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Purpose: To compare intravitreal nesvacumab (anti-angiopoietin-2) + aflibercept vs intravitreal aflibercept injection (IAI) in neovascular age-related macular degeneration (nAMD). Methods: Eyes were randomized (1:2:3) to nesvacumab 3 mg + aflibercept 2 mg (LD combo), nesvacumab 6 mg + aflibercept 2 mg (HD combo), or IAI 2 mg at baseline, week 4, and week 8. The LD combo was continued every 8 weeks (q8w). At week 12, the HD combo was re-randomized to q8w or every 12 weeks (q12w) and IAI was re-randomized to q8w, q12w, or HD combo q8w through week 32. Results: The study comprised 365 eyes. At week 12, the mean best-corrected visual acuity (BCVA) gains from baseline were similar in the LD combo group, HD combo group, and IAI group (5.2 letters, 5.6 letters, and 5.4 letters, respectively); the mean central subfield thickness (CST) reductions were similar (182.2 µm, 200.0 µm, and 178.6 µm, respectively). The mean changes in BCVA and CST through week 36 were similar across groups. At week 12, complete retinal fluid resolution was observed in 49.1% (LD combo), 50.8% (HD combo), and 43.6% (IAI) of eyes; the proportions with a CST of 300 μm or less were similar across groups. Numerical trends at week 32 toward complete retinal fluid resolution with combination treatment were not maintained at week 36. Serious ocular adverse events were infrequent and comparable across groups. Conclusions: In nAMD, nesvacumab + aflibercept showed no additional BCVA or CST benefit over IAI monotherapy.

AR-1105 is a novel biodegradable sustained-release dexamethasone implant designed to deliver 6-month durability. This Phase 2 study evaluated two AR-1105 formulations with different release profiles in patients with macular edema due to retinal vein occlusion.Patients received a single intravitreal injection with 340 µg dexamethasone. In the initial phase, five patients received clinical formulation (CF) 1. In the randomized phase, 44 patients were randomized 1:1 to CF1 or CF2. The follow-up was 6 months. Patients had vision loss due to macular edema diagnosed ≥9 (central retinal vein occlusion) or ≥12 months (branch retinal vein occlusion) before screening, and could be treatment-naive or -experienced (if received prior steroids, must have demonstrated response).Both formulations improved vision and reduced retinal thickening from baseline across all visits. At Month 6, mean changes in best-corrected visual acuity were +4.3 and +8.0 letters, and mean changes in central subfield thickness were -93 µm and -211 µm in CF1 and CF2 randomized patients, respectively. Most common adverse events were reduced visual acuity, worsening macular edema, conjunctival hemorrhage, and increased intraocular pressure. No patients required surgery or laser for intraocular pressure control.Both formulations were well tolerated and demonstrated clinically meaningful and sustained improvements in vision and retinal thickening in patients with retinal vein occlusion with longstanding edema.

BACKGROUND AND OBJECTIVE: To explore the association between best-corrected visual acuity (BCVA) improvement and changes in microperimetry (MP) and color vision in patients with nonexudative age-related macular degeneration following administration of two 1.0-mg intravitreal doses of risuteganib. PATIENTS AND METHODS: In a phase 2a, prospective, double-masked, sham-controlled study, eyes with nonexudative age-related macular degeneration and Early Treatment Diabetic Retinopathy Study BCVA between 20/40 and 20/200 were randomized to intravitreal risuteganib (1.0 mg) or sham injection. The risuteganib group received a second 1.0-mg dose, and patients in the sham group crossed over to receive 1.0 mg of risuteganib at week 16. Exploratory endpoints included changes in color vision and mesopic MP. RESULTS: Thirty-nine patients (risuteganib, n = 25; sham, n = 14) completed the study. There was a significant ( P < .05) correlation between BCVA and the total error score (TES) for both Lanthony and Hue Style. Confusion index was close to the criterion for significance ( P = .056) in the risuteganib group. All color vision metrics demonstrated a trend toward improvement in risuteganib responders (BCVA letter gain ≥8 letters) and no change in the nonresponders, with significant differences seen in confusion index between the risuteganib and control group ( P = .0493) and between responders and nonresponders ( P = .0478). MP showed that risuteganib responders improved in mean sensitivity and change in number of loci ≤11 dB and ≤0 dB, whereas nonresponders worsened. CONCLUSION: All color vision and MP parameters tested trended toward improvement in risuteganib-treated patients and risuteganib responders. Statistically significant improvement was evident in two metrics: confusion index (in risuteganib-treated patients and responders) and number of loci with decreased sensitivity (in responders). A significant correlation between BCVA and both TES Lanthony and TES Hue Style in risuteganib patients provides concurrent evidence of objective and subjective improvement of retinal function. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:430–438.]

BACKGROUND AND OBJECTIVES: To evaluate the safety, tolerability, and biological activity of a topical selective integrin inhibitor (OTT166) eyedrop administered BID for diabetic retinopathy (DR) and diabetic macular edema (DME). STUDY DESIGN/MATERIALS AND METHODS: A prospective, multicenter, randomized, double-masked Phase 1b study. Subjects with nonproliferative DR and DME with central subfield thickness (CST) > 325 microns were randomized to OTT166 eyedrops (2.5% or 5%) BID for 28 days. Subjects were followed for an additional 28 days after treatment cessation. RESULTS: Forty-four subjects were enrolled. No drug-related serious adverse events (SAEs) and two drug-related adverse events (AEs) were reported. OTT166 was well-tolerated with no evidence of ocular toxicity. Best-corrected visual acuity (BCVA) remained stable. Mean central retinal thickness (CRT) overall was variable: +12.8/+1.8 microns at Day 28 (end of treatment) and −50.3/+5.5 microns at Day 56 (end of study) for the 2.5% and 5% groups, respectively. Median CRT overall demonstrated consistent reduction by end of study: −39.0/−16.5 microns for the 2.5% and 5% groups, respectively. Median responses were greater in the treatment-naïve group (−41.5/−26.0 microns for the 2.5% and 5% groups, respectively). Thirty-seven percent of ‘responder’ subjects exhibited a mean reduction in CRT of 46.6 microns on optical coherence tomography (OCT) at end of treatment (Day 28) which persisted to end of the study (Day 56) – mean reduction of 67.4 microns, suggesting a durable effect. CONCLUSION: OTT166 eyedrops were safe, well-tolerated, and demonstrated biological activity in 37% of responders. These results warrant further evaluation of OTT166 eyedrops. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:553–560.]

BACKGROUND AND OBJECTIVE: To evaluate the safety and efficacy of 1.0 mg risuteganib in subjects with nonexudative age-related macular degeneration (AMD). PATIENTS AND METHODS: This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg risuteganib or sham injection. At Week 16, subjects in the risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks. RESULTS: Forty-five subjects (risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met by 48% of the risuteganib group at Week 28 and 7% of the sham group at Week 12 ( P = .013). Of the risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatment-related treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported. CONCLUSIONS: Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32-week observation period. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:327–335.]

