Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial.

BACKGROUND: Geographic atrophy is an advanced form of dry age-related macular degeneration that can lead to irreversible vision loss and high burden of disease. We aimed to assess efficacy and safety of avacincaptad pegol 2 mg in reducing geographic atrophy lesion growth. METHODS: GATHER2 is a randomised, double-masked, sham-controlled, 24-month, phase 3 trial across 205 retina clinics, research hospitals, and academic institutions globally. To be eligible, patients had to be aged 50 years or older with non-centrepoint-involving geographic atrophy and best corrected visual acuity between 20/25 and 20/320 in the study eye. Eligible patients were randomly assigned (1:1) to monthly avacincaptad pegol 2 mg administered as a 100 µL intravitreal injection or sham for the first 12 months. Randomisation was performed using an interactive response technology system with stratification by factors known to be of prognostic importance in age-related macular degeneration. Patients, investigators, study centre staff, sponsor personnel, and data analysts were masked to treatment allocation. The primary endpoint was geographic atrophy lesion size measured by fundus autofluorescence at baseline, month 6, and month 12. Efficacy and safety analyses were done in the modified intention-to-treat and safety populations, respectively. This trial is registered with ClinicalTrials.gov, NCT04435366. FINDINGS: Between June 22, 2020, and July 23, 2021, 1422 patients were screened for eligibility, of whom 448 were enrolled and randomly assigned to avacincaptad pegol 2 mg (n=225) or sham (n=223). One patient in the sham group did not receive study treatment and was excluded from analyses. There were 154 (68%) female patients and 71 (32%) male patients in the avacincaptad pegol 2 mg group, and 156 (70%) female patients and 66 (30%) male patients in the sham group. From baseline to month 12, the mean rate of square-root-transformed geographic atrophy area growth was 0·336 mm/year (SE 0·032) with avacincaptad pegol 2 mg and 0·392 mm/year (0·033) with sham, a difference in growth of 0·056 mm/year (95% CI 0·016-0·096; p=0·0064), representing a 14% difference between the avacincaptad pegol 2 mg group and the sham group. Ocular treatment-emergent adverse events in the study eye occurred in 110 (49%) patients in the avacincaptad pegol 2 mg group and 83 (37%) in the sham group. There were no endophthalmitis, intraocular inflammation, or ischaemic optic neuropathy events over 12 months. To month 12, macular neovascularisation in the study eye occurred in 15 (7%) patients in the avacincaptad pegol 2 mg group and nine (4%) in the sham group, with exudative macular neovascularisation occurring in 11 (5%) in the avacincaptad pegol 2 mg group and seven (3%) in the sham group. INTERPRETATION: Monthly avacincaptad pegol 2 mg was well tolerated and showed significantly slower geographic atrophy growth over 12 months than sham treatment, suggesting that avacincaptad pegol might slow disease progression and potentially change the trajectory of disease for patients with geographic atrophy. FUNDING: Iveric Bio, An Astellas Company.

Three-Year Safety and Efficacy of the 0.19-mg Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: The PALADIN Study.

PURPOSE: To assess the long-term safety and efficacy of the 0.19-mg fluocinolone acetonide (FAc) intravitreal implant (Iluvien; Alimera Sciences, Inc) in patients with diabetic macular edema (DME). DESIGN: Three-year, phase 4, nonrandomized, open-label observational study. PARTICIPANTS: Patients with DME who previously received corticosteroid treatment without a clinically significant rise in intraocular pressure (IOP; all eyes, n = 202 eyes of 159 patients; 36-month completion, n = 94 eyes). METHODS: A prospective, observational study in which patients received a 0.19-mg FAc intravitreal implant at baseline and then were observed for safety-, visual-, anatomic-, and treatment burden-related outcomes for up to 36 months. MAIN OUTCOME MEASURES: Primary safety outcomes included changes in IOP and interventions to manage IOP elevations. Secondary outcomes included changes in best-corrected visual acuity (BCVA), central subfield thickness (CST), and adjunctive DME treatment frequency RESULTS: At 36 months after FAc implantation, study eyes showed a mean CST change of -60.69 µm (P < 0.0001) and a mean BCVA change of +3.61 letters (P = 0.0222) compared with baseline. Overall median treatment frequency decreased from 3.4 treatments/year in the 36 months before FAc implantation to 1 treatment/year in the 36 months after FAc implant, a treatment burden reduction of 70.5%. Furthermore, among the group that completed 36 months of treatment (n = 94 eyes), 25.53% of eyes remained rescue free through 36 months. Mean IOP remained stable throughout the study, and IOP increases to more than 30 mmHg occurred in 10.89% of eyes. Intraocular pressure-related procedures were infrequent, with a surgical rate of 2.97%, with 1.49% attributable to steroid use (vs. surgeries attributable primarily to neovascular glaucoma). In addition, an IOP response of < 25 mmHg after the steroid challenge predicted that 96.92% of eyes would have a similar outcome to 0.19-mg FAc implant at the last visit. Intraocular pressure increases that did occur were manageable with standard treatments (n = 202 eyes). CONCLUSIONS: In patients with DME, the 0.19-mg FAc implant provided improved visual outcomes and reduced treatment burden compared with previous treatments while maintaining a favorable safety profile.

