Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials.

BACKGROUND: Geographic atrophy is a leading cause of progressive, irreversible vision loss. The objectives of OAKS and DERBY were to assess the efficacy and safety of pegcetacoplan compared with sham treatment in patients with geographic atrophy. METHODS: OAKS and DERBY were two 24-month, multicentre, randomised, double-masked, sham-controlled, phase 3 studies, in which patients aged 60 years and older with geographic atrophy secondary to age-related macular degeneration were enrolled at 110 clinical sites and 122 clinical sites worldwide, respectively. Patients were randomly assigned (2:2:1:1) by central web-based randomisation system to intravitreal 15 mg per 0·1 mL pegcetacoplan monthly or every other month, or sham monthly or every other month using stratified permuted block randomisation (stratified by geographic atrophy lesion area at screening, history or presence of active choroidal neovascularisation in the eye not under assessment, and block size of six). Study site staff, patients, reading centre personnel, evaluating physicians, and the funder were masked to group assignment. Sham groups were pooled for the analyses. The primary endpoint was the change from baseline to month 12 in the total area of geographic atrophy lesions in the study eye based on fundus autofluorescence imaging, in the modified intention-to-treat population (ie, all patients who received one or more injections of pegcetacoplan or sham and had a baseline and at least one post-baseline value of lesion area). Key secondary endpoints (measured at 24 months) were change in monocular maximum reading speed of the study eye, change from baseline in mean functional reading independence index score, change from baseline in normal luminance best-corrected visual acuity score, and change from baseline in the mean threshold sensitivity of all points in the study eye by mesopic microperimetry (OAKS only). Safety analyses included patients who were randomly assigned and received at least one injection of pegcetacoplan or sham. The now completed studies are registered with ClinicalTrials.gov, NCT03525613 (OAKS) and NCT03525600 (DERBY). FINDINGS: Between Aug 30, 2018, and July 3, 2020, 1258 patients were enrolled in OAKS and DERBY. The modified intention-to-treat populations comprised 614 (96%) of 637 patients in OAKS (202 receiving pegcetacoplan monthly, 205 pegcetacoplan every other month, and 207 sham) and 597 (96%) of 621 patients in DERBY (201 receiving pegcetacoplan monthly, 201 pegcetacoplan every other month, and 195 sham). In OAKS, pegcetacoplan monthly and pegcetacoplan every other month significantly slowed geographic atrophy lesion growth by 21% (absolute difference in least-squares mean -0·41 mm2, 95% CI -0·64 to -0·18; p=0·0004) and 16% (-0·32 mm2, -0·54 to -0·09; p=0·0055), respectively, compared with sham at 12 months. In DERBY, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth, although it did not reach significance, by 12% (-0·23 mm2, -0·47 to 0·01; p=0·062) and 11% (-0·21 mm2, -0·44 to 0·03; p=0·085), respectively, compared with sham at 12 months. At 24 months, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth by 22% (-0·90 mm2, -1·30 to -0·50; p<0·0001) and 18% (-0·74 mm2, -1·13 to -0·36; p=0·0002) in OAKS, and by 19% (-0·75 mm2, -1·15 to -0·34; p=0·0004) and 16% (-0·63 mm2, -1·05 to -0·22; p=0·0030) in DERBY, respectively, compared with sham. There were no differences in key secondary visual function endpoints at 24 months. Serious ocular treatment-emergent adverse events were reported in five (2%) of 213, four (2%) of 212, and one (<1%) of 211 patients in OAKS, and in four (2%) of 206, two (1%) of 208, and two (1%) of 206 patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. New-onset exudative age-related macular degeneration was reported in 24 (11%), 16 (8%), and four (2%) patients in OAKS, and in 27 (13%), 12 (6%), and nine (4%) patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. INTERPRETATION: Pegcetacoplan, the first treatment approved by the US Food and Drug Administration for geographic atrophy, slowed geographic atrophy lesion growth with an acceptable safety profile. FUNDING: Apellis Pharmaceuticals.

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.

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.

Characterisation and Visual Outcomes of Fulminant Idiopathic Intracranial Hypertension: A Narrative Review.

