CONCLUSION: Many patients experienced improvements in BVA and CST over 12 months of treatment despite receiving less frequent anti-VEGF therapy than recommended in the pivotal trials. The present study showed that extended treatment intervals with bevacizumab were effective in preserving vision of many individuals with high baseline BVA.

Associations between lipid abnormalities and diabetic retinopathy across a large United States national database.

BACKGROUND/OBJECTIVES: While dyslipidaemia has been suggested as a potential risk factor for diabetic retinopathy (DR), previous studies have reported conflicting findings. This study aimed to better characterize the relationship between abnormal serum levels of various lipid markers and the risk of the development and progression of DR. SUBJECTS/METHODS: This retrospective cohort study utilized a United States national database of electronic medical records. Adults with a history of type 2 diabetes mellitus without type 1 diabetes mellitus were divided into cohorts based on the presence of abnormal serum levels of various lipid markers. Propensity score matching was performed to match cohorts with abnormal lipid levels to those with normal lipid levels on covariates. The cohorts were then compared to evaluate the hazard ratios (HR) of receiving a new DR diagnosis, pars plana vitrectomy, panretinal photocoagulation, vitreous haemorrhage, proliferative diabetic retinopathy, diabetic macular oedema (DMO), and traction retinal detachment. RESULTS: The database contained 1,126,231 eligible patients (mean age: 60.8 [14.2] years; 46.0% female). Among patients without prior DR, low HDL (HR = 0.94, CI = 0.90-0.98), total cholesterol (HR = 0.88, CI = 0.85-0.91), and high triglyceride (HR = 0.91, CI = 0.86-0.97) levels were associated with a decreased risk of receiving a DR diagnosis. Among patients with preexisting DR, high LDL levels was associated with an increased risk of DMO (HR = 1.42, CI = 1.15-1.75), whereas low HDL levels was associated with a marginally decreased risk (HR = 0.92, CI = 0.85-0.99). CONCLUSIONS: Elevated levels of markers of dyslipidaemia are inversely associated with the risk of receiving a DR diagnosis, but this relationship is blunted after the onset of DR.

Pharmacological Insights: Mitochondrial ROS Generation by FNC (Azvudine) in Dalton's Lymphoma Cells Revealed by Super Resolution Imaging.

Nucleoside analogs are a common form of chemotherapy that disrupts DNA replication and repair, leading to cell cycle arrest and apoptosis. Reactive oxygen species (ROS) production is a significant mechanism through which these drugs exert their anticancer effects. This study investigated a new nucleoside analog called FNC or Azvudine, and its impact on ROS production and cell viability in Dalton's lymphoma (DL) cells. The study found that FNC treatment resulted in a time- and dose-dependent increase in ROS levels in DL cells. After 15 and 30 min of treatment with 2 and 1 mg/ml of FNC, mitochondrial ROS production was observed in DL cells. Furthermore, prolonged exposure to FNC caused structural alterations and DNA damage in DL cells. The results suggest that FNC's ability to impair DL cell viability may be due to its induction of ROS production and indicate a need for further investigation.

Evidence-Based Use of Bevacizumab in the Management of Neovascular Age-Related Macular Degeneration.

Indicated for colorectal cancer for decades, bevacizumab has been widely used off label to treat retinal diseases, and the benefits of its use, specifically in neovascular age-related macular degeneration, have been demonstrated in multiple clinical trials. The intravitreal delivery of bevacizumab requires it to be aseptically repackaged into individual syringes by compounding pharmacies for use in the eye. Although the repackaging process is permitted by the US Food and Drug Administration, the resultant product does not meet the specific standards of products approved for use as ophthalmic injectables nor is the parenteral innovator solution compliant with ophthalmic standards. Studies have also demonstrated variability in the quality and quantity of repackaged bevacizumab. This narrative review summarizes the evidence and discusses the role of off-label bevacizumab in the treatment and management of retinal diseases, its mechanism of action, current challenges and provides a critical appraisal of current evidence, clinical implications, and future directions. [Ophthalmic Surg Lasers Imaging Retina 2024;55:155-162.].