Practice Guidelines for Ocular Telehealth-Diabetic Retinopathy, Third Edition.

Contributors The following document and appendices represent the third edition of the Practice Guidelines for Ocular Telehealth-Diabetic Retinopathy. These guidelines were developed by the Diabetic Retinopathy Telehealth Practice Guidelines Working Group. This working group consisted of a large number of subject matter experts in clinical applications for telehealth in ophthalmology. The editorial committee consisted of Mark B. Horton, OD, MD, who served as working group chair and Christopher J. Brady, MD, MHS, and Jerry Cavallerano, OD, PhD, who served as cochairs. The writing committees were separated into seven different categories. They are as follows: 1.Clinical/operational: Jerry Cavallerano, OD, PhD (Chair), Gail Barker, PhD, MBA, Christopher J. Brady, MD, MHS, Yao Liu, MD, MS, Siddarth Rathi, MD, MBA, Veeral Sheth, MD, MBA, Paolo Silva, MD, and Ingrid Zimmer-Galler, MD. 2.Equipment: Veeral Sheth, MD (Chair), Mark B. Horton, OD, MD, Siddarth Rathi, MD, MBA, Paolo Silva, MD, and Kristen Stebbins, MSPH. 3.Quality assurance: Mark B. Horton, OD, MD (Chair), Seema Garg, MD, PhD, Yao Liu, MD, MS, and Ingrid Zimmer-Galler, MD. 4.Glaucoma: Yao Liu, MD, MS (Chair) and Siddarth Rathi, MD, MBA. 5.Retinopathy of prematurity: Christopher J. Brady, MD, MHS (Chair) and Ingrid Zimmer-Galler, MD. 6.Age-related macular degeneration: Christopher J. Brady, MD, MHS (Chair) and Ingrid Zimmer-Galler, MD. 7.Autonomous and computer assisted detection, classification and diagnosis of diabetic retinopathy: Michael Abramoff, MD, PhD (Chair), Michael F. Chiang, MD, and Paolo Silva, MD.

Quantifying Fluid and Function in Suboptimal Responders Switched From an Anti-vascular Endothelial Growth Factor (VEGF) to Faricimab.

Background Anti-vascular endothelial growth factor (VEGF) injections have been successful in reducing vision loss from neovascular age-related macular degeneration, a leading cause of blindness. Due to the high treatment burden and suboptimal responses, switching to bi-specific faricimab treatment may lead to improved outcomes. Methods This retrospective chart review evaluated if suboptimal responders to anti-VEGF injections had better outcomes when switched to faricimab. Suboptimal responders were defined as patients with a history of >3 months of injections and the presence of fluid after ≥3 injections. The primary endpoints were best-corrected visual acuity, treatment interval, and fluid levels. Visual acuity measurements and optical coherence tomography were performed before each injection. The total fluid area (TFA) was measured using MATLAB 2023a (MathWorks, Natick, MA, USA). Results Nineteen eyes were included in the analysis. After three faricimab injections, average letters increased from 54.5 to 59.0 (SD: 15.3; p<0.05), and the injection interval was extended from 7.6 to 9.3 weeks (SD: 3.9; p<0.01) after four injections. Patients also experienced anatomical retinal changes, with a reduction in the TFA to 47.3% (p<0.005) after the second injection and a reduction in pigment epithelial detachment height to 82.3% (p<0.005) after one injection. The central subfield thickness was significantly reduced after the second injection (90.6% (SD: 17.6%) p<0.05). Conclusion Switching to faricimab after a suboptimal anti-VEGF response results in improvements in visual acuity, reduced treatment burden, and reduced fluid levels.