Geographic atrophy (GA) secondary to age-related macular degeneration accounts for close to one-quarter of cases of legal blindness in the USA and the UK. Despite this notable disease burden, the pathophysiology of GA is complex and not fully understood, and there is currently no approved treatment to prevent or slow its progression. GA is heterogeneous in its appearance and extent, and underlying associated traits such as drusen and complement factor polymorphisms vary between patients and by ethnicity, posing a challenge for treatment development. The root cause of vision loss in GA is photoreceptor death; therefore, protecting photoreceptors from damage and delaying their degeneration are key to successful GA treatment. There are multiple neuroprotective pathways that may contribute to protecting photoreceptors from damage, and compounds that target these pathways include antioxidants, neurotrophic factors, and catalases. However, the efficacy of previously trialled neuroprotective therapies in GA, such as brimonidine, tandospirone, and NT-501, has been inconsistent; this may be due to their target of action, method of delivery, and/or suboptimal duration of action. Neurotrophic factors, or molecules involved in neuroprotective signalling cascades, may be ideal agents for further investigation for the treatment of GA. Future neuroprotective strategies in GA must focus on the development of agents with a long duration of action that can combat the progression of chronic damage in GA to provide clinically meaningful benefits for patients.

Purpose To establish a process to evaluate and standardize a state-of-the-art nomenclature for reporting neovascular age-related macular degeneration (AMD) data. Design Consensus meeting. Participants An international panel of retina specialists, imaging and image reading center experts, and ocular pathologists. Methods During several meetings organized under the auspices of the Macula Society, an international study group discussed and codified a set nomenclature framework for classifying the subtypes of neovascular AMD and associated lesion components. Main Outcome Measures A consensus classification of neovascular AMD. Results The study group created a standardized working definition of AMD. The components of neovascular AMD were defined and subclassified. Disease consequences of macular neovascularization were delineated. Conclusions The framework of a consensus nomenclature system, a definition of AMD, and a delineation of the subtypes of neovascular AMD were developed. Establishing a uniform set of definitions will facilitate comparison of diverse patient groups and different studies. The framework presented is modified and updated readily, processes that are anticipated to occur on a periodic basis. The study group suggests that the consensus standards outlined in this article be used in future reported studies of neovascular AMD and clinical practice.

Purpose OPT-302 is a novel ‘trap’ inhibitor of vascular endothelial growth factors C and D (VEGF-C/-D). A phase 1 trial assessed the safety of intravitreal (IVT) OPT-302 as monotherapy or combined with ranibizumab (Lucentis) in patients with neovascular age-related macular degeneration (nAMD). Design Phase 1, open-label, dose escalation followed by a randomized dose expansion. Participants Fifty-one patients with nAMD who were either treatment-naive (n=25) or previously treated with anti-VEGF-A therapy (n=26). Methods In the dose escalation, groups of 5 patients in 4 cohorts, received ascending doses of IVT OPT-302 (0.3, 1 or 2 mg) in combination with ranibizumab (0.5 mg); or as monotherapy (2 mg). In the dose expansion, 31 patients were randomized (3:1) to OPT-302 (2 mg) in combination with ranibizumab (n=23) or as monotherapy (n=8). All participants received IVT OPT-302 ± ranibizumab every 4 weeks (q4w) at Days 1, 29 and 57. Main Outcome Measures The primary outcome was safety. Other outcomes included OPT-302 pharmacokinetics (PK) and immunogenicity, need for anti-VEGF-A re-treatment, effects on best corrected visual acuity (BCVA) and anatomical changes. Results OPT-302 ± ranibizumab was well tolerated with no dose limiting toxicities. Systemic exposure following IVT OPT-302 was low with no evidence of immunogenicity. In patients receiving OPT-302 monotherapy, 7/13 (54%) did not require rescue anti-VEGF-A therapy and their mean change in BCVA from baseline to week 12 was +5.6 letters (range, 0-18). Increases in mean BCVA from baseline to week 12 were observed in patients administered combination OPT-302 + ranibizumab with +10.8 letters (95% CI 4, 17; n=18) in treatment-naive and +4.9 letters (95% CI 3, 7; n=19) in previously treated patients respectively. Corresponding reductions in mean central subfield thickness (CST) at week 12 in both groups were -119 μm (95% CI -176 to -62) and -54 μm (95% CI -82 to -26) respectively, while 50% of treatment-naive patients also had no detectable choroidal neovascularization (CNV) at week 12 on fluorescein angiography (FA). Conclusions Intravitreal OPT-302 inhibition of VEGF-C/-D was well tolerated and OPT-302 combination therapy may overcome an escape mechanism to VEGF-A suppression in the management of treatment resistance in nAMD.

Objective Geographic atrophy (GA), a late stage of age-related macular degeneration, is a major cause of irreversible blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan (APL-2), a complement C3 inhibitor, for the treatment of GA. Design Prospective, multicenter, randomized, sham-controlled phase 2 study. Subjects 246 subjects with GA. Methods Subjects with GA were randomly assigned in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every-other-month (EOM) or sham intravitreal injections monthly or EOM, for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. Main outcome measures The primary efficacy endpoint was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea (foveal encroachment), best corrected visual acuity (BCVA), low luminance BCVA (LL-BCVA), and low luminance visual acuity deficit (LL-VD). The primary safety endpoint was the number and severity of treatment emergent adverse events. Results In subjects receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% CI, 9 to 49; p=0·008) and 20% (95% CI, 0 to 40; p=0.067) compared with sham. Post-hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (p=0.0004) and 33% (p=0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and one case of culture negative endophthalmitis occurred in the pegcetacoplan monthly group. New onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes, or 20.9%, and 7/79 eyes, or 8.9%, in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes, or 1.2%). Conclusion Local inhibition of C3 with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham. Phase 3 study will further define the efficacy and safety profile.

The purpose of this study was to compare intravitreal nesvacumab (anti-angiopoietin 2) plus aflibercept with intravitreal aflibercept injection (IAI) in diabetic macular edema.The eyes (n = 302) were randomized (1:2:3) to nesvacumab 3 mg + aflibercept 2 mg (LD combo), nesvacumab 6 mg + aflibercept 2 mg (HD combo), or IAI 2 mg at baseline, Weeks 4 and 8. LD combo continued every 8 weeks (q8w). HD combo was rerandomized at Week 12 to q8w or every 12 weeks (q12w); IAI to q8w, q12w, or HD combo q8w through Week 32.Week 12 best-corrected visual acuity gains for LD and HD combo versus IAI were 6.8, 8.5, and 8.8 letters; Week 36 changes were similar. Central subfield retinal thickness reductions at Week 12 were -169.4, -184.0, and -174.6 µm (nominal P = 0.0183, HD combo vs. IAI); Week 36 reductions for LD combo and HD combo q8w and q12w versus IAI were -210.4, -223.4, and -193.7 versus -61.9 µm (nominal P0.05). At Week 12, 13.3% and 21.3% versus 15.2% had ≥2-step Diabetic Retinopathy Severity Scale improvement (LD and HD combos vs. IAI) and 59.6% and 66.3% versus 53.7% had complete foveal center fluid resolution. Safety was comparable across groups.Nesvacumab + aflibercept demonstrated no additional visual benefit over IAI. Anatomic improvements with HD combo may warrant further investigation.