The Risk of Optic Neuritis following mRNA Coronavirus Disease 2019 Vaccination Compared to Coronavirus Disease 2019 Infection and Other Vaccinations.

PURPOSE: To determine the risk of optic neuritis (ON) after mRNA Coronavirus Disease 2019 (COVID-19) vaccine administration. DESIGN: U.S. National aggregate database retrospective cohort study. PARTICIPANTS: Patients were placed into cohorts based on mRNA COVID-19 vaccination status (no vaccine and positive history of COVID-19 infection, 1 vaccine, or 2 vaccines received) from December 2020 to June 2022. Two control cohorts were created with patients vaccinated against influenza or tetanus diphtheria and pertussis (Tdap) from June 2018 to December 2019. Patients with any history of ON or significant risk factors for ON development including infectious, inflammatory, and neoplastic diseases were excluded. METHODS: A large deidentified database was queried for the Common Procedural Technology codes for immunization encounters specific to first dose and second dose of mRNA COVID-19 vaccine, influenza, or Tdap. Cohorts were 1:1 propensity score matched on age, sex, race, and ethnicity. The risk of ON development after vaccination was calculated and compared for all 5 cohorts with 95% confidence intervals (CIs) reported. MAIN OUTCOME MEASURES: Risk ratio (RR) of ON 21 days after vaccination (or COVID-19 infection) and incidence of ON per 100 000 individuals. RESULTS: After matching, the first dose COVID-19 and influenza vaccine cohorts (n = 1 678 598, mean age [standard deviation] at vaccination of 45.5 [23.3] years and 43.2 [25.5] years, 55% female) the RR of developing ON was 0.44 (95% CI, 0.28-0.80). The first dose of COVID-19 and Tdap vaccinations (n = 797 538, mean age 38.9 [20.0] years, 54.2% female) cohort had 10 and 16 patients develop ON (RR, 0.63; 95% CI, 0.28-1.38). Comparison of COVID-19-vaccinated patients (n = 3 698 848, 48.2 [21.5] years, 54.7% female) to unvaccinated and COVID-19-infected patients (n = 3 698 848, 49.6 [22.0] years, 55.2% female) showed 49 and 506 patients developing ON, respectively (RR, 0.09; 95% CI, 0.07-0.12). The incidence per 100 000 for ON was 1 in the first dose COVID-19 vaccine cohort, 2 in the influenza cohort, and 2 in the Tdap cohort, and 14 in the COVID-19-infected and unvaccinated cohorts. CONCLUSIONS: Risk of ON after mRNA COVID-19 vaccination is rare and comparable to Tdap vaccination, decreased compared with influenza vaccination, and decreased compared with COVID-19 infection in the absence of vaccination. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

TENAYA and LUCERNE: Two-Year Results from the Phase 3 Neovascular Age-Related Macular Degeneration Trials of Faricimab with Treat-and-Extend Dosing in Year 2.

PURPOSE: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A. DESIGN: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) were identically designed, randomized, double-masked, active comparator-controlled phase 3 noninferiority trials. PARTICIPANTS: Treatment-naive patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older. METHODS: Patients were randomized (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks (Q16W) or aflibercept 2.0 mg every 8 weeks (Q8W). Faricimab fixed dosing based on protocol-defined disease activity at weeks 20 and 24 up to week 60, followed up to week 108 by a treat-and-extend personalized treatment interval regimen. MAIN OUTCOME MEASURES: Efficacy analyses included change in best-corrected visual acuity (BCVA) from baseline at 2 years (averaged over weeks 104, 108, and 112) and proportion of patients receiving Q16W, every 12 weeks (Q12W), and Q8W dosing at week 112 in the intention-to-treat population. Safety analyses included ocular adverse events (AEs) in the study eye through study end at week 112. RESULTS: Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment (n = 555 faricimab; n = 558 aflibercept). The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]). At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing. Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112. CONCLUSIONS: Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Characterizing the Journey of Geographic Atrophy Patients in Routine Ophthalmic Practice.