Screen failures in clinical trials in retina.

PURPOSE: Disparities in clinical trials are a major problem due to significant underrepresentation of certain gender, racial and ethnic groups. Several factors including stringent eligibility criteria and recruitment strategies hinder our understanding of retinal disease. Thus, we aimed to study the various reasons of screen failures and specific patient and study characteristics among screen failures. DESIGN: This is a cross-sectional retrospective study METHODS: Screening data of 87 trials from 6 centers were analyzed. Study characteristics (disease studied, phase of trial, route of drug administration) and patient demographics (age, gender, race, ethnicity, and employment status) were compared among different causes of screen failures. Screen failures were broadly classified into six categories: exclusion due to vision-based criteria, exclusion due to imaging findings, exclusion due to other factors, patient-related criteria, physician related criteria and miscellaneous. Descriptive statistics, Pearson Chi-square test and ANOVA were used for statistical analysis. MAIN OUTCOME MEASURES: Determine the prevalence of various reasons for screen failures in multiple trials and its trend among different study and patient characteristics. RESULTS: Among 87 trials and 962 patients, 465(48.2%) patients were successfully randomized and 497(51.8%) patients were classified as screen failures. The trials were conducted for various retinal diseases. Mean age was 76.50 ±10.45 years and 59.4% were females. Predominantly whites(93.4%) and unemployed/retired patients(66.6%) were screened. Of the 497 screen failures, most were due to patients not meeting inclusion criteria of imaging findings (n=221[44.5%]) followed by inclusion of vision-based criteria (n=73 [14.7%]), exclusion due to other factors (n=75[15.1%]), patient-related (n=34[6.8%]), physician-related (n=28[5.6%]) and miscellaneous reasons (n= 39[17.8%]). Reason for screen failure was not available for 27(5.4%) patients. A higher proportion of patients screened for surgical trials (15%) declined to participate in the study compared to non-invasive trials involving topical drugs and photobiomodulation (0%).(p=0.02) CONCLUSION: Patients not meeting the imaging and vision-cased criteria were the most common reasons for screen failures. Whites and unemployed patients predominantly participated in clinical trials. Patients are more inclined to continue participation in non-invasive clinical trials compared to surgical trials. Better recruitment strategies and careful consideration of study criteria can aid in decreasing the rate of screen failures.

Comparison of the efficacy and safety of SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration.

To compare the efficacy and safety of the proposed aflibercept biosimilar SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration, this randomized, double-masked, parallel-group, multicenter study was conducted in 14 countries from 13 August 2020 to 8 September 2022. Patients with neovascular age-related macular degeneration. With subfoveal, juxtafoveal, or extrafoveal choroidal neovascularization were aged 50 years or older. Intravitreal injection of SCD411 or aflibercept (2.0 mg) were administered every 4 weeks for the first three injections and every 8 weeks until week 48. The primary efficacy endpoint was the change in best-corrected visual acuity from baseline to week 8 with an adjusted equivalence margin of ± 3.0 letters. Patients were randomly assigned to receive either SCD411 (n = 288) or reference aflibercept (n = 288). A total of 566 participants (98.3%) completed week 8 of the study. The least-squares mean difference of change in best-corrected visual acuity from baseline to week 8 (SCD411-aflibercept) was - 0.4 letters (90% confidence interval = - 1.6 to 0.9). The incidence of ocular (69 of 287 [24.0%] vs. 71 of 286 [24.8%]) and serious ocular (5 of 287 [1.7%] vs. 3 of 286 [1.0%]) treatment-emergent adverse effects were similar between the SCD411 and aflibercept groups. Immunogenicity analysis revealed a low incidence of neutralizing antibody formation in both groups. In conclusion, SCD411 has equivalent efficacy compared with reference aflibercept in patients with neovascular age-related macular degeneration and has a comparable safety profile. The results support the potential use of SCD411 for the treatment of neovascular age-related macular degeneration.

Vision Loss Reduction with Avacincaptad Pegol for Geographic Atrophy: A 12-Month Post Hoc Analysis of the GATHER1 and GATHER2 Trials.

