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.

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.

COMPARATIVE ANALYSIS OF OCT AND OCT ANGIOGRAPHY CHARACTERISTICS IN EARLY DIABETIC RETINOPATHY.

PURPOSE: To assess the quantitative characteristics of optical coherence tomography (OCT) and OCT angiography (OCTA) for the objective detection of early diabetic retinopathy (DR). METHODS: This was a retrospective and cross-sectional study, which was carried out at a tertiary academic practice with a subspecialty. Twenty control participants, 15 people with diabetics without retinopathy (NoDR), and 22 people with mild nonproliferative diabetic retinopathy (NPDR) were included in this study. Quantitative OCT characteristics were derived from the photoreceptor hyperreflective bands, i.e., inner segment ellipsoid (ISe) and retinal pigment epithelium (RPE). OCTA characteristics, including vessel diameter index (VDI), vessel perimeter index (VPI), and vessel skeleton density (VSD), were evaluated. RESULTS: Quantitative OCT analysis indicated that the ISe intensity was significantly trending downward with DR advancement. Comparative OCTA revealed VDI, VPI, and VSD as the most sensitive characteristics of DR. Correlation analysis of OCT and OCTA characteristics revealed weak variable correlation between the two imaging modalities. CONCLUSION: Quantitative OCT and OCTA analyses revealed photoreceptor and vascular distortions in early DR. Comparative analysis revealed that the OCT intensity ratio, ISe/RPE, has the best sensitivity for early DR detection. Weak variable correlation of the OCT and OCTA characteristics suggests that OCT and OCTA are providing supplementary information for DR detection and classification.

Rhegmatogenous retinal detachment surgery: A review.

Rhegmatogenous retinal detachment (RRD) is a serious surgical condition with significant ocular morbidity if not managed properly. Once untreatable, approaches to the repair of RRD have greatly evolved over the years, leading to outstanding primary surgical success rates. The management of RRD is often a topic of great debate. Scleral buckling, vitrectomy and pneumatic retinopexy have been used successfully for the treatment of RRD. Several factors may affect surgical success and dictate a surgeon's preference for the technique employed. In this review, we provide an overview and supporting literature on the options for RRD repair and their respective preoperative and postoperative considerations in order to guide surgical management.

From Data to Deployment: The Collaborative Community on Ophthalmic Imaging Roadmap for Artificial Intelligence in Age-Related Macular Degeneration.

OBJECTIVE: Health care systems worldwide are challenged to provide adequate care for the 200 million individuals with age-related macular degeneration (AMD). Artificial intelligence (AI) has the potential to make a significant, positive impact on the diagnosis and management of patients with AMD; however, the development of effective AI devices for clinical care faces numerous considerations and challenges, a fact evidenced by a current absence of Food and Drug Administration (FDA)-approved AI devices for AMD. PURPOSE: To delineate the state of AI for AMD, including current data, standards, achievements, and challenges. METHODS: Members of the Collaborative Community on Ophthalmic Imaging Working Group for AI in AMD attended an inaugural meeting on September 7, 2020, to discuss the topic. Subsequently, they undertook a comprehensive review of the medical literature relevant to the topic. Members engaged in meetings and discussion through December 2021 to synthesize the information and arrive at a consensus. RESULTS: Existing infrastructure for robust AI development for AMD includes several large, labeled data sets of color fundus photography and OCT images; however, image data often do not contain the metadata necessary for the development of reliable, valid, and generalizable models. Data sharing for AMD model development is made difficult by restrictions on data privacy and security, although potential solutions are under investigation. Computing resources may be adequate for current applications, but knowledge of machine learning development may be scarce in many clinical ophthalmology settings. Despite these challenges, researchers have produced promising AI models for AMD for screening, diagnosis, prediction, and monitoring. Future goals include defining benchmarks to facilitate regulatory authorization and subsequent clinical setting generalization. CONCLUSIONS: Delivering an FDA-authorized, AI-based device for clinical care in AMD involves numerous considerations, including the identification of an appropriate clinical application; acquisition and development of a large, high-quality data set; development of the AI architecture; training and validation of the model; and functional interactions between the model output and clinical end user. The research efforts undertaken to date represent starting points for the medical devices that eventually will benefit providers, health care systems, and patients.