To evaluate outcomes and disease characteristics in eyes with neovascular age-related macular degeneration that received intravitreal aflibercept injection (IAI) and ranibizumab every 12 weeks or longer (≥q12 weeks) or less than every 12 weeks (q12 weeks) during year 2 of VIEW studies.Post hoc analysis of randomized clinical trial data.In year 1, eyes received ranibizumab q4 weeks (Rq4), IAI 2 mg q4 weeks (2q4), or IAI 2 mg q8 weeks after 3 monthly injections (2q8). In year 2, eyes received pro re nata treatment, with mandatory treatment at least q12 weeks.At week 96, 218 (42.5%), 284 (53.9%), and 245 (47.9%) eyes treated with Rq4, 2q4, and 2q8, respectively, received treatment at ≥q12-week intervals and 295 (57.5%), 243 (46.1%), and 266 (52.1%) eyes at12q-week intervals during the second year. Baseline occult-type choroidal neovascularization (CNV) (P = .0156) and retinal fluid (P.0001) and leakage (P.0001) at week 52 were associated withq12-week dosing. Mean best-corrected visual acuity gains from baseline with Rq4, 2q4, and 2q8 at ≥q12-week interval were 8.7, 9.9, and 9.7 letters at week 52 and 8.5, 8.8, and 9.2 letters at week 96, respectively. The corresponding gains withq12-week dosing were 10.3, 9.7, and 8.9 letters at week 52 and 9.1, 7.7, and 8.1 letters at week 96.Baseline CNV type other than occult and absence of retinal fluid and leakage at week 52 were significantly associated with ≥q12-week dosing. Vision improvements at week 52 following a year of fixed dosing with ranibizumab and IAI were maintained at week 96 in eyes that received treatment ≥q12 weeks andq12 weeks.

Recent reports of retinal vasculitis (some cases were also occlusive) after brolucizumab injection has ignited a poorly understood immunogenicity alert in the form of intraocular inflammation and r...

IMPORTANCE: Anti–vascular endothelial growth factor (VEGF) agents may provide a prophylactic effect in high-risk eyes with intermediate dry age-related macular degeneration (AMD) against conversion to exudative AMD (eAMD), lowering the risk of vision loss. OBJECTIVE: To evaluate intravitreal aflibercept injection (IAI) as prophylaxis against the conversion to eAMD in high-risk eyes at 24 months. DESIGN, SETTING, AND PARTICIPANTS: This single-masked, sham-controlled, randomized clinical trial performed at 4 US clinical sites enrolled patients with intermediate AMD in 1 eye (study eye), defined as presence of more than 10 medium drusen (≥63 to

Purpose: Crystalline maculopathy secondary to chronic retinal detachment (RD) has previously been described. This article proposes a novel mechanism to explain crystalline formation in the absence of RD. Methods: Two patients, who were referred for routine examination, were found to have a crystalline maculopathy in the setting of an asymptomatic, chronic-appearing, peripheral retinal tear. Fundoscopy and optical coherence tomography were used to assess the crystals and tear. No specimens were obtained. Results: We describe 2 cases of a crystalline maculopathy secondary to an asymptomatic peripheral retinal tear. We hypothesized macrophage ingestion of photoreceptor segments emanating from the tear may have contributed to macular crystalline deposition. Conclusions: Because crystalline maculopathy can present in the setting of RD, there may be a shared pathogenesis between the 2 conditions.

Purpose Internal limiting membrane (ILM) flap techniques are used for the management of macular holes (MHs). Status of the flap after surgery often is uncertain. The current study evaluated the status of the ILM flap after MH surgery with superior wide-base ILM flap transposition (SWIFT). Design Retrospective consecutive case series. Participants Eyes undergoing SWIFT for MH. Methods Data were collected on demographic characteristics, preoperative and postoperative visual acuity (VA), and MH status. OCT and indocyanine green (ICG) fluorescence were used to evaluate the MH and the ILM flap status. Main Outcome Measures Status of MH, ILM flap position, and ILM flap integrity. Results Seventeen eyes of 17 patients with a mean age of 65.3 years and mean follow-up of 11.6 months were included in the study. Thirteen eyes had 1 or more high-risk characteristics. Four eyes (24%) were highly myopic, 6 eyes (35%) had chronic MH, and 3 eyes (18%) had a history of prior MH surgery and ILM removal. The mean MH basal diameter was 899.4 μm and the mean inner diameter was 516.1 μm. In 6 eyes, the MH inner diameter was 650 μm. The baseline mean VA equivalent was 0.88 logarithm of the minimum angle of resolution (logMAR). The MH closed in 16 eyes (94%). Indocyanine green fluorescence imaging demonstrated complete coverage of the MH by the ILM flap in 14 eyes (82%), partial coverage in 1 eye (6%), and no coverage in 2 eyes (12%). In the 2 eyes without ILM flap coverage, the MH was closed in 1 eye and remained open in 1 eye. Non–center-involving folding of the ILM flap was present in 4 eyes (24%). At the last follow-up visit, the mean VA equivalent was 0.54 logMAR. Conclusions Superior wide-base ILM flap transposition is a useful technique for the management of high-risk MHs, including persistent MHs with previously removed ILM. After surgery, the ILM flap may be visualized by ICG fluorescence imaging. After SWIFT, ICG imaging indicates that the ILM flap is intact and in a good position in most cases.

Background/aimsTo evaluate the long-term effects of treat-and-extend dosing of ranibizumab with and without navigated focal laser for diabetic macular oedema (DME).MethodsThis is a multicentre, randomised clinical trial where 150 eyes were randomised into three cohorts; Monthly (n=30), TReat and EXtend without macular laser photocoagulation (TREX; n=60), and treat and extend with angiography-GuIded macular LAser photocoagulation (GILA; n=60). During the first 2 years, eyes either received ranibizumab 0.3 mg every 4 weeks or underwent treat-and-extend ranibizumab with or without angiography-guided laser therapy. In the third year, all eyes were treated as needed with ranibizumab for >5 letters vision loss or if the central retinal thickness (CRT) was >325 µm, and all eyes were eligible to receive focal laser.Results109 eyes (73%) completed the 3-year end-point. At week 156, mean best-corrected visual acuity (BCVA) and CRT improved by 6.9, 9.7, 9.5 letters (p=0.60) and 129, 138, 165 µm (p=0.39), in the Monthly, TREX and GILA cohorts, respectively. These improvements were reached prior to week 104 and no significant changes occurred from week 104 to week 156 (BCVA: p=0.34; CRT: p=0.36). The mean number of injections in the third year was 3.0, 3.1, and 2.4 in the Monthly, TREX and GILA cohorts, respectively (p=0.56). 86 eyes (79%) required at least one ranibizumab injection in the third year.ConclusionThe improvements achieved after 2 years of treat-and-extend ranibizumab for DME were maintained in the third year with a mean of 3 intravitreal injections.Trial registration numberFDA IND 119146, NCT01934556.

Cataract and retinal pathology are frequently coexistent ocular morbidities. For instance, patients with cataracts may often be affected by conditions such as age-related macular degeneration, diabetic retinopathy, retinal vascular occlusions, or epiretinal membranes. In those requiring cataract surgery, there has been much debate regarding the effects of the procedure on the progression of their retinal disease. This chapter will review the evidence for these effects in light of evolving diagnostic and treatment modalities.