PURPOSE: To evaluate the impact of reduction in geographic atrophy (GA) lesion growth on visual acuity in the GATHER trials using categorical outcome measures. DESIGN: Randomized, double-masked, sham-controlled phase 3 trials. PARTICIPANTS: Aged ≥50 years with noncenter point-involving GA and best-corrected visual acuity (BCVA) of 25 to 80 ETDRS letters in the study eye. METHODS: GATHER1 consisted of 2 parts. In part 1, 77 patients were randomized 1:1:1 to avacincaptad pegol (ACP) 1 mg, ACP 2 mg, and sham. In part 2, 209 patients were randomized 1:2:2 to ACP 2 mg, ACP 4 mg, and sham. In GATHER2, patients were randomized 1:1 to ACP 2 mg (n = 225) and sham (n = 223). A post hoc analysis of 12-month data for pooled ACP 2 mg and sham groups is reported. MAIN OUTCOME MEASURES: Proportion of study eyes that experienced ≥10-, ≥15-, or ≥20-BCVA ETDRS letter loss from baseline to month 12; time-to-event analysis of persistent vision loss of ≥10, ≥15, or≥ 20 BCVA letters from baseline at ≥2 consecutive visits over 12 months; proportion of study eyes with BCVA loss to a level below driving eligibility threshold at month 12 among those eligible to drive at baseline. RESULTS: Lower proportions of study eyes experienced ≥10-, ≥15-, or ≥20-BCVA letter loss from baseline over 12 months with ACP 2 mg (11.6%, 4.0%, and 1.6%, respectively) versus sham (14.1%, 7.6%, and 4.5%, respectively). There was a reduction in the risk of persistent loss of ≥15 BCVA ETDRS letters with ACP 2 mg (3.4%) versus sham (7.8%) through 12 months. A lower proportion of study eyes treated with ACP 2 mg reached the threshold for driving ineligibility versus sham by 12 months. CONCLUSIONS: Treatment with ACP 2 mg delayed the risk of progression to persistent vision loss (i.e., ≥10-, ≥15-, and ≥20-BCVA letter loss or BCVA loss to a level below driving eligibility threshold) versus sham over 12 months. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Rationale and Design of VOYAGER: Long-term Outcomes of Faricimab and Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema in Clinical Practice.

Purpose: To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision. Design: Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study. Participants: At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries). Methods: Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions. Main Outcome Measures: Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety. Results: Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually. Conclusions: VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Anti-VEGF Pharmaceutical Prior Authorization in Retina Practices.

Importance: Anti-vascular endothelial growth factor (VEGF) intravitreal injections, a mainstay of treatment for many retinal diseases to optimize visual outcomes, have been included in prior authorization (PA) initiatives. However, if clinicians are extremely accurate in their use of anti-VEGF medications, such administrative burdens may need reconsideration. Objective: To quantify PA for anti-VEGF medications (aflibercept, ranibizumab, and bevacizumab) that were approved and determine associated administrative burdens experienced by retina practices. Design, Setting, and Participants: Prospective multicenter quality improvement study conducted from January 2022 through June 2022, and participants were 9 private retina practices across the US. Main Outcomes and Measures: Overall rate of approval of PA requests, reasons for requesting PA, and overall rate of delay of care resulting from PA procedures. Results: In total, 2365 PA requests were recorded, 2225 of which met inclusion criteria. Overall, 2140 (96.2%) requests were approved. The most common reason for requesting PA, at 64% (1423 of 2225 requests), was reauthorization for a previously utilized medication. Of the 2140 approvals, 59.6% (1277) resulted in a delay in care greater than 24 hours, and 40% (863) were given on the date of service. In a granular analysis of a subset of delayed approvals, 23.9% (173 of 725) were approved within 1 day, 15.9% (115 of 725) were approved within 2 to 3 days, 21.5% (156 of 725) were approved within 4 to 7 days, 26.3% (191 of 725) were approved within 8 to 31 days, and 12.4% (90 of 725) were approved within more than 31 days. Overall, PA denial for step therapy was 2.9% (65 of 2225) of requests and uncovered diagnoses was 0.9% (20 of 2225) of requests. The median staff time spent to obtain a single PA was 100 (range, 0-200) minutes. Conclusions and Relevance: In this study, PA requests were almost always approved but led to a delay in patient care in most patients. The current study suggests that the PA process may not be effective for retina specialists if these results can be generalized to other practices in the US and if less burdensome and less costly approaches could result in similar approval rates. Potential short-term solutions may include eliminating the PA process for bevacizumab and reauthorizations for established patients.