QUANTITATIVE OPTICAL COHERENCE TOMOGRAPHY REVEALS ROD PHOTORECEPTOR DEGENERATION in EARLY DIABETIC RETINOPATHY.

PURPOSE: This study is to test the feasibility of optical coherence tomography (OCT) detection of photoreceptor abnormality and to verify that the photoreceptor abnormality is rod predominated in early diabetic retinopathy (DR). METHODS: OCT images were acquired from normal eyes, diabetic eyes with no DR, and mild nonproliferative DR (NPDR). Quantitative features, including thickness measurements quantifying band distances and reflectance intensity features among the external limiting membrane, inner segment ellipsoid, interdigitation zone, and retinal pigment epithelium were determined. Comparative OCT analysis of central fovea, parafovea, and perifovea were implemented to verify that the photoreceptor abnormality is rod predominated in early DR. RESULTS: Thickness abnormalities between the inner segment ellipsoid and interdigitation zone also showed a decreasing trend among cohorts. Reflectance abnormalities of the external limiting membrane, interdigitation zone, and inner segment ellipsoid were observed between healthy, no DR, and mild NPDR eyes. The normalized inner segment ellipsoid/retinal pigment epithelium intensity ratio revealed a significant decreasing trend in the perifovea, but no detectable difference in central fovea. CONCLUSION: Quantitative OCT analysis consistently revealed outer retina, i.e., photoreceptor changes in diabetic patients with no DR and mild NPDR. Comparative analysis of central fovea, parafovea, and perifovea confirmed that the photoreceptor abnormality is rod-predominated in early DR.

VASCULAR COMPLEXITY ANALYSIS IN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF DIABETIC RETINOPATHY.

PURPOSE: This study aimed to verify the feasibility of using vascular complexity features for objective differentiation of controls and nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) patients. METHODS: This was a cross-sectional study conducted in a tertiary, subspecialty, academic practice. The cohort included 20 control subjects, 60 NPDR patients, and 56 PDR patients. Three vascular complexity features, including the vessel complexity index, fractal dimension, and blood vessel tortuosity, were derived from each optical coherence tomography angiography image. A shifting-window measurement was further implemented to identify local feature distortions due to localized neovascularization and mesh structures in PDR. RESULTS: With mean value analysis of the whole-image, only the vessel complexity index and blood vessel tortuosity were able to classify NPDR versus PDR patients. Comparative shifting-window measurement revealed increased sensitivity of complexity feature analysis, particularly for NPDR versus PDR classification. A multivariate regression model indicated that the combination of all three vascular complexity features with shifting-window measurement provided the best classification accuracy for controls versus NPDR versus PDR. CONCLUSION: Vessel complexity index and blood vessel tortuosity were the most sensitive in differentiating NPDR and PDR patients. A shifting-window measurement increased the sensitivity significantly for objective optical coherence tomography angiography classification of diabetic retinopathy.

QUANTITATIVE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES FOR OBJECTIVE CLASSIFICATION AND STAGING OF DIABETIC RETINOPATHY.