Aims This programme investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age-related macular degeneration (nAMD). Methods Topical regorafenib was investigated in an open-label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 μl, 30 mg ml-1 ) three times a day for 12 weeks. The primary endpoint of the phase II/a/b study was mean change in best-corrected visual acuity (BCVA) from baseline to weeks 4 and 12. Results In nAMD patients (N = 51), mean changes in BCVA were +1.2 [90% confidence interval (CI) -0.61, 2.97] and -2.4 (90% CI -4.18, -0.54) letters at weeks 4 and 12, respectively. Ocular treatment-emergent adverse events (TEAEs) (study eye) were reported in 21 patients by week 12. There was one serious ocular TEAE (visual acuity reduced) that was not drug related. Twenty patients required rescue (intravitreal ranibizumab). Conclusions The programme was terminated after phase IIa ended because efficacy was lower than with current nAMD treatments. According to elaborate post hoc analyses, the most likely reason was insufficient exposure in the target compartment (back of the eye).

Purpose The effects of repeated intravitreal aflibercept injection (IAI) on the corneal endothelium were studied in patients with unilateral neovascular age-related macular degeneration. Methods RE-VIEW was a phase 4, open-label, single-arm, multicenter study. Patients received IAI every 8 weeks after 3 monthly doses. Slit-lamp biomicroscopy was performed at all study visits. The central corneal endothelial health was evaluated by specular microscopy in the treated versus untreated fellow eyes at baseline and weeks 24 and 52. Results No slit-lamp abnormalities were noted in 154 enrolled patients (eyes). Baseline versus 52-week mean (±SD) endothelial morphometric values (n = 118) for the treated versus untreated fellow eyes were respectively as follows: endothelial cell density was 2410 ± 364 versus 2388 ± 384 cells/mm at baseline and remained unchanged at 2401 ± 353 versus 2376 ± 364 cells/mm at 52 weeks (P = 0.87); the coefficient of variation was 33.5 ± 4.4% versus 34.0 ± 5.0% at baseline and remained unchanged at 34.2 ± 4.7% versus 34.1 ± 4.9% at 52 weeks (P = 0.18); the percentage of hexagonal cells was 59.5 ± 5.8% versus 59.6 ± 6.4% at baseline and remained unchanged at 59.5 ± 6.0% versus 59.5 ± 5.8% at 52 weeks (P = 0.96). Conclusions Repeated IAI for 52 weeks had no apparent corneal endothelial toxicity noted on specular microscopy in patients treated for neovascular age-related macular degeneration.

Safety of the intravitreal plasma kallikrein inhibitor (KVD001) was tested in patients with diabetic macular edema. KVD001 was well tolerated. Systemic absorption was low. Improvement of retinal edema and vision occurred in most study eyes.

IMPORTANCE: Proactive treatment of nonproliferative diabetic retinopathy (NPDR) reduces the risk of progression to vision-threatening complications. OBJECTIVE: To evaluate vascular endothelial growth factor blockade therapy with intravitreal aflibercept injections in eyes with severe NPDR without diabetic macular edema (DME). DESIGN, SETTING, AND PARTICIPANTS: The Study of the Efficacy and Safety of Intravitreal Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy (PANORAMA) was a double-masked 100-week randomized clinical trial conducted in multiple centers worldwide. The study included 402 adults with Diabetic Retinopathy Severity Scale (DRSS) level 47 or 53 with no DME and best-corrected visual acuity of 20/40 or better. INTERVENTIONS: Intravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval (aflibercept 2q16 group); intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56 (aflibercept 2q8/PRN group); or sham injections (control group). MAIN OUTCOMES AND MEASURES: Proportions of eyes with a 2-step or greater improvement in DRSS level, vision-threatening complications, and center-involved DME from baseline to weeks 24, 52, and 100. RESULTS: Among 402 participants (1 eye per participant), the mean (SD) age was 55.7 (10.5) years; 225 (56.0%) were male, and 310 (77.1%) were White. A total of 135 were randomized to the aflibercept 2q16 group, 134 to the aflibercept 2q8/PRN group, and 133 to the control group. At 24 weeks, treatment with aflibercept resulted in a 2-step or greater improvement in DRSS level in 157 of 269 eyes (58.4%) in the combined aflibercept groups vs 8 of 133 eyes (6.0%) in the control group (adjusted difference, 52.3%; 95% CI, 45.2%-59.5%; P

The hallmark feature of the wet or neovascular form of age-related macular degeneration is the presence of choroidal (or retinal) neovascularization (CNV). If left untreated, CNV may result in significant central vision loss due to complications including exudation, leakage, and ultimately subretinal fibrosis causing remarkable photoreceptor loss. Although the mechanism of development is not fully understood, the process of neovascularization is driven by the upregulation of angiogenic cytokines, principally vascular endothelial growth factor (VEGF). Inhibition of VEGF with intravitreal anti-VEGF therapy has become the standard of care for macular CNV, helping to prevent legal blindness in millions of affected patients worldwide.

Geographic atrophy is an advanced form of age-related macular degeneration that can significantly impact visual function, but has no approved treatment. This review focuses on the pathophysiology of geographic atrophy, particularly the role of complement cascade dysregulation and emerging therapies targeting the complement cascade., Purpose: Geographic atrophy (GA) is an advanced, vision-threatening form of age-related macular degeneration (AMD) affecting approximately five million individuals worldwide. To date, there are no approved therapeutics for GA treatment; however, several are in clinical trials. This review focuses on the pathophysiology of GA, particularly the role of complement cascade dysregulation and emerging therapies targeting the complement cascade. Methods: Primary literature search on PubMed for GA, complement cascade in age-related macular degeneration. ClinicalTrials.gov was searched for natural history studies in GA and clinical trials of drugs targeting the complement cascade for GA. Results: Cumulative damage to the retina by aging, environmental stress, and other factors triggers inflammation via multiple pathways, including the complement cascade. When regulatory components in these pathways are compromised, as with several GA-linked genetic risk factors in the complement cascade, chronic inflammation can ultimately lead to the retinal cell death characteristic of GA. Complement inhibition has been identified as a key candidate for therapeutic intervention, and drugs targeting the complement pathway are currently in clinical trials. Conclusion: The complement cascade is a strategic target for GA therapy. Further research, including on natural history and genetics, is crucial to expand the understanding of GA pathophysiology and identify effective therapeutic targets.