Fulminant idiopathic intracranial hypertension (IIH) is a rapid vision-degrading presentation of IIH with limited published studies. This study composed a narrative review of fulminant IIH with the aim of better characterising fulminant IIH presentation and visual outcomes. SCOPUS and PubMed were searched for papers referencing IIH, benign intracranial hypertension, or pseudotumour cerebri. Abstracts were screened for rapid degradation in vision. All studies were required to meet both the modified Dandy and fulminant IIH criteria. Thirty-six studies met the inclusion criteria. Demographics, treatments, and visual outcome data were collected. Case studies made up 69% of the studies and 31% were case series. In total, 72 patients with fulminant IIH were reported, of which 23.6% were paediatric and 96% were female. Surgical intervention occurred in 85% of patients. Anaemia was present in 11% of patients and 85.7% of paediatric patients had a sixth cranial nerve palsy. In conclusion, we propose the following practice guidelines to assist in diagnosing and treating fulminant IIH patients: 1) patients who present with optic disc oedema require urgent visual field testing to evaluate for vision loss; 2) a paediatric patient presenting with a sixth cranial nerve palsy should have a comprehensive eye examination; 3) fulminant IIH can occur in patients with a normal body mass index; and 4) anaemia should be tested for in the setting of fulminant IIH. As little is known about the optimal treatment mechanisms for this presentation, multi-institutional and international collaborations will be a critical step for future research.

A review of emerging tyrosine kinase inhibitors as durable treatment of neovascular age-related macular degeneration.

INTRODUCTION: Current treatment for age-related macular degeneration poses a large burden on patients and the inability of patients to adhere to this immense burden can lead to worse visual outcomes. Novel treatments have been proposed to extend treatment intervals and reduce visit burden. AREAS COVERED: This review article summarizes phase I and phase II clinical trials of tyrosine kinase inhibitors as durable treatment options for patient with neovascular age-related macular degeneration. EXPERT OPINION: Tyrosine kinase inhibitors have shown substantial promise in reducing treatment burden while maintaining visual acuity and anatomic outcomes with favorable safety profiles. Several platforms have shown positive outcomes in initial trials and are currently moving toward phase III clinical trials.

Impact of an immersive, interactive medical education initiative on guideline-based retinal disease management knowledge/competence and effectual practice change.

BACKGROUND: Retinal diseases, including wet or dry age-related macular degeneration, diabetic macular edema, and diabetic retinopathy (DR), are underdiagnosed and undertreated in the United States. Clinical trials support the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) therapies for several retinal conditions, but real-world data suggest underuse by clinicians, resulting in patients experiencing poorer visual outcomes over time. Continuing education (CE) has demonstrated effectiveness at changing practice behaviors, but more research is needed to understand whether CE can help address diagnostic and treatment gaps. METHODS: This test and control matched pair analysis examined pre-/post-test knowledge of retinal diseases and guideline-based screening and intervention among 10,786 healthcare practitioners (i.e., retina specialists, ophthalmologists, optometrists, primary care providers, diabetes educators, pharmacists/managed care specialists, and other healthcare providers, such as registered nurses, nurse practitioners, and physician assistants) who participated in a modular, interactive CE initiative. An additional medical claims analysis provided data on practice change, evaluating use of VEGF-A inhibitors among retina specialist and ophthalmologist learners (n = 7,827) pre-/post-education, compared to a matched control group of non-learners. Outcomes were pre-/post-test change in knowledge/competence and clinical change in application of anti-VEGF therapy, as identified by the medical claims analysis. RESULTS: Learners significantly improved knowledge/competence scores on early identification and treatment, identifying patients who could benefit from anti-VEGF agents, using guideline-recommended care, recognizing the importance of screening and referral, and recognizing the importance of early detection and care for DR (all P-values = 0.003 to 0.004). Compared with matched controls, learners' incremental total injections for anti-VEGF agents for retinal conditions increased more after the CE intervention (P < 0.001); specifically, there were 18,513 more (new) anti-VEGF injections prescribed versus non-learners (P < 0.001). CONCLUSIONS: This modular, interactive, immersive CE initiative resulted in significant knowledge/competence gains among retinal disease care providers and changes in practice-related treatment behaviors (i.e., appropriate consideration and greater incorporation of guideline-recommended anti-VEGF therapies) among participating ophthalmologists and retina specialists compared to matched controls. Future studies will utilize medical claims data to show longitudinal impact of this CE initiative on treatment behavior among specialists and impact on diagnosis and referral rates among optometrists and primary care providers who participate in future programming.