Evaluating the Artificial Intelligence Performance Growth in Ophthalmic Knowledge.

OBJECTIVE: We aim to compare the capabilities of Chat Generative Pre-Trained Transformer (ChatGPT)-3.5 and ChatGPT-4.0 (OpenAI, San Francisco, CA, USA) in addressing multiple-choice ophthalmic case challenges. METHODS AND ANALYSIS: Both models' accuracy was compared across different ophthalmology subspecialties using multiple-choice ophthalmic clinical cases provided by the American Academy of Ophthalmology (AAO) "Diagnosis This" questions. Additional analysis was based on image content, question difficulty, character length of models' responses, and model's alignment with responses from human respondents. χ2 test, Fisher's exact test, Student's t-test, and one-way analysis of variance (ANOVA) were conducted where appropriate, with p<0.05 considered significant. RESULTS: GPT-4.0 significantly outperformed GPT-3.5 (75% versus 46%, p<0.01), with the most noticeable improvement in neuro-ophthalmology (100% versus 38%, p=0.03). While both models struggled with uveitis and refractive questions, GPT-4.0 excelled in other areas, such as pediatric questions (82%). In image-related questions, GPT-4.0 also displayed superior accuracy that trended toward significance (73% versus 46%, p=0.07). GPT-4.0 performed better with easier questions (93.8% (least difficult) versus 76.2% (middle) versus 53.3% (most), p=0.03) and generated more concise answers than GPT-3.5 (651.7±342.9 versus 1,112.9±328.8 characters, p<0.01). Moreover, GPT-4.0's answers were more in line with those of AAO respondents (57.3% versus 41.4%, p<0.01), showing a strong correlation between its accuracy and the proportion of AAO respondents who selected GPT-4.0's answer (ρ=0.713, p<0.01). CONCLUSION AND RELEVANCE: Our study demonstrated that GPT-4.0 significantly outperforms GPT-3.5 in addressing ophthalmic case challenges, especially in neuro-ophthalmology, with improved accuracy even in image-related questions. These findings underscore the potential of advancing artificial intelligence (AI) models in enhancing ophthalmic diagnostics and medical education.

Long-Term Control of Retinal Thickness Variability and Vision Following the 0.19 mg Fluocinolone Acetonide Implant.

Purpose: To assess the impact of retinal thickness variability (RTV) control on visual and treatment burden outcomes in patients with diabetic macular edema (DME) who received the 0.19 mg fluocinolone acetonide (FAc) intravitreal implant (Iluvien, Alimera Sciences). Methods: This post hoc analysis examined the outcomes of a 3-year, phase 4, nonrandomized, open-label observational study. Retinal thickness was measured as central subfield thickness (CST). RTV was quantified by CST area under the curve (CST-AUC), retinal thickness amplitude (RTA), and retinal thickness standard deviation (RTSD). Visual outcomes were measured as best-corrected visual acuity (BCVA), and treatment burden was measured as the number of yearly supplemental DME treatments. Results: The percentage of eyes with a CST ≤300 µm fluctuated throughout the study but was significantly increased relative to baseline at 36 months (baseline: 32.9% vs 36 months: 46.8%; P < .05). FAc significantly reduced RTV in all measures more than 36 months (P < .0001). When divided into quartiles, eyes with the best RTV control post FAc had the greatest BCVA gains and improved disease control (ie, reduced need for supplemental therapy). The last-observed BCVA letter score exhibited linear correlations with CST-AUC (R2 = -0.100), RTA (R2 = -0.125), and RTSD (R2 = -0.162). A multivariate linear regression with baseline BCVA as a covariate displayed improved correlations with the last-observed BCVA, CST-AUC (R2 = -0.448), RTA (R2 = -0.432), and RTSD (R2 = -0.436). Conclusions: The sustained corticosteroid release of the 0.19 mg FAc implant reduced RTV in patients with DME, which directly correlated with significantly improved vision and a reduced supplemental treatment burden.

Examining the Role of Telemedicine in Diabetic Retinopathy.