Purpose To compare monthly dosing with a treat and extend algorithm using ranibizumab 0.3 mg with and without angiography-guided macular laser photocoagulation for center-involving diabetic macular edema (DME). Design Multicenter, prospective, randomized clinical trial. Participants A total of 150 eyes from 116 subjects were randomized into 3 cohorts: Monthly (n = 30), TReat and EXtend without macular laser photocoagulation (TREX; n = 60), and treat and extend with angiography-GuIded macular LAser photocoagulation (GILA; n = 60). Methods Monthly cohort eyes received ranibizumab 0.3 mg every 4 weeks. Eyes in the TREX and GILA cohorts received 4 monthly injections of ranibizumab 0.3 mg followed by a treat and extend algorithm based on disease activity. Eyes in the GILA cohort also received angiography-guided macular laser photocoagulation at month 1 and again every 3 months for microaneurysm leakage. Main Outcome Measures Change in mean best-corrected visual acuity (BCVA), mean central retinal thickness (CRT), number of injections from baseline to 1 year, and percentage gaining/losing 2 and 3 lines of vision. Results Baseline demographics were well balanced among the cohorts. A total of 137 eyes (91%) completed the 1-year end point visit. At 1 year, the mean BCVA improved by 8.6, 9.6, and 9.5 letters in the Monthly, TREX, and GILA cohorts, respectively ( P = 0.8). There was no significant difference between the cohorts in the percentage gaining/losing 2 and 3 lines of vision. The CRT improved by 123 μm, 146 μm, and 166 μm in the Monthly, TREX, and GILA cohorts, respectively ( P = 0.47). The mean number of macular laser treatments in the GILA cohort at 1 year was 2.9 (range, 1–4). The number of injections was significantly reduced in both the TREX (10.7) and GILA (10.1) cohorts compared with the Monthly cohort (13.1, P Conclusions This prospective, randomized trial found that treat and extend dosing of ranibizumab 0.3 mg with and without angiography-guided macular laser photocoagulation significantly decreased the number of injections given while providing similar visual and anatomic outcomes compared with monthly dosing at 1 year. Adding angiography-guided laser photocoagulation to this dosing algorithm did not significantly improve outcomes at 1 year.

PurposeTo determine whether the efficacy and safety achieved with 2.0 mg intravitreal aflibercept injections (IAIs) for diabetic macular edema (DME) during the phase III VISTA DME trial were maintained with individualized, as-needed treatment.DesignPhase IV, multicenter, open-label extension study.MethodsSixty patients completing VISTA DME elected to enter the ENDURANCE extension study. All patients received IAIs in the presence of clinically relevant DME. Patients were observed at 4-, 8-, or 12-week intervals depending on the need for treatment. Main outcome measures were mean IAIs given through month 12 (M12), the proportion of patients receiving no IAIs, and the role of macular laser in decreasing treatment burden among patients requiring ongoing IAIs.ResultsA mean of 4.5 IAIs were administered through M12. Eighteen (30%) patients required no IAIs, and among those who met IAI retreatment criteria, a mean of 6.0 IAIs were administered through M12. Best-corrected visual acuity gains achieved during VISTA DME were maintained and stable with individualized dosing during ENDURANCE, fluctuating by

To evaluate trends and outcomes of scleral buckle as adjunct to pars plana vitrectomy for management of retinal detachment.Retrospective case series including 300 consecutive cases of retinal detachment that underwent pars plana vitrectomy. The series was divided into three consecutive groups: Group A (first 100 cases), Group B (second 100 cases), and Group C (third 100 cases).Three hundred eyes of 289 patients, mean age 61.0 years, were included in the study. The mean follow-up was 31.3 months for Group A, 28.5 months for Group B, and 12.0 months for Group C (P0.001). The baseline mean logarithm of the minimum angle of resolution equivalent was 1.58 for Group A, 1.31 for Group B, and 1.33 for Group C (P = 0.15). Supplemental scleral buckle was performed in 53% of Group A, 35% of Group B, and 17% of Group C (P0.001). Single surgery reattachment rate was 93% for Group A, 95% for Group B, and 97% for Group C (P = 0.48). The mean change in logarithm of the minimum angle of resolution equivalent was -0.84 for Group A, -0.81 for Group B, and -0.71 for Group C (P = 0.50).The study demonstrates decreasing use of supplemental scleral buckle in the era of small gauge vitrectomy surgery and wide-angle viewing systems while the outcomes remain stable. Selective, less frequent use of supplemental scleral buckle is compatible with good anatomical and visual outcomes.

Purpose To perform 11- and 2-year health care sector (ophthalmic) and societal cost perspective reference case, cost-utility analyses comparing bevacizumab, ranibizumab, and aflibercept monotherapies for neovascular age-related macular degeneration (NVAMD). Design Cost-utility analysis. Methods The authors performed 11-year and 2-year ophthalmic and societal cost perspective, cost-utility analyses comparing bevacizumab, ranibizumab, and aflibercept monotherapies for neovascular age-related macular degeneration (NVAMD). We employed patient utilities, bilateral outcomes, 2018 U.S. dollars, vision-related mortality, a Medicare fee schedule, and CATT (Comparison of Age-Related Macular Degeneration Treatments) study and VIEW (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD) trial. Cochrane data were also used. S etting : Center for Value-Based Medicine. P atient / study population : patients with NVAMD. I ntervention : Cost-utility analyses using published data. Data-modeled 10-year vision outcomes were modeled forward to year 11. M ain outcome measurement : These included cost-utility ratios (CURs), costs, and quality-adjusted life-years (QALYs) gained. $100,00/QALY was considered the US cost-effectiveness upper limit. Results Bevacizumab and ranibizumab each conferred an 11-year, 1.339 QALY gain versus observation. Aflibercept conferred a 1.380 QALY gain. Aflibercept conferred greater QALY gain for less cost than ranibizumab but was not cost-effective compared to bevacizumab ($1,151,451/QALY incremental CUR). The average ophthalmic cost perspective CUR for bevacizumab was $11,033/QALY, $79,600/QALY for ranibizumab, and $44,801/QALY for aflibercept. Eleven-year therapies saved a 1.0 year-of-life loss without treatment from the 11.0-year life expectancy. Early treatment was 138%-149% more cost-effective than late treatment. Two-year therapy prevented a 1-month-of-life loss, and revealed bevacizumab, ranibizumab, and aflibercept conferred 0.141, 0.141, and 0.164 QALY gains, respectively, with corresponding average CURs of $40,371/QALY, $335,726/QALY, and $168,006/QALY, respectively. Conclusions From an ophthalmic (medical) cost perspective, bevacizumab, ranibizumab, and aflibercept NVAMD monotherapies were all cost-effective over 11 years, with bevacizumab 6.21× more cost-effective than ranibizumab and 3.06× more cost-effective than aflibercept. Two-year modeling revealed bevacizumab was cost-effective, whereas ranibizumab and aflibercept were not. Early treatment was critical for obtaining optimal vision and cost-effectiveness, as is long-term follow-up and adherence to treatment.

Purpose To perform a societal cost-benefit analysis comparing intravitreal bevacizumab (Avastin), ranibizumab (Lucentis), and aflibercept (Eylea) monotherapies for treating neovascular age-related macular degeneration (NVAMD). Design Cost-benefit analysis. Methods Center for Value-Based Medicine using published clinical trial and Medicare data. Patient population: 168,400 estimated 2018 U.S. patients with new-onset NVAMD. Procedure(s): cost-benefit analysis using 2018 U.S. real dollars. Outcome measurements: 11-year direct ophthalmic medical costs expended for bevacizumab, ranibizumab, and aflibercept monotherapies were compared with ophthalmic and nonophthalmic direct medical, direct nonmedical, and indirect medical (productivity) costs saved by the therapies. Results Bevacizumab monotherapy had an individual, 11-year $14,772 treatment cost and net $357,680 societal return (11-year 2,421% return on investment [ROI]). Ranibizumab therapy cost $106,582 and returned $265,870 to society (249% ROI), whereas aflibercept treatment cost $61,811 and returned $310,611 to society (503% ROI). The 2018 NVAMD overall treatment cohort, 11-year net societal gain was $28.5 billion to patients and insurers, with $24.2 billion (84.9%) coming from bevacizumab therapy, $0.7 billion (2.5%) from ranibizumab therapy, and $3.6 billion (12.6%) from aflibercept therapy. Substituting bevacizumab for ranibizumab and aflibercept in the 2018 new-onset NVAMD patients would save an estimated $1.343 billion over 11 years. Vascular endothelial growth factor-inhibitor (VEGF-I) therapy in 2018 should contribute $12.2 billion to the Gross Domestic Product over 11 years. Late treatment would decrease this by 78% to $2.7 billion. Conclusions Intravitreal NVAMD bevacizumab, ranibizumab and aflibercept monotherapies accrue considerable financial, ROIs to patients and insurers as they increase national wealth.