Brolucizumab for the treatment of diabetic macular edema.

PURPOSE OF REVIEW: To review the available data supporting the use of brolucizumab in the treatment of diabetic macular edema (DME). RECENT FINDINGS: Brolucizumab is a humanized single- chain variable antibody fragment (scFv), the smallest functional subunit of an antibody approved for intravitreal use. Three phase III studies demonstrate that at 52 weeks, brolucizumab has statistically superior anatomical outcomes of reducing retinal thickness (54.0-57.5% of brolucizumab treated eyes achieved central subfield thickness <280 µm compared to 40.1 - 41.4% of aflibercept treated eyes) and retinal fluid (present in 54.2-60.3% of brolucizumab treated eyes compared to 72.9-78.2% of aflibercept treated eyes). Brolucizumab also demonstrated a prolonged durability up to 16 weeks, thus reducing treatment burden. The visual outcomes appear noninferior to current anti-VEGF agents with an increased risk for intraocular inflammatory events (0.3-4.7% compared to 0.6-1.7%). SUMMARY: Results from recent phase III trials showing the efficacy and safety of brolucizumab presents an additional therapeutic option in the DME treatment landscape. It can reduce treatment burden in DME with increased inter-treatment intervals while conferring efficacy in both functional and anatomical outcomes. Caution should be taken regarding the risks of intraocular inflammation, retinal vasculitis, and retinal vascular occlusion.

EFFECT OF RETINAL THICKNESS VARIABILITY ON VISUAL OUTCOMES AND FLUID PERSISTENCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Post Hoc Analysis of the HAWK and HARRIER Studies.

PURPOSE: To determine the association between central subfield thickness (CST) variability and visual outcomes in eyes with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapies. METHODS: In this post hoc, treatment-agnostic analysis, patients (N = 1,752) were grouped into quartiles of increasing CST variation. The association between CST variability and best-corrected visual acuity was measured from baseline, or from the end of the loading phase, until the end of the study using a multilevel modeling for repeated-measures model. The association between CST variability and the presence of retinal fluid was also assessed. RESULTS: Increased CST variability was associated with worse best-corrected visual acuity outcomes at the end of study, with a least-square mean difference in best-corrected visual acuity of 8.9 Early Treatment Diabetic Retinopathy Study letters between the quartiles with the lowest and highest CST variability at the final visit. Increased variability was also associated with a higher mean fraction of visits with the presence of fluid. CONCLUSION: More stable CST was associated with better visual outcomes at the end of treatment suggesting that CST variability may provide a more reliable prognostic marker of visual outcomes than the presence of fluid alone, with the potential to enhance the clinical care of neovascular age-related macular degeneration patients.

Characterization of ophthalmic presentations to emergency departments in the United States: 2010-2018.

BACKGROUND: Both traumatic and nontraumatic ocular issues often present to the emergency department. Understanding the epidemiology of ocular presentations to the emergency department not only informs current resource allocation, but also provides opportunities to evaluate the efficacy of prior healthcare access interventions. PURPOSE: To characterize emergency department utilization in the United States for ophthalmic encounters between 2010 and 2018. METHODS: Cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey database, a nationally representative sample of United States emergency department visits. 4284 deidentified emergency department patient encounters with an ICD-10 ophthalmic diagnosis from 2010 to 2018 were analyzed. The main outcome measures were the composition and characteristics of ophthalmic emergency department encounters over time. MAIN FINDINGS: 4284 ophthalmic visits were identified which represented an estimated 23.1 million visits (95% CI, 20.8 million-25.5 million). 31.6% (95% CI, 29.6-33.8) of ophthalmic visits were traumatic. Conjunctivitis was the most common non-traumatic diagnosis (32.8%, 95% CI, 30.7-35.0), while superficial injury of the cornea was the most common traumatic diagnosis (13.9%, 95% CI, 12.5-15.3). A greater proportion of emergency department visits involving the sclera and cornea were made by men (58.7%, 95% CI, 53.7%-63.6%; P = 0.02), whereas more women visited for visual disturbances (57.8%, 95% CI, 51.3%-64.4%; P = 0.01). Longitudinal trends of ophthalmic visits revealed an increase in public insurance payers in 2014, which corresponds to Medicaid expansion and implementation of mandated coverage for pediatric vision care. After stratification, this increase continued to be present in nontraumatic visits, but not traumatic ones. CONCLUSIONS: Ophthalmic emergency department visits in the United States between 2010 and 2018 were typically for non-traumatic eye issues. Diagnoses varied greatly by patient demographics, such as age and gender. Understanding these variations is valuable for preparing emergency departments for ocular presentations and providing guidance for future practice.