With the increasing prevalence of diabetic retinopathy (DR), screening is of the utmost importance to prevent vision loss for patients and reduce financial costs for the healthcare system. Unfortunately, it appears that the capacity of optometrists and ophthalmologists to adequately perform in-person screenings of DR will be insufficient within the coming years. Telemedicine offers the opportunity to expand access to screening while reducing the economic and temporal burden associated with current in-person protocols. The present literature review summarizes the latest developments in telemedicine for DR screening, considerations for stakeholders, barriers to implementation, and future directions in this area. As the role of telemedicine in DR screening continues to expand, further work will be necessary to continually optimize practices and improve long-term patient outcomes.

Efficacy and Safety of Brolucizumab for Diabetic Macular Edema: The KINGFISHER Randomized Clinical Trial.

Importance: Despite the effectiveness of existing anti-vascular endothelial growth factor (VEGF) therapies, a need remains for further treatment options to improve response rates and/or reduce injection or monitoring frequency in patients with diabetic macular edema (DME). Objective: To evaluate the efficacy and safety of brolucizumab vs aflibercept dosed every 4 weeks in participants with DME. Design, Participants, and Setting: This 52-week, double-masked, phase 3 randomized clinical trial included treatment-naive adults and adults who had previously received anti-VEGF therapy. Data were collected from September 2019 to March 2020, and data were analyzed from April 2020 to February 2021. Intervention: Brolucizumab, 6 mg, intravitreal injection every 4 weeks or aflibercept, 2 mg, intravitreal injection every 4 weeks. Main Outcomes and Measures: Participants were randomized 2:1 to brolucizumab, 6 mg, or aflibercept, 2 mg. The primary end point was change from baseline in best-corrected visual acuity at week 52. Secondary end points were the proportion of participants with a 2-step improvement or greater from baseline in Diabetic Retinopathy Severity Scale score, the proportion of eyes with absence of both subretinal fluid and intraretinal fluid, change from baseline in central subfield thickness, and safety at week 52. Results: A total of 517 participants were randomized to brolucizumab (n = 346) or aflibercept (n = 171); 299 (57.8%) were male, and the mean (SD) age was 60.7 (10.2) years. Brolucizumab was noninferior to aflibercept in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score) change from baseline at week 52 (brolucizumab, 12.2-letter improvement; aflibercept, 11.0-letter improvement; difference, 1.1; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P < .001). Brolucizumab was superior to aflibercept for the proportion of eyes without subretinal and intraretinal fluid (brolucizumab, 144 of 346 [41.6%]; aflibercept, 38 of 171 [22.2%]; difference, 20.0%; 95% CI, 12.5to 28.6; P < .001) and mean central subfield thickness change from baseline at week 52 (brolucizumab, -237.8 µm; aflibercept, -196.5 µm; difference, -41.4; 95% CI, -58.9 to -23.8; P < .001). Incidence of intraocular inflammation was 4.0% (14 of 346) in the brolucizumab arm and 2.9% (5 of 171) in the aflibercept arm, incidence of retinal vasculitis was 0.9% (3 of 346) and 0.6% (1 of 171), respectively, and incidence of retinal vascular occlusion was 0.3% (1 of 346) and 0.6% (1 of 171). One participant in the brolucizumab arm had retinal artery occlusion. Conclusions and Relevance: In these study participants with DME, no clinically meaningful differences in visual outcomes were noted between the brolucizumab and aflibercept arms; some superior anatomic improvements were noted in the brolucizumab arm. No new safety concerns were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03917472.

The real-world efficacy and safety of faricimab in neovascular age-related macular degeneration: the TRUCKEE study - 6 month results.

BACKGROUND/OBJECTIVE: Investigate real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD). SUBJECTS/METHODS: Multicenter, retrospective chart review was conducted on patients treated with faricimab for nAMD from February 2022 to September 2022. Collected data includes background demographics, treatment history, best-corrected visual acuity (BCVA), anatomic changes, and adverse events as safety markers. The main outcome measures are changes in BCVA, changes in central subfield thickness (CST) and adverse events. Secondary outcome measures included treatment intervals and presence of retinal fluid. RESULTS: After one injection of faricimab, all eyes (n = 376), previously-treated (n = 337) and treatment-naïve (n = 39) eyes demonstrated a + 1.1 letter (p = 0.035), a + 0.7 letter (p = 0.196) and a + 4.9 letter (p = 0.076) improvement in BCVA, respectively, and a - 31.3 µM (p < 0.001), a - 25.3 µM (p < 0.001) and a - 84.5 µM (p < 0.001) reduction in CST, respectively. After three injections of faricimab, all eyes (n = 94), previously-treated (n = 81) and treatment-naïve (n = 13) eyes demonstrated a + 3.4 letter (p = 0.03), a + 2.7 letter (p = 0.045) and a + 8.1 letter (p = 0.437) improvement in BCVA, and a - 43.4 µM (p < 0.001), a - 38.1 µM (p < 0.001) and a - 80.1 µM (p < 0.204) reduction in CST, respectively. One case of intraocular inflammation was observed after four injections of faricimab and resolved with topical steroids. One case of infectious endophthalmitis was treated with intravitreal antibiotics and resolved. CONCLUSIONS: Faricimab has demonstrated improvement or maintenance of visual acuity for patients with nAMD, along with rapid improvement of anatomical parameters. It has been well-tolerated with low incidence of treatable intraocular inflammation. Future data will continue to investigate faricimab for real-world patients with nAMD.