Background To investigate whether neovascularization may arise and be detectable in drusen, as reported in histopathologic studies, by OCTA prior to developing exudation and to assess its prevalence in a cohort of patients with intermediate AMD. Methods Retrospective cross-sectional study of 128 patients with intermediate AMD recruited as part of a separate ongoing clinical trial conducted at multiple large tertiary referral retina clinics. One hundred and twenty-eight consecutive patients with exudative AMD in one eye and intermediate non-exudative AMD in the fellow eye were enrolled and analyzed between September 2015 and March 2017. Results SD-OCTA identified vascularization within drusen in 7 of 128 eyes, for a prevalence of 5.5%. A total of 12 instances of vascularized drusen were noted. Out of the 12 vascularized drusen noted, 7 were located in the parafoveal region or subfoveal region and 5 was in the extrafoveal region. 9 of 12 instances of vascularized drusen exhibited a uniform sub-RPE hyperreflectivity, whilst 3 of 12 exhibited more heterogenous reflectivity. In all 12 instances, FA images failed to identify the neovascular nature of vascularized drusen. Conclusions Our results demonstrate the utility of SD-OCTA for the diagnosis of vascularized drusen in patients with intermediate non-exudative AMD. Longitudinal studies are needed to delineate the evolution and conversion risk of these lesions over time, which can be of substantial clinical relevance.

In the past decade, anti-vascular endothelial growth factor (VEGF) therapy has become more popular and the standard of care for several retinal diseases including exudative age-related macular degeneration (AMD) (Brown et al., 2006; Martin et al., 2012; Rosenfeld et al., 2006; Tufail et al., 2010), diabetic macular edema (DME) (Brown et al., 2013; Do et al., 2012; Do et al., 2013; TDRCR, 2015), and macular edema (ME) due to retinal vein occlusion (RVO) (Brown et al., 2010; Brown et al., 2013; Campochiaro et al., 2010; Wu et al., 2008). Ranibizumab (Lucentis®, Genentech, San Francisco, CA) is a humanized, recombinant, monoclonal antibody fragment. Intended for intraocular use, a 0.5mg/0.05ml dose is approved by the Food and Drug Administration for exudative AMD and ME due to RVO; a 0.3mg/0.05ml dose is approved by the FDA for DME, and diabetic retinopathy (DR). Bevacizumab (Avastin®, Genentech, San Francisco, CA) is a humanized monoclonal human immunoglobulin gamma 1 (IgG1) antibody that selectively binds to circulating VEGF and inhibit its binding to cell surface receptors. A 1.25mg/0.05ml is used off-label in the United States and is commonly used worldwide for exudative AMD, DME and RVO. Aflibercept (Eylea®, Regeneron Pharmaceuticals, Tarrytown, NY) is a recombinant protein receptor decoy composed of two VEGF receptors 1 and 2 fused with the Fc region of human IgG1. Compared to the former two anti-VEGF drugs, it has a higher binding affinity for VEGF and it also binds to VEGF-B and Placental growth factor (PGF). A concentration of 2.0mg/0.05ml is approved by the FDA for wet AMD, DME, ME due to RVO, and DR in patients with DME. Ziv-aflibercept (Zaltrap®, Sanofi Aventis, Bridgewater, NJ and Regeneron Pharmaceuticals, Tarrytown, NY), also known as VEGF Trap-oncologic, contains 25 mg/ml ziv-aflibercept, however contains higher sucrose concentrations than aflibercept (Eylea), which results in higher osmolality (Bayer, 2014; Group, 2012). Ziv-aflibercept is approved by the FDA for treatment of resistant or progressing metastatic colorectal cancer. However, Mansour et al. (Mansour et al., 2015; Mansour et al., 2017a; Mansour et al., 2017b); de Oliveira Dias et al. (de Oliveira Dias et al., 2015; de Oliveira Dias et al., 2017; de Oliveira Dias et al., 2016); and Chhablani et al., (Chhablani, 2015; Chhablani et al., 2017), among other authors, have published several reports finding good outcomes and no apparent safety issues in a series of patients treated with intravitreal ziv-aflibercept. Previous studies have shown that anti-VEGF drugs in clinically significant doses do not affect cell viability in vitro in a human retinal pigment epithelium (RPE) cell line (ARPE-19) (Luthra et al., 2006; Malik et al., 2014b). Nonetheless, subtle cytotoxic changes in RPE cells, such as decrease in mitochondrial membrane potential, could be observed even at clinical doses for some anti-VEGF drugs (Malik et al., 2014b). Numerous publications have described in vitro differential responses to the different anti-VEGF drugs in various retinal cells (Deissler et al., 2012; Klettner et al., 2010; Schnichels et al., 2013). Muller cells are predominant glial cells in the retina and provide structural and metabolic support to retinal neurons. Several studies have described numerous functions of Muller cells, including regulation of cellular homeostasis and pH, modulation of neurotransmitter recycling, contribution to the blood-retinal barrier by surrounding retinal capillaries with glial processes (Limb et al., 2002; Reichenbach and Bringmann, 2013), acting as light collectors by directing light to photoreceptors (Franze et al., 2007; Reichenbach and Bringmann, 2013), and secretion and regulation of VEGF and pigment epithelium derived factor (PEDF) (Garcia and Vecino, 2003; Limb et al., 2002; Reichenbach and Bringmann, 2013). Muller cells have also been associated with retinal neuroprotection, wound healing and regeneration (Garcia and Vecino, 2003). The purpose of this study was to evaluate the in vitro response and differences in gene expression of human retinal Muller cells treated with different concentrations of ranibizumab, bevacizumab, aflibercept or ziv-aflibercept. Assays for cell viability, metabolic activity, mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) and apoptosis were used to evaluate responses to the anti-VEGF drugs. In addition, differences in the expression levels for angiogenesis-related, pro-apoptotic, inflammation and oxidative stress genes were assessed.