PURPOSE: This study aims to characterize quantitative optical coherence tomography angiography (OCTA) features of nonproliferative diabetic retinopathy (NPDR) and to validate them for computer-aided NPDR staging. METHODS: One hundred and twenty OCTA images from 60 NPDR (mild, moderate, and severe stages) patients and 40 images from 20 control subjects were used for this study conducted in a tertiary, subspecialty, academic practice. Both eyes were photographed and all the OCTAs were 6 mm × 6 mm macular scans. Six quantitative features, that is, blood vessel tortuosity, blood vascular caliber, vessel perimeter index, blood vessel density, foveal avascular zone area, and foveal avascular zone contour irregularity (FAZ-CI) were derived from each OCTA image. A support vector machine classification model was trained and tested for computer-aided classification of NPDR stages. Sensitivity, specificity, and accuracy were used as performance metrics of computer-aided classification, and receiver operation characteristics curve was plotted to measure the sensitivity-specificity tradeoff of the classification algorithm. RESULTS: Among 6 individual OCTA features, blood vessel density shows the best classification accuracies, 93.89% and 90.89% for control versus disease and control versus mild NPDR, respectively. Combined feature classification achieved improved accuracies, 94.41% and 92.96%, respectively. Moreover, the temporal-perifoveal region was the most sensitive region for early detection of DR. For multiclass classification, support vector machine algorithm achieved 84% accuracy. CONCLUSION: Blood vessel density was observed as the most sensitive feature, and temporal-perifoveal region was the most sensitive region for early detection of DR. Quantitative OCTA analysis enabled computer-aided identification and staging of NPDR.

ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.

PURPOSE: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. METHODS: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. RESULTS: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. CONCLUSION: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

Electrophysiological and pupillometric measures of inner retina function in nonproliferative diabetic retinopathy.

PURPOSE: To evaluate three measures of inner retina function, the pattern electroretinogram (pERG), the photopic negative response (PhNR), and the post-illumination pupil response (PIPR) in diabetics with and without nonproliferative diabetic retinopathy (NPDR). METHODS: Fifteen non-diabetic control subjects and 45 type 2 diabetic subjects participated (15 have no clinically apparent retinopathy [NDR], 15 have mild NPDR, and 15 have moderate/severe NPDR). The pERG was elicited by a contrast-reversing checkerboard pattern, and the PhNR was measured in response to a full-field, long-wavelength flash presented against a short-wavelength adapting field. The PIPR was elicited by a full-field, 450 cd/m2, short-wavelength flash. All responses were recorded and analyzed using conventional techniques. One-way ANOVAs were performed to compare the pERG, PhNR, and PIPR among the control and diabetic groups. RESULTS: ANOVA indicated statistically significant differences among the control and diabetic subjects for all three measures. Holm-Sidak post hoc comparisons indicated small, nonsignificant reductions in the pERG (8%), PhNR (8%), and PIPR (10%) for the NDR group compared to the controls (all p > 0.25). In contrast, there were significant reductions in the pERG (35), PhNR (34%), and PIPR (30%) for the mild NPDR group compared to the controls (all p < 0.01). Likewise, there were significant reductions in the pERG (40%), PhNR (32%), and PIPR (32%) for the moderate/severe NPDR group compared to the controls (all p < 0.01). CONCLUSION: Abnormalities of the pERG, PhNR, and PIPR suggest inner retina neural dysfunction in diabetics who have clinically apparent vascular abnormalities. Taken together, these measures provide a noninvasive, objective approach to study neural dysfunction in these individuals.

AMPLITUDE LOSS OF THE HIGH-FREQUENCY FLICKER ELECTRORETINOGRAM IN EARLY DIABETIC RETINOPATHY.

PURPOSE: To evaluate retinal dysfunction in diabetic patients who have mild or no nonproliferative diabetic retinopathy (DR) using the high-frequency flicker electroretinogram. METHODS: Light-adapted flicker electroretinograms were recorded from 15 diabetic patients who have no clinically apparent retinopathy, 15 diabetic patients who have mild nonproliferative DR, and 15 nondiabetic, age-equivalent controls. Electroretinograms were elicited by full-field flicker at 2 temporal frequencies, 31.25 and 62.5 Hz, and were recorded using conventional techniques. Amplitude and timing of the flicker responses were compared among the groups and correlated with clinical characteristics including age, acuity, disease duration, and HbA1c. RESULTS: The 31.25-Hz flicker amplitude was slightly, but nonsignificantly, smaller for subjects with no DR and mild nonproliferative DR , compared with the control group (both t < 1.38, P > 0.31); small, nonsignificant response delays for both patient groups were also observed (both t < 1.57, P > 0.12). By contrast, there were significant amplitude reductions for the 62.5-Hz flicker stimulus: mean amplitude was reduced by 32% for subjects with no DR and by 41% for subjects with mild nonproliferative DR (both t > 2.92 and P < 0.01). Response timing at 62.5 Hz did not differ significantly from control for either group (both t < 1.2 and P > 0.39). Electroretinogram amplitude and timing were not correlated significantly with clinical characteristics. CONCLUSION: The 62.5-Hz flicker electroretinogram is useful for evaluating retinal dysfunction in diabetic patients who have mild or no DR because this response can be significantly reduced. Attenuation of the high-frequency flicker electroretinogram, which is primarily generated by bipolar cells, suggests a relatively early retinal site of neural dysfunction.