Patient Satisfaction in the Era of COVID-19: Virtual Visit versus In-person Visit Satisfaction.

SIGNIFICANCE: Teleophthalmology became widely used during the coronavirus 2019 pandemic; however, the quality of this care remains to be understood. PURPOSE: This study aimed to compare patient satisfaction levels from virtual and in-person visits based on post-visit surveys, as well as investigate demographic characteristics that may predict patient satisfaction with virtual visits. METHODS: Virtual (n = 2943) and in-person (n = 56,175) visits from March 19, 2020, to July 31, 2020, were identified using the electronic health record system. For in-person visits, a random subset of 3000 visits was acquired using a random number generator. Of these, 2266 virtual and 2590 in-person visits met the inclusion criteria. Patients who completed the Telemedicine for Medical Practice Survey and Medical Practice Survey were analyzed in this report. Nonparametric Mann-Whitney test was used to compare scores between groups. RESULTS: Two hundred eleven virtual patients (9.31%; 82 phone, 115 video, 14 hybrid) and 307 in-person patients (11.85%) completed the Telemedicine for Medical Practice Survey and Medical Practice Survey, respectively. Satisfaction scores were similar and high in both groups-virtual visit satisfaction scores averaged 4.82, whereas in-person visit satisfaction averaged 4.85 (P = .80, θ = 0.501 [0.493 to 0.509]). Only one question yielded significantly different satisfaction scores, and no demographic variables were significant predictors of satisfaction scores. CONCLUSIONS: Patient satisfaction is comparable between virtual and in-person visits, validating the continued usage of telemedicine for eye care visits.

Ocular occupational injuries in the United States between 2011-2018.

BACKGROUND: Current advocacy literature in occupational eye injury focuses on demographics and industries with the largest number of injuries. Additional demographics may also benefit from targeted advocacy that experience a greater proportion of eye injuries relative to all other occupational injuries. AIMS: To characterize which demographic groups are experiencing occupational ocular injuries in the United States. METHODS: This cross-sectional study examined de-identified individuals who experienced ocular workplace injuries from 2011 to 2018 and were reported to the survey of occupational injuries and illnesses (SOII). Data were stratified and analysed based on SOII reported characteristics. RESULTS: 197 160 out of 9 197 350 (2%) ocular workplace injuries were reported. 152 940 (78%) injuries occurred in males. Relative to all workplace injuries experienced by industry, farming, fishing and forestry saw the highest percentage of ocular injuries (6%), followed by production, and installation (4%), maintenance and repairs (4%). Employers cited contact with objects (65%) and exposure to harmful substances (26%) as leading reasons for eye injury. Relative to all injuries, chemicals frequently injured the eye (27%). CONCLUSIONS: A disproportionate number of American ocular workplace injuries occur in males who are likely relatively young. Industries such as fishing, farming and forestry see a high frequency of ocular injury relative to all occupational injuries. Hispanics see a slight increase in ocular occupational injury relative to other injuries. Advocates of occupational ocular safety should consider expanding their targeted audiences to include individuals who are part of demographics and occupations that more frequently experience an ocular workplace injury relative to all injuries.

Racial, Ethnic, and Insurance-Based Disparities Upon Initiation of Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema in the US.