Fluctuations in central foveal thickness and association with vision outcomes with anti-VEGF therapy for nAMD: HARBOR post hoc analysis.

Objective: To evaluate correlations between variability in central foveal thickness (CFT) and vision with ranibizumab in a HARBOR post hoc analysis. Methods and analysis: Patients with neovascular age-related macular degeneration (nAMD; N=1097) received monthly or as-needed (PRN) ranibizumab (0.5 or 2.0 mg) for 24 months. Fluctuation scores were used to assess CFT variability; every time CFT increased and then decreased (or vice versa), numeric value of the change was added to the score. Magnitude of change <50 µm was considered clinically insignificant and did not count towards the score. Fluctuation scores were grouped into quartiles. Least squares mean (LSM) changes in best-corrected visual acuity (BCVA) were plotted against fluctuation score quartiles for CFT, subretinal fluid (SRF) height, neurosensory retina and neurosensory retina + subretinal hyper-reflective material. Results: Patients with lower fluctuations scores (quartiles 1-3) had greatest vision gains at month 24, with LSM changes from baseline of 9.0-10.8 and 8.7-10.6 letters in the monthly and PRN arms, respectively. Corresponding changes for quartile 4 were 6.7 and 6.5 letters, respectively. There were no differences between quartiles for association between fluctuations in SRF height and BCVA gains. There were inverse correlations between magnitude of fluctuations in neurosensory and inner retina thickness and BCVA gains for quartile 4 vs quartiles 1-3. Patients in quartiles 1 and 2 showed rapid, robust BCVA gains, whereas those in quartiles 3 and 4 had lesser responses. Conclusions: Fluctuations in retinal thickening with ranibizumab may be associated with treatment response in patients with nAMD. Trial registration number: NCT00891735.

Targeting the Complement Cascade for Treatment of Dry Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the elderly population. AMD is characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). Regarding the latter type, there is growing evidence supporting an association between the pathophysiology of dry AMD and key proteins in the complement cascade. The complement cascade works as a central part of the innate immune system by defending against foreign pathogens and modified self-tissues. Through three distinct pathways, a series of plasma and membrane-associated serum proteins are activated upon identification of a foreign entity. Several of these proteins have been implicated in the development and progression of dry AMD. Potential therapeutic targets include C1q, C3, C5, complement factors (B, D, H, I), membrane attack complex, and properdin. In this review, we provide an understanding of the role of the complement system in dry AMD and discuss the emerging therapies in early phase clinical trials. The tentative hope is that these drugs may offer the potential to intervene at earlier stages in dry AMD pathogenesis, thereby preventing progression to late disease.

Telemedicine for Retinal Disease During the COVID-19 Pandemic: Survey of the Patient Perspective.