PurposeTo evaluate outcomes of small-gauge pars plana vitrectomy (PPV) for the treatment of rhegmatogenous retinal detachment (RD) without scleral-depressed shaving of the vitreous base.MethodsRetrospective, consecutive case series. Surgical technique included small-gauge PPV (25G, 23G, 25G+ or 27G) and wide-angle vitrectomy viewing system in all cases. No cases were excluded based on the level of complexity of RD. Outcome measures were retinal reattachment rates and Snellen visual acuity (best-corrected visual activity [BCVA]).Results312 eyes of 301 patients, mean age 60.8 years, and mean follow-up 23.1 months. Baseline characteristics included macula-off RD in 207 (66%) eyes, psudophakia in 124 (40%) eyes, high myopia in 74 (24%) eyes and giant retinal tear in 14 (5%) eyes. The retina was reattached with one procedure in 296 (95%) eyes. Final retinal reattachment was achieved in 310 (99%) eyes. The BCVA at baseline was >20/40 in 76 (24%) eyes, 20/50–20/100 in 48 (15%) eyes, 20/200–20/400 in 46 (15%) eyes and 20/40 in 168 (54%) eyes, 20/50–20/100 in 60 (19%) eyes, 20/200–20/400 in 49 (16%) eyes and ConclusionSmall-gauge PPV without scleral-depressed vitreous base shaving can be associated with good anatomical and visual outcomes. Case selection based on the complexity of RD may not be required when considering small-gauge PPV.

To define the frequency and quantify the progression of macular atrophy (MA) in patients with neovascular age-related macular degeneration undergoing treatment with antivascular endothelial growth factor therapy for2 years.Fifty-four eyes of 46 patients (86.7 ± 6.8 years, 53.7% women) diagnosed with wet age-related macular degeneration were included in this retrospective study. Eyes that received photodynamic therapy or laser treatment were excluded. All eyes were imaged at baseline and after 2 years with the Cirrus spectral domain optical coherence tomography using a 512 × 128 macular cube scan protocol centered on the fovea. Optical coherence tomography en face fundus images were obtained for each 3-dimensional data set using the U.S. Food and Drug Administration-cleared Advanced RPE Analysis software, which automatically identifies atrophic areas by segmenting regions of increased reflectivity in en face choroidal slab images. Segmentation errors were manually corrected by trained Doheny Image Reading Center graders using a standardized grading protocol. The prevalence rates of atrophy at baseline and at 2-years follow-up and enlargement rates were computed. Baseline demographic factors and types and numbers of antivascular endothelial growth factor injections received over time were correlated with the development and enlargement of atrophy.Macular atrophy was noted at baseline in 32 (59.3%) eyes and progressed in all eyes over the next 2 years. Among the 28 eyes without atrophy at baseline, MA developed by 2 years in 6 eyes (21.4% of eyes without MA at baseline). Of note, 22 eyes (40.7% of overall cohort) never developed atrophy during the course of the study. Among eyes with atrophy at baseline, the annual growth rate of MA was found to be 0.89 ± 0.93 mm. A multiple regression analysis was performed to evaluate the influence of gender, age, smoking status, medication injected, and number of injections on MA. Except for the number of total injections (R = 0.3, P0.01), the studied variables could not significantly predict development or progression of MA (F [0.73, 13] = 0.378, P = 0.86, R = 0.05). However, the study was not powered to detect small effects.Macular atrophy is a frequent finding in eyes with wet age-related macular degeneration both before and after antivascular endothelial growth factor therapy. The frequency of new optical coherence tomography-defined atrophy (21% at 2 years) after starting therapy was close to the rates reported in CATT, IVAN, and HARBOR. The rate of MA enlargement was positively correlated with the number of injections, but did not appear to be greater than that reported for atrophy in the absence of choroidal neovascularization.

Mitochondrial (mt) DNA haplogroups, defined by specific single nucleotide polymorphism (SNP) patterns, represent populations of diverse geographic origins and have been associated with increased risk or protection of many diseases. The H haplogroup is the most common European haplogroup while the K haplogroup is highly associated with the Ashkenazi Jewish population. Transmitochondrial cybrids (cell lines with identical nuclei, but mtDNA from either H (n = 8) or K (n = 8) subjects) were analyzed by the Seahorse flux analyzer, quantitative polymerase chain reaction (Q-PCR) and immunohistochemistry (IHC). Cybrids were treated with amyloid-β peptides and cell viabilities were measured. Other cybrids were demethylated with 5-aza-2′-deoxycytidine (5-aza-dC) and expression levels for APOE and NFkB2 were measured. Results show K cybrids have (a) significantly lower mtDNA copy numbers, (b) higher expression levels for MT-DNA encoded genes critical for oxidative phosphorylation, (c) lower Spare Respiratory Capacity, (d) increased expression of inhibitors of the complement pathway and important inflammasome-related genes; and (e) significantly higher levels of APOE transcription that were independent of methylation status. After exposure to amyloid-β1–42 peptides (active form), H haplogroup cybrids demonstrated decreased cell viability compared to those treated with amyloid-β42–1 (inactive form) (p < 0.0001), while this was not observed in the K cybrids (p = 0.2). K cybrids had significantly higher total global methylation levels and differences in expression levels for two acetylation genes and four methylation genes. Demethylation with 5-aza-dC altered expression levels for NFkB2, while APOE transcription patterns were unchanged. Our findings support the hypothesis that mtDNA-nuclear retrograde signaling may mediate expression levels of APOE, a key factor in many age-related diseases. Future studies will focus on identification of the mitochondrial-nuclear retrograde signaling mechanism(s) contributing to these mtDNA-mediated differences.

To compare study and fellow eyes in subjects with age-related macular degeneration (AMD) for 7-year outcomes arising from contrasting treatment histories and disease statuses.Multicenter cohort study, predetermined secondary analysis.A total of 65 participants from the ranibizumab-treatment arms of the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR), Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the Treatment of Neovascular AMD (MARINA), and Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (HORIZON) trials, recruited for an update evaluation from 14 study sites.Seven-year visual outcomes and retinal imaging data were compared with the ANCHOR, MARINA, and HORIZON databases. Under the ANCHOR and MARINA protocols, study eyes had received monthly ranibizumab injections for the initial 2 years, during which fellow eyes were prohibited from anti-vascular endothelial growth factor (VEGF) treatments.Percentage of subjects with study eye vision better than fellow eye, vision change from baseline to year 7, and mean area of macular atrophy (MA) were predetermined secondary end points.Fellow eyes with exudative AMD had received a mean 7.3 total injections of anti-VEGF agents in the mean 3.4 years off-study. For the 35% of subjects with exudative AMD in both eyes at baseline, within-patient comparisons at year 7 showed better vision in the study eye in 82%, with better mean final vision in study eyes (54.7 vs. 27.3 letters in fellow eyes, P0.001). Also in this subgroup, study eyes, which had received 2 years of high-frequency ranibizumab, had less severe MA than the respective fellow eye at year 7 in 88% of patients (mean area ± standard deviation 2.8±2.2 mm(2) vs. 5.8±2.5 mm(2) in the fellow eyes, P = 0.0013). Final fellow eye vision outcome was significantly correlated with MA severity (coefficient -6.95, P0.001), and patients' inter-eye vision difference corresponded to the degree of MA asymmetry.Exudative fellow eyes remained at risk for further vision decline in later years under management with low-frequency anti-VEGF therapy. In patients with bilateral exudative AMD at baseline, final vision at year 7 was significantly better in study eyes than in fellow eyes, and MA was less severe. Macular atrophy area correlated with final visual outcomes, determined inter-eye vision differences, and was not attributable to high-frequency ranibizumab therapy.