PURPOSE: This study characterizes the association of risk factors including race, ethnicity, and insurance status with presenting visual acuity (VA) and diabetic retinopathy (DR) severity in patients initiating treatment with anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: The Academy Intelligent Research in Sight (IRIS) Registry database was queried for patients who initiated anti-VEGF injection treatment for DME between 2012 and 2020 (n = 203 707). METHODS: Multivariate regression analyses were conducted to understand how race, ethnicity, insurance status, and geographic location were associated with baseline features. MAIN OUTCOME MEASURES: Visual acuity and DR severity. RESULTS: Patients on Medicare and private insurance presented with higher baseline VA compared with patients on Medicaid (median of 2.31 and 4.17 greater Early Treatment Diabetic Retinopathy Scale [ETDRS] letters, respectively P < 0.01). White and non-Hispanic patients presented with better VA compared with their counterparts (median of 0.68 and 2.53 greater ETDRS letters, respectively; P < 0.01). Black and Hispanic patients presented with a worse baseline DR severity compared with White and non-Hispanic patients (odds ratio, 1.23 and 1.71, respectively; P < 0.01). CONCLUSIONS: There are ethnic and insurance-based disparities in VA and disease severity upon initiation of anti-VEGF therapy for DME treatment. Public health initiatives could improve timely initiation of treatment.

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial. DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA). SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246. INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period. MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity. RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy. CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.

HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To report the 96-week outcomes from HAWK and HARRIER. DESIGN: Phase 3, prospective, randomized, double-masked, multicenter studies comparing efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with neovascular age-related macular degeneration (nAMD). PARTICIPANTS: Treatment-naïve eyes with nAMD were randomized 1:1:1 to brolucizumab 3 mg (n = 358), brolucizumab 6 mg (n = 360), aflibercept 2 mg (n = 360; HAWK) or 1:1 to brolucizumab 6 mg (n = 370), aflibercept 2 mg (n = 369; HARRIER). METHODS: After 3 monthly loading doses, brolucizumab patients received every (q)-12-week (w) dosing, possibly adjusting to q8w dosing if disease activity was present at predefined disease activity assessment (DAA) visits. Aflibercept was dosed in a fixed q8w regimen. Visual and anatomic parameters were assessed throughout. Primary end point was at week 48 (48w), confirmed at 96w. MAIN OUTCOME MEASURES: Mean best-corrected visual acuity (BCVA) change from baseline, proportion of patients on an q12w regimen, retinal thickness, retinal fluid changes, and safety, all to 96w. RESULTS: Mean change (least squares [LS] mean ± standard error) in BCVA from baseline to 96w in HAWK was 5.6±0.79 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for brolucizumab 3 mg, 5.90±0.78 letters for brolucizumab 6 mg, and 5.3±0.78 letters for aflibercept and in HARRIER was 6.1±0.73 letters for brolucizumab 6 mg and 6.6 ± 0.73 letters for aflibercept. Greater central subfield thickness reductions were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean, -174.8 µm vs. -148.7 µm; 95% confidence interval for treatment difference, -46.2 to -5.9 µm; P = 0.0115) and HARRIER (LS mean, -197.7 µm vs. -155.1 µm; 95% confidence interval for treatment difference, -62.0 to -23.3 µm; P < 0.0001). The proportions of eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF) at 96w in HAWK were 31% (P = 0.0688) and 24% (P = 0.0002) for brolucizumab 3 mg and 6 mg and 37% for aflibercept, whereas in HARRIER, they were 24% for brolucizumab 6 mg (P < 0.0001) and 39% for aflibercept. At 92w (last DAA), a 45.4% and 38.6% probability was observed for brolucizumab 6 mg patients of maintaining an q12w treatment regimen in HAWK and HARRIER, respectively. Brolucizumab exhibited an overall well-tolerated safety profile. CONCLUSIONS: Visual outcomes from 48w to 96w confirm the efficacy achieved at 48w. Brolucizumab demonstrated greater fluid resolution compared with aflibercept. The q12w potential for brolucizumab observed at 48w was maintained to 96w.

Photobiomodulation therapy in age-related macular degeneration.

PURPOSE OF REVIEW: To review the available data supporting the use of photobiomodulation therapy (PBT) in the treatment of age-related macular degeneration (AMD). RECENT FINDINGS: PBT might be used in treating nonexudative AMD. Limited evidence suggests that exudative AMD may also benefit from PBT. SUMMARY: The optimal device would deliver doses of 60 J/cm2 or more with a multiwavelength composition through the pupil over short treatment intervals. Safe upper limits have not been established. More studies are needed to evaluate the efficacy of PBT in treating exudative and nonexudative AMD.