INTRODUCTION: Amidst the COVID-19 pandemic, telemedicine has emerged as a safe and cost-effective alternative to traditional ophthalmology clinic visits. This study evaluated patient attitudes towards telemedicine at a full-service, retina-only practice to identify areas for growth in implementation. METHODS: A survey was distributed to established patients at University Retina and Macula Associates following the completion of a telemedicine encounter in July 2021. On a 5-point Likert scale, patients compared telemedicine to in-person visits for six domains: ability to ease COVID-related anxiety, efficiency, patient education, quality of care, fulfillment of personal needs, and convenience. Pearson's χ2 and Fisher's exact test were used to assess correlations between demographic factors and patient attitudes or preference towards telemedicine. RESULTS: Among 103 respondents, two-thirds (68.7%) preferred in-person compared to telemedicine encounters. Overall, patients had a neutral attitude towards telemedicine [mean Likert rating (SD) = 3.11/5 ± 0.82]. Questions assessing "patient education" and "telemedicine efficiency" received the greatest proportion of positive and negative responses, respectively. Positive attitudes were more frequent among patients with prior telemedicine experience (87.5%) compared to never-users (71.8%; p = 0.046). Patients ≥ 75 years old tended to negatively assess telemedicine regarding reduction of COVID-19-related anxiety, efficiency, patient education, and physician facetime (p < 0.05 for all). A positive but non-significant trend was observed between higher education level and positive attitude towards telemedicine (p = 0.18). Telehealth never-users more often negatively rated receiving adequate facetime with the physician virtually (54.7%) compared to prior users (25.6%; p = 0.004). Younger age, prior history of telemedicine use, and higher education level were associated with increased preference for telemedicine (p < 0.05 for all). CONCLUSION: Our findings revealed hesitance remains among patients towards adoption of telemedicine. Targeting age-, experience-, and education-related barriers will be invaluable for increasing acceptance of this healthcare delivery model.

Conjunctiva and Tenon's Capsule Handling in the Port Delivery System with Ranibizumab Implant Insertion Procedure: Surgical Pearls.

OBJECTIVES: To describe conjunctiva and Tenon's capsule handling during the Port Delivery System with ranibizumab (PDS) implant insertion procedure including up-front assessments, planning, and instrumentation, with emphasis placed on the peritomy, scleral dissection, and closure steps. METHODS: Surgical pearls based on experience accumulated in the PDS clinical trial program in patients with retinal diseases. RESULTS: Preoperative preparation, specific instruments, and meticulous techniques are key to optimizing surgical outcomes. Before surgery, assessment of factors that affect conjunctival integrity and an in-office conjunctiva examination are conducted. Gentle, purposeful conjunctiva and Tenon's capsule handling with nontoothed forceps and suturing with a BV needle are recommended to prevent tissue damage. The peritomy is 6 mm by 6 mm, centered around the planned implant location in the superotemporal quadrant. A complete sub-Tenon's capsule dissection is achieved using a wide, robust lateral and posterior dissection technique to free tissue from the sclera and minimize tension. The globe is stabilized during scleral cutdown by grasping the sclera with fine-toothed forceps away from the incision edge to prevent tissue delamination. When closing the peritomy, both the conjunctiva and Tenon's capsule are completely captured and sutured with scleral anchoring at the apex of the peritomy to help prevent conjunctival retraction and erosion. Mitigation and detection of adverse events is critical to successful surgical outcomes. CONCLUSIONS: The PDS implant insertion procedure is straightforward, but it requires planned preoperative preparation, specific instruments, and meticulous techniques. The surgical pearls described here offer insights for optimizing outcomes. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:266-273.].

A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with neovascular age-related macular degeneration. DESIGN: A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study. METHODS: Trial includes n = 90 patients with active choroidal neovascularization due to neovascular age-related macular degeneration and under anti-vascular endothelial growth factor treatment. All patients received an intravitreal injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then 3 times a day for the last 4 weeks. MAIN OUTCOME MEASURE: The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness, and changes of visual acuity from baseline to day 84. RESULTS: The extended per protocol set included 70 patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by day 84 (P = .8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency. CONCLUSION: In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.

New and Innovative Treatments for Neovascular Age-Related Macular Degeneration (nAMD).

Age-related macular degeneration (AMD) is one of the most common causes of vision loss. Advanced forms of AMD are seen in primarily two types-neovascular AMD (nAMD) with the presence of choroid neovascularization and non-neovascular AMD (nnAMD) with geographic atrophy. Neovascular AMD is characterized by choroidal neovascularization (CNV), which leads to a cascade of complications, including exudation, leakage, and ultimately fibrosis with photoreceptor loss. Inhibition of VEGF represents the current standard of care. However, there is a tremendous gap between the outcomes in randomized clinical trials and real-world settings. New agents for nAMD might offer the potential to improve treatment outcomes and reduce treatment of frequent intravitreal injections. We summarize all the newer molecules, their pivotal clinical trial results, and their unique mechanisms of action; these include longer-acting agents, combination strategies, sustained release, and genetic therapies.