Purpose To evaluate visual and anatomic outcomes after intravitreal aflibercept injection (IAI) versus laser in diabetic macular edema (DME) patients with and without prior anti–vascular endothelial growth factor (VEGF) treatment for DME. Design Post hoc analysis of eyes from 2 similarly designed, phase 3 trials, VISTA and VIVID. Participants Patients (eyes) with DME with central involvement from VISTA (n = 461) and VIVID (n = 404). Methods Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or macular laser photocoagulation. Main Outcome Measures This study reports exploratory outcomes through week 100. Analyses focused on VISTA because more patients received prior anti-VEGF therapy in VISTA (42.9%) versus VIVID (8.9%). Results Of 42.9% of patients in VISTA who received prior anti-VEGF treatment, 83.3% to 92.6% received ≥ 1 prior injections of bevacizumab, and 71.4% to 82.4% received bevacizumab only as prior anti-VEGF treatment for a duration ranging from 28 days to 3.9 years. In patients with prior anti-VEGF treatment, mean best-corrected visual acuity (BCVA) changes from baseline in the IAI 2q4, IAI 2q8, and laser groups were +10.4 letters, +10.5 letters, and −0.7 letters at week 52 and +10.9 letters, +10.8 letters, and −0.8 letters at week 100, respectively. Corresponding changes in patients without prior anti-VEGF treatment were +14.1 letters, +11.0 letters, and +0.9 letters at week 52 and +12.0 letters, +11.3 letters, and +2.1 letters at week 100. In patients with prior anti-VEGF treatment, mean reductions in central retinal thickness were 180.2 μm, 192.2 μm, and 90.9 μm at week 52 and 180.1 μm, 196.4 μm, and 94.1 μm at week 100. Corresponding reductions in patients without prior anti-VEGF treatment were 190.3 μm, 175.7 μm, and 61.0 μm at week 52 and 200.0 μm, 186.7 μm, and 76.9 μm at week 100. The most frequent serious ocular adverse event was vitreous hemorrhage (1.3%, 0.7%, and 1.9%, respectively). Conclusions Visual and anatomic improvements over laser with both IAI regimens were significant and similar through week 100 in subgroups of patients in VISTA with and without prior anti-VEGF treatment for DME.

Purpose To determine week 52 efficacy and safety outcomes in eyes with macular edema after branch retinal vein occlusion (BRVO) treated with 2 mg intravitreal aflibercept injection (IAI) compared with grid laser. Design VIBRANT was a double-masked, randomized, phase 3 trial. Participants Eyes randomized and treated in VIBRANT were followed to week 52. Methods In the IAI group, eyes received IAI every 4 weeks through week 24 and IAI every 8 weeks through week 48 with rescue grid laser if needed at week 36. In the grid laser group, all eyes received grid laser at baseline and, if prespecified rescue criteria were met, 1 additional laser from week 12 to 20 and IAI every 8 weeks after 3 monthly doses from week 24 onward (the laser/IAI group). Main Outcome Measures The primary outcome measure was percentage of eyes with improvement from baseline best-corrected visual acuity (BCVA) letter score ≥15 at week 24. All outcome measures at week 52 were exploratory, and P values are considered nominal. Results The percentage of eyes with improvement from baseline letter score ≥15 in the IAI and laser/IAI groups was 52.7% versus 26.7% ( P = 0.0003) at week 24 and 57.1% versus 41.1% ( P = 0.0296) at week 52. The corresponding mean change from baseline BCVA letter score was 17.0 versus 6.9 ( P P = 0.0035) at week 52. The mean reduction from baseline central retinal thickness was 280.5 μm versus 128.0 μm ( P P = 0.0218) at week 52. In the IAI group, 10.6% of eyes received rescue laser at week 36, and in the laser/IAI group, 80.7% received rescue IAI from week 24 to week 48. Traumatic cataract in 1 eye (1.1%) in the IAI group was the only ocular serious adverse event. Conclusions After 6 monthly IAI, injections every 8 weeks maintained control of macular edema and visual benefits through week 52. In the laser group, rescue IAI given from week 24 onward resulted in substantial visual improvements at week 52.

To prospectively evaluate a treat and extend algorithm of ranibizumab with and without navigated laser to monthly dosing for center-involving diabetic macular edema.This was a multicenter, randomized, clinical trial.One hundred fifty eyes were randomized into 3 cohorts: monthly (n = 30), treat and extend without laser photocoagulation (TREX; n = 60), and treat and extend with angiography-guided laser photocoagulation (GILA; n = 60). Monthly cohort eyes received ranibizumab 0.3 mg every 4 weeks. TREX and GILA cohort eyes received 4 monthly injections of ranibizumab 0.3 mg followed by a treat and extend dosing strategy. GILA cohort eyes also received navigated focal laser at month 1 and again every 3 months as needed. The primary outcomes included the mean change in best-corrected visual acuity and central retinal thickness and the number of injections from baseline to 2 years.At 2 years, mean best-corrected visual acuity and central retinal thickness improved by 7.5, 9.6, and 9.0 letters (P = .75) and 139, 140, and 175 μm (P = .09), in the monthly, TREX, and GILA cohorts, respectively. The mean number of injections was significantly reduced in both the TREX (18.9) and GILA (17.5) cohorts compared with the monthly cohort (24.7, P.001). Between the TREX and GILA cohorts, there was no significant difference in the mean treatment interval, mean maximal treatment interval, or percentage of eyes extended to 12 weeks. The total 2-year incidence of Anti-Platelet Trialists' Collaboration events was 6.7%.The treat and extend algorithm of ranibizumab in the TREX-DME trial resulted in significantly fewer injections and yielded visual and anatomic gains comparable to monthly dosing at 2 years.

Mitochondrial (mt) DNA haplogroups, defined by specific single nucleotide polymorphism (SNPs) patterns, represent populations of diverse geographic origins and may play a role in disparate disease susceptibilities found in different ethnic/racial populations. The most common European haplogroup is H, while the K haplogroup is highly associated with Ashkenazi Jewish populations. Studies using transmitochondrial cybrids (cell lines with identical nuclei but mitochondria from either H or K haplogroup subjects) demonstrated significant molecular and biological differences but mechanisms for these disparities are unclear. In this study, we hypothesized that there is differential retrograde signaling occurring between the Stimulator of Interferon Genes (STING) pathway and H versus K mtDNA haplogroups. Results showed that K cybrids exhibit increased levels of cytoplasmic mtDNA fragments. After STING Knock-Down, H cybrids had lower expression levels for EGFR, BRCA1, DNMT3A, DNMT3B, HDAC1, and IFNα genes, but upregulated DNMT3A compared to control H cybrids. The STING-KD K cybrids showed downregulation of EGFR, DNMT3A, HDAC1, HCAD9, CFH, and CHI, along with upregulation of DNMT1 and IL-6 compared to control K cybrids. Since all cybrids have identical nuclei, the STING DNA sensor system interacts differently with K haplogroup mtDNA compared to H mtDNA for genes related to cancer (EGFR, BRCA1), methylation (DNMT1, DNMT3A, DNMT3B), acetylation (HDAC1, HDCA9), complement (CFH, CHI) and inflammation (IFNα, IL-6). In summary, in non-pathologic conditions, (a) STING is an important retrograde signaling mechanism(s) and (b) cybrids possessing Ashkenazi Jewish mtDNA (K haplogroup) interact with the STING complex differently compared to H cybrids which affects various disease-related pathways.