RETINAL FLUID AND THICKNESS AS MEASURES OF DISEASE ACTIVITY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: Retinal fluid and thickness are important anatomical features of disease activity in neovascular age-related macular degeneration, as evidenced by clinical trials that have used these features for inclusion criteria, retreatment criteria, and outcome measures of the efficacy of intravitreal injections of anti-vascular endothelial growth factor agents. METHODS: A literature review of anatomical measures of disease activity was conducted. RESULTS: Treatment goals for neovascular age-related macular degeneration include improving/maintaining vision by drying the retina, and several analyses have evaluated the relationship between visual function and anatomy. The change in retinal thickness has been found to correlate with the change in the visual acuity, and variation in retinal thickness may predict visual acuity outcomes. In addition, specific fluid compartments may have different prognostic values. For example, the presence of intraretinal fluid has been associated with poorer visual acuity, whereas the presence of subretinal fluid has been associated with better visual acuity. Retinal fluid and thickness are important for selecting dosing interval durations in clinical trials and clinical practice. CONCLUSION: Retinal thickness and retinal fluid are common anatomical measures of disease activity in neovascular age-related macular degeneration. Further research is required to fully elucidate the relationship between anatomical features and visual outcomes in neovascular age-related macular degeneration.

THE ANGIOPOIETIN/TIE PATHWAY IN RETINAL VASCULAR DISEASES: A Review.

PURPOSE: To provide a concise overview for ophthalmologists and practicing retina specialists of available clinical evidence of manipulating the angiopoietin/tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains (Tie) pathway and its potential as a therapeutic target in retinal vascular diseases. METHODS: A literature search for articles on the angiopoietin/Tie pathway and molecules targeting this pathway that have reached Phase 2 or 3 trials was undertaken on PubMed, Association for Research in Vision and Ophthalmology meeting abstracts (2014-2019), and ClinicalTrials.gov databases. Additional information on identified pipeline drugs was obtained from publicly available information on company websites. RESULTS: The PubMed and Association for Research in Vision and Ophthalmology meeting abstract search yielded 462 results, of which 251 publications not relevant to the scope of the review were excluded. Of the 141 trials related to the angiopoietin/Tie pathway on ClinicalTrials.gov, seven trials focusing on diseases covered in this review were selected. Vision/anatomic outcomes from key clinical trials on molecules targeting the angiopoietin/Tie pathway in patients with retinal vascular diseases are discussed. CONCLUSION: Initial clinical evidence suggests a potential benefit of targeting the angiopoietin/Tie pathway and vascular endothelial growth factor-A over anti-vascular endothelial growth factor-A monotherapy alone, in part due to of the synergistic nature of the pathways.

CONSEQUENCES OF LAPSES IN TREATMENT WITH VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN ROUTINE CLINICAL PRACTICE.

PURPOSE: Evaluating outcomes in patients receiving intravitreal antivascular endothelial growth factor (VEGF) inhibitors for neovascular age-related macular degeneration whom experience a lapse in treatment. METHODS: A retrospective chart review evaluating 3,304 patients ≥18 years who experienced treatment lapses ≥3 months compared with control counterparts. Demographic information, macular thickness as measured by central subfield thickness, and visual acuity were collected at baseline, the first postlapse appointment, and at 3, 6, and 12 months after the lapse for the study group. RESULTS: Lapse (n = 241) and control patients (n = 241) had similar baseline visual acuity and central subfield thickness (Early Treatment Diabetic Retinopathy Study: 58.9 ± 20.2 [20/63] vs. 59.2 ± 20.1 [20/63]; central subfield thickness: 252.4 ± 63.2 µm vs. 259.8 ± 66.2 µm, P = 0.21). Analysis revealed that lapse patients experienced a significant increase in central subfield thickness after lapse when compared with controls (279.4 ± 86.9 µm vs. 253.7 ± 65.9 µm, P < 0.01), which normalized on resumption of treatment (259.1 ± 79 µm vs. 246.8 ± 57.6 µm, P = 0.06). Study patients also experienced loss in the visual acuity after lapse when compared with controls (52.9 ± 23.6 Early Treatment Diabetic Retinopathy Study [20/100] vs. 59.9 ± 20.8 [20/63] Early Treatment Diabetic Retinopathy Study, P < 0.01) that did not recover through 12 months of follow-up. CONCLUSION: Patients with neovascular age-related macular degeneration who have lapses in care are at risk for poorer outcomes. Although macular thickness normalizes on resumption of treatment, their decline in the visual acuity does not recover.