BACKGROUND AND OBJECTIVE: Geographic atrophy (GA) is a form of late-stage age-related macular degeneration (AMD). This study aims to characterize the journey of patients with GA in real-world ophthalmology practice. PATIENTS AND METHODS: This is a retrospective cohort study of 100 patients with GA and 100 with intermediate AMD (iAMD). RESULTS: Approximately one-third of GA patients' eyes had GA at the time of their initial AMD diagnosis, and nearly half of the iAMD patients' eyes had iAMD at that time. When holding confounders constant, GA patients experienced significantly worse visual acuity outcomes, and a significantly higher proportion required referrals for low vision evaluation, needed assistance for activities of daily living, failed to meet driving standards, and met criteria for legal blindness when compared to iAMD controls. CONCLUSIONS: Many patients have already progressed to GA by the time they receive an AMD diagnosis, emphasizing the importance of providing early detection and intervention, especially considering novel treatment options. [Ophthalmic Surg Lasers Imaging Retina 2024;55:204-210.].

Propensity-Matched Analysis of the Risk of Age-Related Macular Degeneration with Systemic Immune-Mediated Inflammatory Disease.

PURPOSE: The pathogenesis of age-related macular degeneration (AMD) involves aberrant complement activation and is a leading cause of vision loss worldwide. Complement aberrations are also implicated in many systemic immune-mediated inflammatory diseases (IMIDs), but the relationship between AMD and these conditions remains undescribed. The aim of this study is to first assess the association between AMD and IMIDs, and then assess the risk of AMD in patients with specific IMIDs associated with AMD. DESIGN: Cross-sectional study and cohort study. SUBJECTS AND CONTROLS: Patients with AMD were compared with control patients with cataracts and no AMD to ensure evaluation by an ophthalmologist. Patients with IMIDs were compared with patients without IMIDs but with cataracts. METHODS: This study used deidentified data from a national database (2006-2023), using International Classification of Diseases 10 codes to select for IMIDs. Propensity score matching was based on patients on age, sex, race, ethnicity, and smoking. Odds ratios were generated for IMIDs and compared between AMD and control patients. For IMIDs associated with AMD, the risk of AMD in patients with the IMID versus patients without IMIDs was determined utilizing a cohort study design. MAIN OUTCOME MEASURES: Odds ratio of IMID, risk ratios (RRs), and 95% confidence intervals (CIs) of AMD diagnosis, given an IMID. RESULTS: After propensity score matching, AMD and control cohorts (n = 217 197 each) had a mean ± standard deviation age of 74.7 ± 10.4 years, were 56% female, and 9% of patients smoked. Age-related macular degeneration showed associations with systemic lupus erythematosus (SLE), Crohn's disease, ulcerative colitis, rheumatoid arthritis (RA), psoriasis, sarcoidosis, scleroderma, giant cell arteritis, and vasculitis. Cohorts for each positively associated IMID were created and matched to control cohorts with no IMID history. Patients with RA (RR, 1.40; 95% CI, 1.30-1.49), SLE (RR, 1.73; 95% CI, 1.37-2.18), Crohn's disease (RR, 1.42; 95% CI, 1.20-1.71), ulcerative colitis (RR, 1.45; 95% CI, 1.29-1.63), psoriasis (RR, 1.48; 95% CI, 1.37-1.60), vasculitis (RR, 1.48; 95% CI, 1.33-1.64), scleroderma (RR, 1.65; 95% CI, 1.35-2.02), and sarcoidosis (RR, 1.42; 95% CI, 1.24-1.62) showed a higher risk of developing AMD compared with controls. CONCLUSIONS: The results suggest that there is an increased risk of developing AMD in patients with RA, SLE, Crohn's disease, ulcerative colitis, psoriasis, vasculitis, scleroderma, and sarcoidosis compared with patients with no IMIDs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

FNC (4'-azido-2'-deoxy-2'-fluoro(arbino)cytidine) as an Effective Therapeutic Agent for NHL: ROS Generation, Cell Cycle Arrest, and Mitochondrial-Mediated Apoptosis.