COMPARISON OF VISUAL AND ANATOMICAL OUTCOMES OF EYES UNDERGOING TYPE I BOSTON KERATOPROSTHESIS WITH COMBINATION PARS PLANA VITRECTOMY WITH EYES WITHOUT COMBINATION VITRECTOMY.

PURPOSE: To determine whether 1-year visual and anatomical results after surgery combining pars plana vitrectomy, Boston keratoprosthesis, and a glaucoma drainage device as needed are similar, better, or worse than Boston keratoprosthesis initial implantation alone. METHODS: We performed a retrospective review of adult patients undergoing Boston keratoprosthesis at our institution. Visual acuity outcomes, anatomical results, and complication rates of patients undergoing combination surgery (including pars plana vitrectomy and a posterior glaucoma drainage device) were compared with those undergoing keratoprosthesis placement alone. RESULTS: There were 70 eyes in the keratoprosthesis alone group and 55 eyes in the keratoprosthesis with pars plana vitrectomy group. Mean follow-up durations were 54.67 months in the keratoprosthesis alone group and 48.41 months in the combination group. Baseline mean Snellen equivalent visual acuities were worse for the combination group compared with the keratoprosthesis alone group (P = 0.027). Visual acuities improved postoperatively by 1 month after keratoprosthesis implantation for both groups and improved three or more lines of Snellen acuity in the majority of eyes for both groups (≥72% by 12 months). Eyes undergoing pars plana vitrectomy had lower rates of de novo (P = 0.015) and significantly lower rates of secondary procedures (P = 0.002) at 1 year. One year complications rates for retroprosthetic membrane formation, retinal detachment, hypotony, cystoid macular edema, epiretinal membrane formation, endophthalmitis, and corneal melting were similar for both groups. CONCLUSION: Compared with keratoprosthesis alone, combining keratoprosthesis with pars plana vitrectomy and a glaucoma drainage device as needed, resulted in lower rates of de novo glaucoma, lower rates of additional surgical procedures, similar visual acuity outcomes at 1 year, and did not result in higher complication rates.

Worldwide Argus II implantation: recommendations to optimize patient outcomes.

BACKGROUND: A position paper based on the collective experiences of Argus II Retinal Prosthesis System investigators to review strategies to optimize outcomes in patients with retinitis pigmentosa undergoing retinal prosthesis implantation. METHODS: Retinal surgeons, device programmers, and rehabilitation specialists from Europe, Canada, Middle East, and the United States were convened to the first international Argus II Investigator Meeting held in Ann Arbor, MI in March 2015. The recommendations from the collective experiences were collected. Factors associated with successful outcomes were determined. RESULTS: Factors leading to successful outcomes begin with appropriate patient selection, expectation counseling, and preoperative retinal assessment. Challenges to surgical implantation include presence of staphyloma and inadequate Tenon's capsule or conjunctiva. Modified surgical technique may reduce risks of complications such as hypotony and conjunctival erosion. Rehabilitation efforts and correlation with validated outcome measures following implantation are critical. CONCLUSIONS: Bringing together Argus II investigators allowed the identification of strategies to optimize patient outcomes. Establishing an on-line collaborative network will foster coordinated research efforts to advance outcome assessment and rehabilitation strategies.