Bariatric Surgery versus Intensive Medical Therapy for Diabetes - 5-Year Outcomes.

BACKGROUND: Long-term results from randomized, controlled trials that compare medical therapy with surgical therapy in patients with type 2 diabetes are limited. METHODS: We assessed outcomes 5 years after 150 patients who had type 2 diabetes and a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 27 to 43 were randomly assigned to receive intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. The primary outcome was a glycated hemoglobin level of 6.0% or less with or without the use of diabetes medications. RESULTS: Of the 150 patients who underwent randomization, 1 patient died during the 5-year follow-up period; 134 of the remaining 149 patients (90%) completed 5 years of follow-up. At baseline, the mean (±SD) age of the 134 patients was 49±8 years, 66% were women, the mean glycated hemoglobin level was 9.2±1.5%, and the mean BMI was 37±3.5. At 5 years, the criterion for the primary end point was met by 2 of 38 patients (5%) who received medical therapy alone, as compared with 14 of 49 patients (29%) who underwent gastric bypass (unadjusted P=0.01, adjusted P=0.03, P=0.08 in the intention-to-treat analysis) and 11 of 47 patients (23%) who underwent sleeve gastrectomy (unadjusted P=0.03, adjusted P=0.07, P=0.17 in the intention-to-treat analysis). Patients who underwent surgical procedures had a greater mean percentage reduction from baseline in glycated hemoglobin level than did patients who received medical therapy alone (2.1% vs. 0.3%, P=0.003). At 5 years, changes from baseline observed in the gastric-bypass and sleeve-gastrectomy groups were superior to the changes seen in the medical-therapy group with respect to body weight (-23%, -19%, and -5% in the gastric-bypass, sleeve-gastrectomy, and medical-therapy groups, respectively), triglyceride level (-40%, -29%, and -8%), high-density lipoprotein cholesterol level (32%, 30%, and 7%), use of insulin (-35%, -34%, and -13%), and quality-of-life measures (general health score increases of 17, 16, and 0.3; scores on the RAND 36-Item Health Survey ranged from 0 to 100, with higher scores indicating better health) (P<0.05 for all comparisons). No major late surgical complications were reported except for one reoperation. CONCLUSIONS: Five-year outcome data showed that, among patients with type 2 diabetes and a BMI of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia. (Funded by Ethicon Endo-Surgery and others; STAMPEDE ClinicalTrials.gov number, NCT00432809 .).

Effects of Quality Improvement Education in Diabetic Retinopathy on Routine Clinical Practice Patterns of Optometrists.

SIGNIFICANCE: Optometrists play a preventive role in diabetic care by detecting early signs of diabetic retinopathy (DR), a leading cause of blindness in adults. This study demonstrates that additional training can improve optometrists' ability to assess the presence and severity of DR in individuals with diabetes. PURPOSE: This study aimed to determine the impact of a quality improvement intervention involving education, assessment, and feedback on improving the evaluation and referral patterns of optometrists with regard to their patients with diabetes. METHODS: A pre-interventional and post-interventional analysis of optometrist practices was conducted through a retrospective chart review of diabetic patient encounters from July 2018 to March 2019. Dilated fundus examination (DFE) documentation, follow-up scheduling, referral practices, and usage of various imaging modalities were collected from patient records. Concordance of DR severity recordings between DFE findings, assessment and plan notes, and International Classification of Diseases codes was calculated. RESULTS: After intervention, the proportion of optometrists who conducted a DFE significantly increased from 79.5 (95% confidence interval [CI], 77.3 to 81.7%) to 84.4% (95% CI, 82.4 to 86.4%). In addition, the rate of improper follow-up instructions decreased from 13.8 (95% CI, 12.0 to 15.7%) to 10.8% (95% CI, 9.2 to 12.6%), and the decrease was significant (P = .02). Although overall referrals decreased from 19.8 (95% CI, 17.6 to 21.9%) to 14.6% (95% CI, 12.6 to 16.5%), optometrists were as likely to refer to retinal specialists. Finally, concordance between documented DFE findings, assessment and plan notes, and International Classification of Diseases codes significantly increased from 78.8 (95% CI, 76.5 to 81.0%) to 88.7% (95% CI, 86.9 to 90.4%). CONCLUSIONS: Providing optometrists education in screening and assessing DR is effective in improving diabetic patient care.