Cytotoxic nucleoside analogs (NAs) hold great promise in cancer therapeutics by mimicking endogenous nucleosides and interfering with crucial cellular processes. Here, we investigate the potential of the novel cytidine analog, 4'-azido-2'-deoxy-2'-fluoro(arbino)cytidine (FNC), as a therapeutic agent for Non-Hodgkin lymphoma (NHL) using Dalton's lymphoma (DL) as a T-cell lymphoma model. FNC demonstrated dose- and time-dependent inhibition of DL cell growth and proliferation. IC-50 values of FNC were measured at 1 µM, 0.5 µM, and 0.1 µM after 24, 48, and 72 h, respectively. Further elucidation of FNC's mechanism of action uncovers its role in inducing apoptosis in DL cells. Notable DNA fragmentation and nuclear condensation point to activated apoptotic pathways. FNC-induced apoptosis was concomitant with changes in cellular membranes, characterized by membrane rupture and altered morphology. The robust anticancer effects of FNC are linked to its capacity to induce reactive oxygen species (ROS) production, prompting oxidative stress-mediated apoptosis. Additionally, FNC disrupted mitochondrial membrane potential (MMP), leading to mitochondrial dysfunction, further promoting apoptosis. Dysregulation of apoptotic genes, with upregulation of Bax and downregulation of Bcl-2 and Bcl-xl, implicates the mitochondrial-mediated apoptosis pathway. Furthermore, FNC-induced G2/M phase cell cycle arrest was mediated through modulation of the cell cycle inhibitor p21. Overall, this study highlights the potential of FNC as a promising therapeutic agent for NHL.

Visual acuity changes in the preoperative period in patients undergoing cataract surgery.

OBJECTIVE: This study quantifies change in best visual acuity (BVA) over the preoperative period and assesses factors associated with postoperative outcomes. DESIGN: Retrospective chart review conducted at a single institution. PARTICIPANTS: A total of 691 patients underwent cataract surgery and had a preoperative assessment 0-30 days prior to surgery following their surgical evaluation. METHODS: Baseline demographics and past medical and clinical data were collected through electronic medical record query. BVA was noted at initial surgical evaluation, preoperative assessment, and nearest postoperative assessment. RESULTS: A total of 691 patients (911 eyes) were included with mean BVAs at the initial evaluation, preoperative assessment, and postoperative assessment of 68.3 ± 16.8, 64.6 ± 18.5, and 81.1 ± 12.0 ETDRS letters, respectively. Mean BVA was significantly higher postoperatively compared with the preoperative assessment and initial evaluation (p < 0.0001). There was a mean of 53.8 days between initial surgical evaluation and surgery date and a mean of 49.9 days between the preoperative assessment and initial surgical evaluation. The mean interval between the preoperative assessment and surgery was 11.7 days. In the preoperative period, 9.1% of eyes experienced worsening of BVA by >3 eyes and 0.9% experienced improvement of BVA by >3 lines. Time to surgery was significantly associated with change in postoperative BVA (effect size, -0.03 ETDRS letters; p = 0.015) but was not significant on multiple linear regression. BVA at initial evaluation, glaucoma, and glaucoma surgery were all significantly associated with postoperative outcomes. CONCLUSION: Most eyes experienced stable vision in the preoperative period for cataract surgery. On average, patients with high BVAs at the time of initial surgical evaluation may be able to defer surgery without the risk of poorer surgical outcomes.